Aryl 3-oxopiperazine carboxamides and heteroaryl 3-oxopiperazine carboxamides as Nav1.8 inhibitors

Abstract

The novel compounds represented by structural formula (I) and their pharma- ceutically acceptable salts are inhibitors of Nav1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control, and suppression of diseases mediated by Nav1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention, or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders. [Formula 1] TIFF2024519487000073.tif62154

Description

[Background technology]

[0001] Voltage-gated sodium channels (VGSCs) mediate the selective influx of sodium ions into excitable cells and play a central role in the initiation and propagation of action potentials (Yu et al., Genome Biology 4:207 (2003)). Voltage-gated sodium channels are ubiquitous in the central and peripheral nervous systems, playing a central role in the initiation and propagation of action potentials, as well as in skeletal and cardiac muscle, where action potentials trigger cell contraction (Goldin et al., Ann NY Acad Sci. 1999 Apr 30; 868:38-50). Alterations in the function or expression of VGSCs can significantly affect the excitability of normal cells ("Huang et al., J Neurosci. 2013 Aug 28; 33 (35):14087-97", "Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81", "Kist et al., PLoS One. 2016 Sep 6;11(9):e0161789", and "Schreiber et al., World J Diabetes. 2015 Apr 15;6(3):432-44").

[0002] Voltage-gated sodium channels are polymeric complexes characterized by one α-subunit that forms an ion-conducting aqueous pore and at least one β-subunit that modulates the dynamics and voltage dependence of channel gating. (SNS, PN3, or Na) v Na, also known as 1.8 v Nine distinct α subunits encompassing 1.8 have been identified and characterized in mammalian voltage-gated sodium channels (Goldin et al., Neuron. 2000 Nov; 28 (2):365-8).

[0003] Sodium channel expression can be tissue-specific. v1.8 Voltage-gated sodium ion channels (VGSCs) are primarily expressed in sensory neurons involved in transmitting information from the periphery (e.g., skin, muscles, and joints) to the central nervous system via the spinal cord. Sodium channels are essential to this process because their activity is required for the initiation and propagation of action potentials triggered by harmful stimuli (thermal, mechanical, and chemical) that activate peripheral nociceptors (Catterall et al., Nat Chem Biol. 2017 Apr 13;13(5):455-463). Increased levels of VGSC protein on the cell surface or changes in VGSC channel activity can lead to disease conditions such as migraine, post-ischemic neurodegeneration, epilepsy, and chronic neuropathic and inflammatory pain states. The acquisition of functional mutations in Nav1.7, Nav1.8, and Nav1.9 manifests in various pain syndromes in which patients experience spontaneous pain in the absence of external stimuli ("Bennett et al., Lancet Neurol. 2014 Jun;13(6):587-99", "Huang et al., J Neurosci. 2013 Aug 28;33(35):14087-97", "Kist et al., PLoS One. 2016 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").

[0004] Na v1.8 Voltage-gated sodium channels are thought to play a role in various diseases, including neuropathic pain, chronic itch, and inflammatory pain perception ("Belkouch et al., J Neuroinflammation. 2014 Mar 7;11:45", "Coward et al., Pain. 2000 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., Neuron. 2010 Nov 4;68(3):543-56", and "Zhao et al., J Clin Invest. 2013").

[0005] Most voltage-gated sodium channels are conserved among various subtypes, so using therapeutics that do not show subtype selectivity can cause serious side effects. Therefore, therapeutics suitable for use in treating nociception, cough, or itch disorders require specificity in their action, for example, between the action on the Na v 1.5 sodium channel (which is thought to be important for regulating cardiac function) and the Na v 1.8 sodium channel (which is thought to be important in disorders caused by inflammatory nociception or itch and Na channels that have malfunctioned and / or been upregulated). v There is a need to distinguish between these two actions. <00​​​​​​​​1.8 It is thought that it may be useful in treating or preventing diseases, disorders, and conditions caused by dysfunction of voltage-gated sodium ion channels (Han et al., J Neurol Neurosurg Psychiatry 2014 May;85(5):499-505), and such diseases, disorders, and conditions include, but are not limited to, migraines, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, neuropathic pain, chronic itching, and pruritic disorders.

[0007] Na v 1.8 Potent Na with selective activity for sodium ion channels v 1.8 Sodium ion channel activity inhibitors are still needed. As a result, the compounds of the present invention are Na v 1.8 Receptors and Na v 1.8 It is useful for treating and preventing diseases, disorders, and conditions involving voltage-gated sodium ion channels.

[0008] The role of the Nav1.8 sodium ion channel is discussed in the following publications: "Bennett et al., Physical Medicine and Rehabilitation Clinics of North America, 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., Lancet, 380:2163-2196 (2012)".

[0009] Na v1.8 Compounds useful for treating conditions related to sodium ion channels are disclosed in the following publications: "ACS Med. Chem. Lett. 2015, 6, 650", "BJP 2015, 172, 2654", "PNAS 2007, 104, 8520", "J. Med. Chem. 2008, 51, 407", "JPET 2008, 324, 1204", and "Neuropharmacology 2010, 59, 201".

[0010] Na v 1.8 The compounds are also disclosed in: WO2009 / 049180, WO2009 / 049181, WO2009 / 049183, WO2014 / 120808, WO2014 / 120815, WO2014 / 120820, WO2015 / 010065, and WO2015 / 089361, WO2 017 / 209322, US8,519,137, US9,051,270, US9,108,903, US9,163,042, US9,783,501, WO2020 / 092667, WO2019 / 014352, 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 [License 8] WO2015 / 089361 [License 9] WO2017 / 209322 [License 10] US8,519,137 [License 11] US9,051,270 [License 12] US9,108,903 [License 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

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[0013] This invention relates to structural formula I: [ka]

[0014] This relates to a novel compound represented by structural formula I and its pharmaceutically acceptable salts, hydrates, and solvates. The compound represented by structural formula I and its embodiments are Na v 1.8 Inhibitors of sodium ion channel activity (or Na v 1.8 inhibitors) and are used to treat nociception, osteoarthritis, peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, itching, atopic dermatitis, allergic or contact dermatitis, renal failure, cholestasis, pruritus, acute itching, chronic itching, migraine, post-ischemic neurodegeneration, epilepsy, pain, inflammatory pain, spontaneous pain, acute pain, acute pain, acute pain resulting from fractures, musculoskeletal injury, pancreatitis and renal colic, perioperative pain, postoperative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, phantom limb pain, sciatica, pain resulting from 2° or 3° burns, optic neuritis, cancer and chemotherapy-related pain, chronic pelvic pain, pain syndromes and complex regional pain syndromes, etc. v 1.8 Sodium ion channel activity may be useful in treating and preventing diseases, disorders, and conditions mediated by sodium ion channel activity. In one embodiment of the present invention, the condition, disease, or disorder is a pain disorder, acute pain disorder, or chronic pain disorder. In another embodiment of the present invention, the condition, disease, or disorder is an acute pain disorder.

[0015] The present invention also relates to pharmaceutical compositions comprising the compound of the present invention and a pharmaceutically acceptable carrier.

[0016] The present invention further relates to the administration of the compounds and pharmaceutical compositions of the present invention to subjects in need of the Na v 1.8 The invention also relates to methods for the treatment, management, prevention, mitigation, improvement, suppression or control of disorders, diseases and conditions that may respond to inhibition of sodium ion channel activity.

[0017] The present invention further includes Na v 1.8 The present invention also relates to the use of the compounds for producing agents useful in the treatment of diseases, disorders, and conditions that can respond to inhibition of sodium ion channel activity.

[0018] The present invention further relates to the treatment or prevention of these diseases, disorders and conditions by administering the compounds of the present invention in combination with another agent in a therapeutically effective amount that may be useful in treating the diseases, disorders and conditions. The present invention further relates to a method for preparing the compounds of the present invention. [Modes for carrying out the invention]

[0019] This invention relates to structural formula I: [ka]

[0020] [During the ceremony, One of A and B is (1) Aryl, and, (2) Heteroaryl Selected from the group consisting of, Here, each aryl and heteroaryl is either unsubstituted or R a It is substituted with 1 to 5 substituents selected from, and The other of A and B is, (1) Aryl, and, (2) Heteroaryl Selected from the group consisting of, Here, B is either not substituted, or R b It is substituted with 1 to 5 substituents selected from the following: However, if A is an aryl, then B is not an aryl; 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 eS(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 cycloheteroalkyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from; 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 、及び、 (17)-(CH2) s NR e R j selected from the group consisting of where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with 1 to 5 substituents selected from R d ; and where R 2 and R 3 and the carbon atom to which they are attached can form a -C 3-5 cycloalkyl ring, and where R 2 and R 4 and the carbon atom to which they are attached can form a -C 3-5 cycloalkyl ring; R 3 is (1) hydrogen, (2) -C 1-6 alkyl, (3) -C 2-6 alkenyl, (4) -C 2-6 alkynyl, (5) -C 3-6 cycloalkyl, (6) -C 2-6 cycloheteroalkyl, (7) -C 1-6Alkyl-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 cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from; R 4 teeth, (1) Hydrogen, (2)-C 1-6Alkyl, (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 cycloheteroalkyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from, and Here, R 4 and R 5 And the carbon atoms to which they are bonded are -C 3-5 It can form a cycloalkyl ring; 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 cycloheteroalkyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from, and Here, R 5 and R 7 And the carbon atoms to which they are bonded can form 4-membered, 5-membered, or 6-membered saturated rings; 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) 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 cycloheteroalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from, and Here, R 6 and R 7 And the carbon atoms to which they are bonded are -C 3-5 It can form a cycloalkyl ring; 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 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 cycloheteroalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from; 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 unsubstituted or R e It is substituted with 1 to 5 substituents selected from; 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 substituted with 1 to 5 substituents selected from halogens; 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 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 1-6Alkyl-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 -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 1-6Alkyl-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 Alkyl 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)-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 -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 Heterocycloalkyl, (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 Heterocycloalkyl, (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, CH2CF3, CF2CH3, -C 1-6 Alkyl and OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups; 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. This relates to a novel compound represented by [formula] or a pharmaceutically acceptable salt thereof.

[0021] The present invention has many embodiments, which are summarized below. The present invention encompasses the compounds shown, and further encompasses the individual diastereoisomers, enantiomers and epimers of said compounds, as well as mixtures of said diastereoisomers and / or enantiomers (this includes racemic mixtures).

[0022] In one embodiment of the present invention, A is selected from the group consisting of aryls and heteroaryls, where each aryl and heteroaryl is either unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, A is selected from the group consisting of phenyl, pyridine, pyrazole, oxazole, imidazopyridine, pyrimidine and thiazole, where A is unsubstituted or R a It is substituted with 1 to 5 substituents selected from the following.

[0023] In another embodiment of the present invention, A is selected from the group consisting of aryls and heteroaryls, where each aryl and heteroaryl is either unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, A is selected from the group consisting of phenyl, pyridine, pyrazole, oxazole and thiazolyl, where A is unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In another embodiment, A is selected from the group consisting of phenyl and pyridine, where phenyl and pyridine are unsubstituted or R a It is substituted with 1 to 5 substituents selected from the following.

[0024] In another embodiment of the present invention, A is selected from the group consisting of aryls and heteroaryls, where each aryl and heteroaryl is either unsubstituted or R aIt is substituted with 1 to 5 substituents selected from, where if A is an aryl, B is not an aryl. In one class of this embodiment, A is selected from the group consisting of phenyl, pyridine, pyrazole, oxazole, imidazopyridine, pyrimidine and thiazole, where A is unsubstituted or R a It is substituted with 1 to 5 substituents selected from, except that if A is phenyl, then B is not phenyl.

[0025] In another embodiment, A is selected from the group consisting of phenyl and pyridine, where phenyl and pyridine are unsubstituted or R a It is substituted with 1 to 5 substituents selected from, except that if A is phenyl, then B is not phenyl.

[0026] In another embodiment, A is selected from the group consisting of phenyl and pyridine, where phenyl and pyridine are R a It is substituted with 1 to 5 substituents selected from, except that if A is phenyl, then B is not phenyl.

[0027] In another embodiment of the present invention, A is an aryl, where the aryl is either unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, A is phenyl, where phenyl is unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, A is phenyl, where phenyl is R a It is substituted with 1 to 5 substituents selected from the following.

[0028] In another embodiment of the present invention, A is an aryl, where the aryl is either unsubstituted or R aIt is substituted with 1 to 5 substituents selected from, where if A is aryl, B is not aryl. In one class of this embodiment, A is phenyl, where phenyl is unsubstituted or R a It is substituted with 1 to 5 substituents selected from, except that if A is phenyl, then B is not phenyl. In another class of this embodiment, A is phenyl, where phenyl is R a It is substituted with 1 to 5 substituents selected from, except that if A is phenyl, then B is not phenyl.

[0029] In another embodiment of the present invention, A is a heteroaryl, where the heteroaryl is either unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, A is selected from the group consisting of pyridine, pyrazole, oxazole and thiazole, where A is unsubstituted or R a It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, A is pyridine, where pyridine is unsubstituted or R a It is substituted with 1 to 5 substituents selected from the following.

[0030] In one embodiment of the present invention, B is independently selected from the group consisting of aryls and heteroaryls, where B is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from, however, A and B cannot both be aryl. In one class of this embodiment, B is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazole, thiazole, imidazo[1,2-a]pyridine, oxazole, benzofuran, benzoxazole, indazole and thiazolopyridine, where B is unsubstituted or R b It is substituted with 1 to 5 substituents selected from, except that if B is phenyl, A is not aryl.

[0031] In another embodiment, B is a heteroaryl, where the heteroaryl is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, B is independently selected from the group consisting of pyridine, pyrimidine, pyrazole, thiazole, imidazo[1,2-a]pyridine, oxazole, benzofuran, benzoxazole, indazole and thiazolopyridine, where B is unsubstituted or R b It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, B is independently selected from the group consisting of pyridine, pyrimidine, pyrazole, thiazole and imidazo[1,2-a]pyridine, where B is unsubstituted or R b It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, B is independently selected from the group consisting of pyridine, pyrazole and thiazole, where B is unsubstituted or R b It is substituted with 1 to 5 substituents selected from the following.

[0032] In another embodiment, B is an aryl, where the aryl is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from, where A is not aryl. In one class of this embodiment, B is phenyl, where phenyl is unsubstituted or R b It is substituted with 1 to 5 substituents selected from, where A is not aryl. In another class of this embodiment, B is phenyl, where phenyl is R b It is substituted with 1 to 5 substituents selected from, where A is not an aryl substituent.

[0033] In one embodiment of the present invention, R 1 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 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 R j ,-(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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from the following.

[0034] In another embodiment of the present invention, R 1 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyls, where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R cIt is substituted with 1 to 5 substituents selected from the following.

[0035] In another embodiment of the present invention, R 1 is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyl groups, where each alkyl, cycloalkyl, and cycloheteroalkyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from the following.

[0036] In another embodiment of the present invention, R 1 is hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where each alkyl and cycloalkyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 1 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, and cyclopropyl, where cyclopropyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from. In another embodiment of the present invention, R 1 It is hydrogen.

[0037] In another embodiment of the present invention, R 1 is -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 1 The group is selected from the group consisting of -CH3 and -CH2CH3.

[0038] In another embodiment of the present invention, R 1 is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted or R cIt is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 1 is cyclopropyl, where the cycloalkyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from the following.

[0039] In one embodiment of the present invention, 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 jSelected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from, where R 2 and R 3 And the carbon atoms to which they are bonded 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 It can form a cycloalkyl ring.

[0040] In another embodiment of the present invention, 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 eS(O) m NR e R j and -(CH2) s NR e R j Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from, where R 2 and R 3 And the carbon atoms to which they are bonded are -C 3-5 It can form a cycloalkyl ring.

[0041] In another embodiment of the present invention, 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 NRe S(O) m NR e R j and -(CH2) s NR e R j Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from, where R 2 and R 4 And the carbon atoms to which they are bonded are -C 3-5 It can form a cycloalkyl ring.

[0042] In another embodiment of the present invention, 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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0043] In another embodiment of the present invention, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyls, where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0044] In another embodiment of the present invention, R 2 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 3-6 Selected from the group consisting of cycloalkyl groups, where each alkyl, alkenyl, and cycloalkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0045] In another embodiment of the present invention, R 2 is hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where each alkyl and cycloalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 2is selected from the group consisting of hydrogen, -CH3, CH2F, -CH2CH3, -CH(CH3)2 and cyclopropyl, where cyclopropyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from. In another embodiment of the present invention, R 2 It is hydrogen.

[0046] In another embodiment of the present invention, R 2 is -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 2 The group is selected from -CH3, -CF3, CH2F, -CH2CH3, and -CH(CH3)2. In another class of this embodiment, R 2 The group is selected from the group consisting of -CH3 and CH2F.

[0047] In another embodiment of the present invention, R 2 is -C 3-6 It is a cycloalkyl group, where each cycloalkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 2 is cyclopropyl, where cyclopropyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0048] In one embodiment of the present invention, 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 Rj ,-(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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0049] In another embodiment of the present invention, R 3 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyls, where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0050] In another embodiment of the present invention, R 3 is hydrogen, -C 1-6 Alkyl, -C2-6 Alkenyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyl groups, where each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0051] In another embodiment of the present invention, R 3 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 3-6 Selected from the group consisting of cycloalkyl groups, where each alkyl, alkenyl, and cycloalkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0052] In another embodiment of the present invention, R 3 is hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where each alkyl and cycloalkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 3 The group is selected from hydrogen, -CH3, -CF3, CH2F, -CH2CH3, -CH(CH3)2 and cyclopropyl, where cyclopropyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0053] In another embodiment of the present invention, R 3 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, where the alkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 3 R is selected from the group consisting of hydrogen, -CH3, and -CH2F. In another embodiment of the present invention, R 3 It is hydrogen.

[0054] In another embodiment of the present invention, R 3 is -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with 1 to 5 substituents selected from R d . In one class of this embodiment, R 3 is selected from the group consisting of -CH3, CH2F, -CH2CH3, and -CH(CH3)2. In another class of this embodiment, R 3 is -CH3 or -CH2F.

[0055] In another embodiment of the present invention, R 3 is -C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with 1 to 5 substituents selected from R d . In one class of this embodiment, R 3 is cyclopropyl, where the cyclopropyl is unsubstituted or substituted with 1 to 5 substituents selected from R d .

[0056] In one embodiment of the present invention, R 4 is hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​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)<00921>NR e R j selected from the group consisting of, wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with 1 to 5 substituents selected from R f and, wherein R 4 and R 5 and the carbon atom to which they are attached can form a -C 3-5 cycloalkyl ring. <OO02785> In another embodiment of the present invention, R 4 is hydrogen, -C 1-6 alkyl, -C<000OO930>alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C 2-6 cycloheteroalkyl, -C 1-6 alkyl - O - C 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 eC(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 selected from the group consisting of, wherein each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with 1 to 5 substituents selected from R f .

[0058] In another embodiment of the present invention, R 4 is selected from the group consisting of hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C 2-6 cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with 1 to 5 substituents selected from R f .

[0059] In another embodiment of the present invention, R 4 is selected from the group consisting of hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 3-6 cycloalkyl and -C 2-6 cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with 1 to 5 substituents selected from R fIt is substituted with 1 to 5 substituents selected from the following.

[0060] In another embodiment of the present invention, R 4 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 3-6 Selected from the group consisting of cycloalkyl groups, where each alkyl, alkenyl, and cycloalkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0061] In another embodiment of the present invention, R 4 is hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where alkyl and cycloalkyl are either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 4 is selected from the group consisting of hydrogen, -CH3, CH2F, -CH2CH3, -CH(CH3)2 and cyclopropyl, where cyclopropyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0062] In another embodiment of the present invention, R 4 is hydrogen or -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 4 R is selected from the group consisting of hydrogen, -CH3, CH2F, -CH2CH3, and -CH(CH3)2. In another embodiment of the present invention, R 4 It is hydrogen.

[0063] In another embodiment of the present invention, R 4 is -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R fIt is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 4 The group is selected from -CH3, CH2F, -CH2CH3, and -CH(CH3)2.

[0064] In another embodiment of the present invention, R 4 is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 4 is cyclopropyl, where cyclopropyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0065] In one embodiment of the present invention, 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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from, and here, R 5 and R 7 The carbon atoms to which they are bonded can form 4-membered, 5-membered, or 6-membered saturated rings.

[0066] In another embodiment of the present invention, 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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from, and here, R 5 and R 7 The carbon atoms to which they are bonded can form a five-membered saturated ring.

[0067] In another embodiment of the present invention, 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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0068] In another embodiment of the present invention, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyls, where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0069] In another embodiment of the present invention, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyl groups, where each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0070] In another embodiment of the present invention, R 5 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 3-6Selected from the group consisting of cycloalkyl groups, where each alkyl, alkenyl, and cycloalkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0071] In another embodiment of the present invention, R 5 is hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where alkyl and cycloalkyl are either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 5 is selected from the group consisting of hydrogen, -CH3, CH2F, -CH2CH3, -CH(CH3)2 and cyclopropyl, where cyclopropyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0072] In another embodiment of the present invention, R 5 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, where the alkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 5 R is selected from the group consisting of hydrogen, -CH3, CH2F, -CH2CH3, and -CH(CH3)2. In another embodiment of the present invention, R 5 It is hydrogen.

[0073] In another embodiment of the present invention, R 5 is -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 5 The group is selected from -CH3, CH2F, -CH2CH3, and -CH(CH3)2.

[0074] In another embodiment of the present invention, R 5is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 5 is cyclopropyl, where cyclopropyl is either unsubstituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0075] In one embodiment of the present invention, 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 Rj Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from, and here, R 6 and R 7 And the carbon atoms to which they are bonded are -C 3-5 It can form a cycloalkyl ring.

[0076] In another embodiment of the present invention, 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 NRe R j Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0077] In another embodiment of the present invention, R 6 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyls, where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0078] In another embodiment of the present invention, R 6 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyl groups, where each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0079] In another embodiment of the present invention, R 6 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 3-6 Selected from the group consisting of cycloalkyl groups, where each alkyl, alkenyl, and cycloalkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0080] In another embodiment of the present invention, R 6 is hydrogen, -C 1-6 Alkyl and -C3-6 Selected from the group consisting of cycloalkyls, where each alkyl and cycloalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 6 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, CH(CH3)2, and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 6 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0081] In another class of this embodiment, R 6 is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0082] In another embodiment of the present invention, R 6 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, where the alkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 6 R is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH(CH3)2, and -CH2F. In another class of this embodiment, R 6 R is selected from the group consisting of hydrogen, -CH3, and -CH2CH3. In another embodiment of the present invention, R 6 It is hydrogen.

[0083] In another embodiment of the present invention, R 6 is -C 1-6 Alkyl and -C 3-6Selected from the group consisting of cycloalkyls, where alkyl and cycloalkyl are either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 6 The group is selected from -CH3, -CH2CH3, -CH(CH3)2, -CH2F and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0084] In another embodiment of the present invention, R 6 is -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 6 The group is selected from -CH3, -CH2CH3, -CH(CH3)2 and -CH2F. In another class of this embodiment, R 6 R is selected from the group consisting of -CH3 and -CH2CH3. In another class of this embodiment, R 6 It is -CH3.

[0085] In another embodiment of the present invention, R 6 is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 6 is cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0086] In one embodiment of the present invention, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C1-6 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 Selected from the group consisting of, where each CH2, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0087] In another embodiment of the present invention, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyls, where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is either unsubstituted or R gIt is substituted with 1 to 5 substituents selected from the following.

[0088] In another embodiment of the present invention, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 3-6 Cycloalkyl, -C 2-6 Selected from the group consisting of cycloheteroalkyl groups, where each alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0089] In another embodiment of the present invention, R 7 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 3-6 Selected from the group consisting of cycloalkyl groups, where each alkyl, alkenyl, and cycloalkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0090] In another embodiment of the present invention, R 7 is hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where each alkyl and cycloalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 7 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 7 is selected from the group consisting of hydrogen, -CH3, -CH2CH3, and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R7 is selected from the group consisting of hydrogen, -CH3, and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another embodiment of the present invention, R 7 It is hydrogen.

[0091] In another embodiment of the present invention, R 7 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, where the alkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 7 R is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH(CH3)2, and -CH2F. In another class of this embodiment, R 7 R is selected from the group consisting of hydrogen, -CH3, and -CH2CH3. In another class of this embodiment, R 7 This is selected from the group consisting of hydrogen and -CH3.

[0092] In another embodiment of the present invention, R 7 is -C 1-6 Alkyl and -C 3-6 Selected from the group consisting of cycloalkyls, where each alkyl and cycloalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 7 The group is selected from -CH3, -CH2CH3, -CH(CH3)2, -CH2F and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 7 The group is selected from the group consisting of -CH3, -CH2CH3 and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 7is selected from the group consisting of -CH3 and cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 7 The group is selected from the group consisting of -CH3 and cyclopropyl, where cyclopropyl is unsubstituted.

[0093] In another embodiment of the present invention, R 7 is -C 1-6 Selected from the group consisting of alkyl groups, where the alkyl group is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 7 The group is selected from -CH3, -CH2CH3, -CH(CH3)2 and -CH2F. In another class of this embodiment, R 7 R is selected from the group consisting of -CH3 and -CH2CH3. In another class of this embodiment, R 7 It is -CH3.

[0094] In another embodiment of the present invention, R 7 is -C 3-6 Selected from the group consisting of cycloalkyls, where the cycloalkyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 7 is cyclopropyl, where cyclopropyl is either unsubstituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0095] In one embodiment of the present invention, R 8 is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Selected from the group consisting of cycloheteroalkyl groups, where each alkyl, cycloalkyl, and cycloheteroalkyl is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0096] In another embodiment of the present invention, R 8 is hydrogen and -C 1-6 Selected from the group consisting of alkyl groups, where the alkyl group is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 8 R is selected from the group consisting of hydrogen and -CH3. In another embodiment of the present invention, R 8 It is hydrogen.

[0097] In another embodiment of the present invention, R 8 is -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 8 It is -CH3.

[0098] In one embodiment of the present invention, R 9 is hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl and -C 2-6 Selected from the group consisting of alkynyls, where each alkyl, alkenyl, and alkynyl is either unsubstituted or substituted with 1 to 5 substituents selected from halogens.

[0099] In another embodiment of the present invention, R 9 is hydrogen and -C 1-6 Selected from the group consisting of alkyls, where each alkyl is either unsubstituted or substituted with 1 to 5 substituents selected from halogens. In one class of this embodiment, R 9 R is selected from the group consisting of hydrogen, -CH3, and -CH2CH3. In another class of this embodiment, R 9 R is selected from the group consisting of hydrogen and -CH3. In another embodiment of the present invention, R 9 It is hydrogen.

[0100] In another embodiment of the present invention, R 9 is -C 1-6 Selected from the group consisting of alkyls, where each alkyl is either unsubstituted or substituted with 1 to 5 substituents selected from halogens. In one class of this embodiment of the present invention, R 9 The group is selected from the group consisting of -CH3 and -CH2CH3.

[0101] In one embodiment of the present invention, each R a CN, oxo, halogen, -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -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, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Cycloheteroalkyl, -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 Cycloheteroalkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(CH2) p -OC 3-6Cycloalkyl, -(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 L and -NR k R L Independently selected from the group consisting of, where each R a It 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.

[0102] In another embodiment of the present invention, each R a CN, oxo, halogen, -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -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, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Cycloheteroalkyl, -C2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(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 a It 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.

[0103] In another embodiment of the present invention, each R a CN, oxo, halogen, -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -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 1-6Alkyl, -(CH2) p -OC 3-6 Cycloalkyl and -(CH2) p -OC 2-6 Independently selected from the group consisting of cycloheteralkyls, where each R a It 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.

[0104] In another embodiment of the present invention, each R a CN, oxo, halogen, -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -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 Independently selected from the group consisting of cycloheteralkyls, where each R a It 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.

[0105] In another embodiment of the present invention, each R a CN, oxo, halogen, -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, -C 2-6Cycloheteroalkyl, aryl, heteroaryl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2-6 Independently selected from the group consisting of cycloheteralkyls, where each R a It 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.

[0106] In another embodiment of the present invention, each R a CN, halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2-6 Independently selected from the group consisting of cycloheteralkyls, where each R a It 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.

[0107] In another embodiment of the present invention, each R a CN, halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, aryl, -OC 1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R a It 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. In one class of this embodiment, each R aThe group is independently selected from CN, F, Cl, -CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CF2CH3, =CH2, cyclopropyl, phenyl, -OCF3, -OCH3, -OCHF2, -OCH2CF3 and -O-cyclopropyl, where each cyclopropyl and phenyl is either unsubstituted or halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0108] In another embodiment of the present invention, each R a CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R a It 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. In another class of this embodiment, each R a R is independently selected from the group consisting of CN, F, Cl, -CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CF2CH3, -OCF3, -OCH3, -OCHF2, -OCH2CF3 and -O-cyclopropyl, where cyclopropyl is either unsubstituted or substituted with 1 to 6 substituents selected from CN, F, Cl, CF3, OH, CH3 and -OCH3. In another class of this embodiment, each R a The molecule is independently selected from the group consisting of F, Cl, -CH3, -CF3, -OCF3, and -O-cyclopropyl, where cyclopropyl is either unsubstituted or substituted with 1 to 6 substituents selected from F, Cl, CF3, OH, CH3, and -OCH3.

[0109] In another embodiment of the present invention, each R a is halogen, -C 1-6 Alkyl, -OC1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R a It 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. In one class of this embodiment, each R a is halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R a R is either unsubstituted or substituted with 1 to 6 substituents selected from halogen, CF3, OH, CH3, and -OCH3. In another class of this embodiment, each R a R is independently selected from the group consisting of F, Cl, -CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CF2CH3, -OCF3, -OCH3, -OCHF2, -OCH2CF3 and -O-cyclopropyl, where cyclopropyl is either unsubstituted or substituted with 1 to 6 substituents selected from F, Cl, CF3, OH, CH3 and -OCH3. In another class of this embodiment, each R a R is independently selected from the group consisting of F, Cl, -CH3, -CF3, -OCF3 and -O-cyclopropyl, where cyclopropyl is either unsubstituted or substituted with 1 to 6 substituents selected from F, Cl, CF3, OH, CH3 and -OCH3. In another class of this embodiment, each R a The molecule is independently selected from the group consisting of F, Cl, -CF3, -OCF3, and -O-cyclopropyl, where cyclopropyl is either unsubstituted or substituted with 1 to 6 substituents selected from F, Cl, CF3, OH, CH3, and -OCH3.

[0110] In another embodiment of the present invention, R aThe molecule is independently selected from the group consisting of CN, F, C, CF3, CHF2, cyclopropyl, 4-fluorophenyl, OCH2CF3, OCF3, OCHF2, and O-cyclopropyl, where cyclopropyl is either unsubstituted or substituted with 1 to 6 substituents selected from F, Cl, CF3, OH, CH3, and -OCH3.

[0111] In one embodiment of the present invention, 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 Cycloalkyl, -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, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Cycloheteroalkyl, -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 Cycloheteroalkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p-OC 2-6 Heterocycloalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocycloalkyl, -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 These are 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.

[0112] In another embodiment of the present invention, 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 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, (CH2)2-phenyl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6Cycloheteroalkyl, -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 Cycloheteroalkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Heterocycloalkyl, -(CH2) p -O-aryl and -(CH2) p Independently selected from the group consisting of -O-heteroaryls, where each R b These are 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.

[0113] In another embodiment of the present invention, 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 Cycloalkyl, -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 2-6Cycloheteroalkyl, -OH, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl and -(CH2) p -OC 2-6 Independently selected from the group consisting of heterocycloalkyls, where each R b These are 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. In another embodiment of the present invention, each R b CN, oxo, halogen, -S(O)2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2-6 Independently selected from the group consisting of heterocycloalkyls, where each R b These are 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.

[0114] In another embodiment of the present invention, each R b CN, halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl and -OC 2-6 Independently selected from the group consisting of heterocycloalkyls, where each R bThese are 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.

[0115] In another embodiment of the present invention, each R b CN, halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, aryl, -OC 1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R b These are 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. In one class of this embodiment of the present invention, each R b CN, halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, aryl, -OC 1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R b It is either unsubstituted or substituted with 1 to 6 substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3, and -OCH3.

[0116] In another class of this embodiment of the present invention, each R bR is independently selected from the group consisting of CN, F, Cl, -CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CF2CH3, =CH2, cyclopropyl, phenyl, -OCF3, -OCH3, -OCHF2, -OCH2CF3 and -O-cyclopropyl, where each cyclopropyl and phenyl is either unsubstituted or substituted with 1 to 6 substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3 and -OCH3. In another class of this embodiment of the present invention, each R b The molecule is independently selected from the group consisting of CN, F, Cl, -CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CF2CH3, =CH2, cyclopropyl, phenyl, -OCF3, -OCH3, -OCHF2, -OCH2CF3, and -O-cyclopropyl, where each cyclopropyl and phenyl molecule is either unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3, and -OCH3.

[0117] In another embodiment of the present invention, each R b is halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, aryl, -OC 1-6 Alkyl and -OC 3-6 Independently selected from the group consisting of cycloalkyl, where each R b These are 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. In one class of this embodiment of the present invention, each R b is halogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 3-6 Cycloalkyl, aryl, -OC 1-6 Alkyl and -OC 3-6Independently selected from the group consisting of cycloalkyl, where each R b R is either unsubstituted or substituted with 1 to 6 substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3 and -OCH3. In another class of this embodiment of the present invention, each R b R is independently selected from the group consisting of F, Cl, -CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CF2CH3, =CH2, cyclopropyl, phenyl, -OCF3, -OCH3, -OCHF2, -OCH2CF3 and -O-cyclopropyl, where each cyclopropyl and phenyl is either unsubstituted or substituted with 1 to 6 substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3 and -OCH3. In another class of this embodiment of the present invention, each R b The group is independently selected from F, Cl, -CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CF2CH3, =CH2, cyclopropyl, phenyl, -OCF3, -OCH3, -OCHF2, -OCH2CF3, and -O-cyclopropyl, where each cyclopropyl and phenyl is either unsubstituted or substituted with one to five substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3, and -OCH3.

[0118] In another embodiment of the present invention, each R b is halogen, -C 1-6 Alkyl and -OC 1-6 Independently selected from the group consisting of alkyl groups, where each R b R is either unsubstituted or substituted with 1 to 6 substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -CH3, and -OCH3. In one class of this embodiment, each R bThe group consisting of F, Cl, -CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CF2CH3, -OCF3, -OCH3, -OCHF2, and -OCH2CF3 is independently selected. In another class of this embodiment, each R b The group consisting of F, Cl, -CH3, -CH(CH3)2, -CF3, -CHF2, -CH2CF3, -CF2CH3, -OCF3, -OCH3, -OCHF2, and -OCH2CF3 is independently selected. In another class of this embodiment, each R b The group is independently selected from F, Cl, -CF3, -OCHF2, and -OCH2CF3.

[0119] In one embodiment of the present invention, R c is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R c is -C 1-6 Alkyl, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R c is -C 1-6 Selected from alkyl and halogen, where the alkyl is either unsubstituted or substituted with 1 to 3 halogens. In another embodiment of the present invention, R c is -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or substituted with one to three halogens. In another embodiment of the present invention, R c It is a halogen.

[0120] In one embodiment of the present invention, R d is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, Rd is -C 1-6 Alkyl, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R d is -C 1-6 Selected from alkyl and halogen, where the alkyl is either unsubstituted or substituted with 1 to 3 halogens. In another embodiment of the present invention, R d is -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or substituted with one to three halogens. In another embodiment of the present invention, R d is a halogen. In one class of this embodiment, R d It is F.

[0121] In one embodiment of the present invention, R e is hydrogen and C 1-6 Selected from alkyl groups. In another embodiment of the present invention, R e is hydrogen. In another embodiment of the present invention, R e C 1-6 It is alkyl.

[0122] In one embodiment of the present invention, R f is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R f is -C 1-6 Alkyl, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R f is -C 1-6 Selected from alkyl and halogen, where the alkyl is either unsubstituted or substituted with 1 to 3 halogens. In another embodiment of the present invention, R f is -C 1-6It is an alkyl group, where the alkyl group is either unsubstituted or substituted with one to three halogens. In another embodiment of the present invention, R f is a halogen. In one class of this embodiment, R f It is F.

[0123] In one embodiment of the present invention, R g is -C 1-6 Alkyl, OH, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R g is -C 1-6 Alkyl, halogen, and -OC 1-6 Selected from alkyl, where the alkyl is either unsubstituted or substituted with 1-3 halogens. In another embodiment of the present invention, R g is -C 1-6 Selected from alkyl and halogen, where the alkyl is either unsubstituted or substituted with 1 to 3 halogens. In another embodiment of the present invention, R g is -C 1-6 It is an alkyl group, where the alkyl group is either unsubstituted or substituted with one to three halogens. In another embodiment of the present invention, R g is a halogen. In one class of this embodiment, R g It is F.

[0124] In one embodiment of the present invention, R h is hydrogen, C 1-6 Alkyl, C 3-6 Selected from cycloalkyl, aryl, and heteroaryl. In another embodiment of the present invention, R h is hydrogen, C 1-6 Alkyl and C 3-6 Selected from cycloalkyl. In another embodiment of the present invention, R h is hydrogen and -C 1-6 Selected from alkyl groups. In another embodiment of the present invention, R h is hydrogen. In another embodiment of the present invention, Rh C 1-6 It is alkyl.

[0125] In one embodiment of the present invention, R i is hydrogen, C 1-6 Alkyl, C 3-6 Selected from cycloalkyl, aryl, and heteroaryl. In another embodiment of the present invention, R i is hydrogen, C 1-6 Alkyl and C 3-6 Selected from cycloalkyl. In another embodiment of the present invention, R i is hydrogen and -C 1-6 Selected from alkyl groups. In another embodiment of the present invention, R i is hydrogen. In another embodiment of the present invention, R i C 1-6 It is alkyl.

[0126] In one embodiment of the present invention, R j is hydrogen, C 1-6 Alkyl, C 3-6 Alkenil, C 3-6 Alkinyl, C 3-6 Cycloalkyl, C 2-5 Selected from cycloheteralkyl, aryl, and heteroaryl.

[0127] In another embodiment of the present invention, R j is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-5 Selected from cycloheteralkyl, aryl, and heteroaryl.

[0128] In another embodiment of the present invention, R j is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 2-5 Selected from cycloheteralkyls. In another embodiment of the present invention, R j is hydrogen, C 1-6 Alkyl and C 3-6 Selected from cycloalkyl. In another embodiment of the present invention, R jis hydrogen and C 1-6 Selected from alkyl groups. In another embodiment of the present invention, R j is hydrogen. In another embodiment of the present invention, R j C 1-6 It is alkyl.

[0129] In one embodiment of the present invention, R k is hydrogen and C 1-6 Selected from alkyl groups. In another embodiment of the present invention, R k is hydrogen. In another embodiment of the present invention, R k C 1-6 It is alkyl.

[0130] In one embodiment of the present invention, R L is hydrogen, C 1-6 Alkyl, C 3-6 Selected from cycloalkyl, aryl, and heteroaryl. In another embodiment of the present invention, R L is hydrogen, C 1-6 Alkyl and C 3-6 Selected from cycloalkyl. In another embodiment of the present invention, R L is hydrogen and -C 1-6 Selected from alkyl groups. In another embodiment of the present invention, R L is hydrogen. In another embodiment of the present invention, R L C 1-6 It is alkyl.

[0131] 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 another embodiment, m is 1. In another embodiment, m is 2.

[0132] In one embodiment, n is 2, 3, 4, 5, or 6. In another embodiment, n is 2, 3, 4, or 5. In another embodiment, n is 2, 3, or 4. In another embodiment, n is 2 or 3. In another embodiment, n is 2 or 4. In another embodiment, n is 2, 3, 4, or 5. In another embodiment, n is 3. In another embodiment, n is 4. In another embodiment, n is 5. In another embodiment, n is 6.

[0133] In one embodiment, p is 0, 1, 2, or 3. In another embodiment, p is 0, 1, or 2. In another embodiment, p is 0, 1, or 3. In another embodiment, p is 1, 2, or 3. In another embodiment, p is 1, 2, or 3. In another embodiment, p is 1, 2, or 3. In another embodiment, p is 0, 1. In another embodiment, p is 0, 2, or 3. In another embodiment, p is 0, 1, 2, or 3. In another embodiment, p is 0, 1, 2, or 3. In another embodiment, p is 3.

[0134] In one embodiment, q is 0, 1, 2, or 3. In another embodiment, q is 0, 1, or 2. In another embodiment, q is 0, 1, or 3. In another embodiment, q is 1, 2, or 3. In another embodiment, q is 1 or 2. In another 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 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3.

[0135] 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 another embodiment, r is 1. In another embodiment, r is 2.

[0136] 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 6. In another embodiment, s is 1, 2, 3, 4, or 5. In another embodiment, s is 0, 1, 2, 3, or 4. In another embodiment, s is 1, 2, 3, or 4. In another embodiment, s is 0, 1, 2, or 3. In another embodiment, s is 1, 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 another embodiment, s is 4. In another embodiment, s is 5. In another embodiment, s is 6.

[0137] In one embodiment, t is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, t is 0, 1, 2, 3, 4, or 5. In another embodiment, t is 1, 2, 3, 4, 5, or 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 1, 2, 3, or 4. In another embodiment, t is 0, 1, 2, or 3. In another embodiment, t is 1, 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 another embodiment, t is 4. In another embodiment, t is 5. In another embodiment, t is 6.

[0138] In another embodiment of the present invention, the present invention relates to structural formula Ia: [ka]

[0139] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0140] In another embodiment of the present invention, the present invention relates to structural formula Ib: [ka]

[0141] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0142] In one class of this embodiment, the pyridyl ring is [ka]

[0143] That is the case.

[0144] In another class of this embodiment, the pyridyl ring is [ka]

[0145] That is the case.

[0146] In another class of this embodiment, the pyridyl ring is [ka]

[0147] That is the case.

[0148] In another embodiment of the present invention, the present invention relates to structural formula Ic: [ka]

[0149] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0150] In another embodiment of the present invention, the present invention relates to structural formula Id: [ka]

[0151] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0152] In another embodiment of the present invention, the present invention relates to structural formula Ie: [ka]

[0153] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0154] In another embodiment of the present invention, the present invention relates to the structural formula If: [ka]

[0155] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0156] In another embodiment of the present invention, the present invention relates to structural formula Ig: [ka]

[0157] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0158] In one class of this embodiment, the pyridyl ring is [ka]

[0159] That is the case.

[0160] In another class of this embodiment, the pyridyl ring is [ka]

[0161] That is the case.

[0162] In another class of this embodiment, the pyridyl ring is [ka]

[0163] That is the case.

[0164] In another embodiment of the present invention, the present invention relates to structural formula Ih: [ka]

[0165] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0166] In another embodiment of the present invention, the present invention relates to structural formula Ii: [ka]

[0167] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0168] In another embodiment of the present invention, the present invention relates to structural formula Ij: [ka]

[0169] This relates to a compound represented by or a pharmaceutically acceptable salt thereof.

[0170] The compounds represented by structural formula I include the compounds represented by structural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and Ij, as well as their pharmaceutically acceptable salts, hydrates, and solvates.

[0171] Another embodiment of the present invention is structural formula I [wherein, A is (1) Aryl, and, (2) Heteroaryl Selected from the group consisting of, Here, each aryl and heteroaryl is either unsubstituted or R a It is substituted with 1 to 5 substituents selected from; and, B, 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.

[0172] Another embodiment of the present invention is structural formula I [wherein, A is (1) Phenyl, (2) Pyridine, (3) Pyrazole, (4) Oxazole and, (5) Thiazole Selected from the group consisting of, Here, A is either not substituted, or R a It is substituted with 1 to 5 substituents selected from; B is (1) Aryl, and, (2) Heteroaryl Independently selected from the group consisting of, Here, B is either not substituted, or R b It is substituted with 1 to 5 substituents selected from; R 1 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 c It is substituted with 1 to 5 substituents selected from; 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 It is substituted with 1 to 5 substituents selected from; 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 It is substituted with 1 to 5 substituents selected from; R 4 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 It is substituted with 1 to 5 substituents selected from; 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 It is substituted with 1 to 5 substituents selected from; R 6 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 g It is substituted with 1 to 5 substituents selected from; R 7 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 g It is substituted with 1 to 5 substituents selected from; R 8 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from; R 9 teeth, (1) Hydrogen, and (2)-C 1-6 Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or substituted with 1 to 5 substituents selected from halogens; 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 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)-OH, (17)-OC 1-6 Alkyl, (18)-OC 3-6 Cycloalkyl, and, (19)-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 Alkyl 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 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 Heterocycloalkyl Independently selected from the group consisting of, Here, each R b These are 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; 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 of the present invention 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 It is substituted with 1 to 5 substituents selected from; B is a heteroaryl, where the heteroaryl is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from; R 1 , R 2 , R 3 , R 4 and R 5 is hydrogen; R 6 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 g It is substituted with 1 to 5 substituents selected from; R 7 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 g It is substituted with 1 to 5 substituents selected from; R 8 and R 9 is hydrogen; Each R a teeth, (1) CN, (2) Halogen, (3)-C 1-6 Alkyl, (4)-C 1-6 Alkenil, (5)-C 3-6 Cycloalkyl, aryl, (6)-OC 1-6 Alkyl, and (7)-OC 3-6 Cycloalkyl Independently selected from the group consisting of, Here, each R a It 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; Each R b teeth, (1) CN, (2) Halogen, (3)-C 1-6 Alkyl, (4)-C 1-6 Alkenil, (5)-C 3-6 Cycloalkyl, (6) New C 2-6 Cycloheteroalkyl, (7) Ariel, (8) Heteroaryl, (9)-OC 1-6 Alkyl, (10)-OC 3-6 Cycloalkyl, and, (11)-OC 2-6 Heterocycloalkyl Independently selected from the group consisting of, Here, each R b These are 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; 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.

[0174] Na v 1.8 Examples of compounds useful as inhibitors of channel activity in the present invention include, but are not limited to, the following compounds: (1) (2R)-N-((R)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (2) (2R)-N-((S)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (3) N-((R or S)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (4) N-((S or R)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (5) (2R)-N-((R or S)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (6) (2R)-N-((S or R)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (7) (2R)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (8) (2R)-N-((S or R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (9) (2R)-N-((R)-(4-chlorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (10) (2R)-N-((S)-(4-chlorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (11) (2R)-N-((R)-(3,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (12) (2R)-N-((S)-(3,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (13) (2R)-N-((R)-(3-chloro-4,5-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (14) (2R)-N-((S)-(3-chloro-4,5-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (15) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (16) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (17) (2R)-N-((R)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (18) (2R)-N-((S)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (19) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (20) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (21) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)imidazo[1,2-a]pyridine-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (22) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)imidazo[1,2-a]pyridine-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (23) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (24) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (25) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (26) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (27) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (28) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (29) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (30) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (31) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (32) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (33) (2R)-N-((R)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (34) (2R)-N-((S)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (35) (2R)-N-((R)-(3,4-dichlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (36) (2R)-N-((S)-(3,4-dichlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (37) (2R)-N-((R)-(4-fluoro-3-(trifluoromethoxy)phenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (38) (2R)-N-((S)-(4-fluoro-3-(trifluoromethoxy)phenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (39) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (40) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (41) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (42) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (43) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(5-chloro-6-(trifluoromethylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (44) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (45) (2R)-N-((R)-(4-chloro-3-cyanophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (46) (2R)-N-((R)-(3-chloro-4-cyanophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (47) (2R)-N-((S)-(3-chloro-4-cyanophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (48) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-cyclopropoxy-3-fluorophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (49) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-cyclopropoxy-3-fluorophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (50) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (51) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (52) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclopropylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (53) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclopropylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (54) (2R)-N-((R)-(3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (55) (2R)-N-((S)-(3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (56) (2R)-N-((R)-(3,4-dichloro-2-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (57) (2R)-N-((S)-(3,4-dichloro-2-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (58) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (59) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (60) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (61) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (62) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (63) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (64) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-cyclo-propylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (65) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-cyclo-propylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (66) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (67) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (68) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (69) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (70) N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (71) N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (72) N-(R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (73) N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-(S or R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (74) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (75) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (76) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-isopropyl-3-oxopiperazine-1-carboxamide; (77) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(S or R)-2-isopropyl-3-oxopiperazine-1-carboxamide; (78) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-ethyl-3-oxopiperazine-1-carboxamide; (79) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-ethyl-3-oxopiperazine-1-carboxamide; (80) N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-(R or S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (81) N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-(S or R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (82) N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (83) N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (84) N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2,2-dimethyl-3-oxopiperazine-1-carboxamide; (85) N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2,2-dimethyl-3-oxopiperazine-1-carboxamide; (86) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (87) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (88) (2S)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (89) (2S)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (90) (3S)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-3-methyl-5-oxopiperazine-1-carboxamide; (91) (3R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-3-methyl-5-oxopiperazine-1-carboxamide; (92) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-(fluoromethyl)-5-oxopiperazine-1-carboxamide; (93) (2S)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-(fluoromethyl)-5-oxopiperazine-1-carboxamide; (94) (2R)-N-((R)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (95) (2R)-N-((S)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (96) (2R)-N-((R)-(3,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (97) (2R)-N-((S)-(3,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (98) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (99) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (100) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoro-methoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (101) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (102) (2R)-N-((R)-(4-chloro-3-cyanophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (103) (2R)-N-((S)-(4-chloro-3-cyanophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (104) (2R)-N-((R)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (105) (2R)-N-((S)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (106) N-((R)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (107) N-((S)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (108) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (109) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (110) (2R)-N-((R)-(3-fluoro-4-(trifluoromethoxy)phenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (111) (2R)-N-((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (112) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(2,2,2-trifluoroethoxy)phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (113) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(2,2,2-trifluoroethoxy)phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (114) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(3-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (115) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(3-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (116) (2R)-N-((R)-(4-cyclopropoxy-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (117) (2R)-N-((S)-(4-cyclopropoxy-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (118) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (119) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (120) (2R)-N-((R)-(5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (121) (2R)-N-((S)-(5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (122) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (123) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (124) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (125) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (126) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (127) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (128) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(1-(4-fluorophenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (129) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(1-(4-fluorophenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (130) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (131) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (132) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (133) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (134) (2R)-N-((R)-(4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (135) (2R)-N-((S)-(4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (136) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (137) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (138) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (139) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (140) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (141) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (142) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (143) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (144) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (145) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (146) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (147) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (148) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (149) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (150)x(2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (151) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (152) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (153) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (154) N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (155) N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (156) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (157) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (158) N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (159) N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (160) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (161) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (162) ((2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (163) ((2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (164) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (165) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (166) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(2-(trifluoromethyl)thiazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (167) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(2-(trifluoromethyl)thiazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (168) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (169) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (170) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (171) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (172) (2R)-2-methyl-3-oxo-N-((R)-(4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)piperazine-1-carboxamide; and, (173) (2R)-2-methyl-3-oxo-N-((S)-(4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)piperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0175] Na v 1.8 Examples of compounds useful as inhibitors of channel activity in the present invention include, but are not limited to, the following compounds: (1) (2R)-N-((R)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (2) (2R)-N-((S)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (3) (2R)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (4) (2R)-N-((R)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (5) (2R)-N-((S)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (6) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (7) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (8) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; and, (9) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.

[0176] While the specific stereochemistry described above is preferred, other stereoisomers, including diastereoisomers, enantiomers, epimers, and mixtures thereof, are also acceptable. v It may be useful in the treatment of diseases involving 1.8.

[0177] A synthesis method for producing the above compounds is disclosed in the examples shown below. Where details of the synthesis are not provided in the examples, the compounds can be readily produced by those skilled in medicinal chemistry or synthetic organic chemistry by applying the synthesis information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. In the case of such compounds, the individual stereoisomers, including enantiomers, diastereoisomers, and mixtures thereof, are also compounds of the present invention.

[0178] definition "Ac" stands for acetyl, which is CH3C(=O)-.

[0179] Unless otherwise defined regarding the carbon chain, "alkyl" refers to a saturated carbon chain that can be linear, branched, or a combination thereof. Other groups with the prefix "alk," such as alkoxy and alkanoyl, can also be linear, branched, or a combination thereof, unless otherwise defined regarding the carbon chain. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, octyl, and nonyl.

[0180] Unless otherwise defined, "alkenyl" means a carbon chain containing at least one carbon-carbon double bond, which can be a straight chain, a branched chain, or a combination thereof. Examples of alkenyls include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl. In one embodiment of the present invention, the alkenyl is a -C1 alkenyl or =CH2.

[0181] Unless otherwise defined, "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which can be linear, branched, or a combination thereof. Examples of alkynyls include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl.

[0182] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, or bridging carbon ring having a specified number of carbon atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one embodiment, the cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In another embodiment, the cycloalkyl is cyclopropane.

[0183] "Cycloheteroalkyl" means a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, spirocyclic, or bridging ring or ring system having a specified number of carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2), and O. The cycloheteroalkyl ring may be substituted at its ring carbon and / or its ring nitrogen or ring sulfur. Examples of cycloheteroalkyls include tetrahydrofuran, pyrrolidine, tetrahydrothiophene, azetidine, piperazine, piperidine, morpholine, oxetane, and tetrahydropyran. In one embodiment of the present invention, the cycloheteroalkyl is selected from azetidine, piperidine, pyrrolidine, tetrahydropyran, and tetrahydrofuran.

[0184] "Aryl" means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or aromatic ring system containing 6 to 14 carbon atoms, where at least one of the rings is aromatic. Examples of aryls include phenyl and naphthyl. In one embodiment of the present invention, the aryl is phenyl. In another embodiment of the present invention, the aryl is selected from phenyl and naphthalene.

[0185] A "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring or ring system containing 5 to 14 ring atoms, and at least one ring heteroatom selected from N, NH, S (including SO and SO2), and O, where at least one of the rings containing the heteroatom is aromatic. Examples of heteroaryls include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridadinyl, pyrazinyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, and dibenzofuranyl. In one embodiment of the present invention, the heteroaryl is selected from pyridine, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, thiazole, oxazole, benzofuran, benzoxazole, benzothiazole, indole, indazole, imidazopyridine, thiophene, and thiazolopyridine. In another embodiment of the present invention, the heteroaryl is selected from pyridine and thiazole. In another embodiment, the heteroaryl is selected from pyridine, pyrazole, oxazole, and thiazole. In another embodiment, the heteroaryl is pyridine. In another embodiment, the heteroaryl is thiazole. In another embodiment, the heteroaryl is pyrazole. In another embodiment, the heteroaryl is oxazole. In another embodiment, the heteroaryl is selected from pyridine, pyrimidine, pyrazole, thiazole, imidazo[1,2-a]pyridine, oxazole, benzofuran, benzoxazole, indazole, and thiazolopyridine. In another embodiment, the heteroaryl is selected from oxazole, pyridine, pyrimidine, pyrazole, thiazole, and imidazo[1,2-a]pyridine. In another embodiment, the heteroaryl is selected from pyridine, pyrimidine, pyrazole, thiazole, and imidazo[1,2-a]pyridine. In another embodiment, the heteroaryl is selected from pyridine, pyrazole, and thiazole.

[0186] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, halogen is fluorine, chlorine, or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is fluorine or bromine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine.

[0187] "Me" stands for methyl.

[0188] "Okiso" represents =O.

[0189] "Saturated" means that it contains only single bonds.

[0190] "Unsaturated" means containing at least one double or triple bond. In one embodiment, "unsaturated" means containing at least one double bond. In another embodiment, "unsaturated" means containing one double bond. In another embodiment, "unsaturated" means containing at least one triple bond. In yet another embodiment, "unsaturated" means containing one triple bond.

[0191] Variable part (for example, R 1 , R a If any of the constituent elements or formula I appear two or more times, its definition in each instance is independent of its definition in all other instances. Furthermore, combinations of substituents and / or variable parts are permitted only if such combinations result in a stable compound. A wavy line crossing a bond in a substituent variable part represents a bond point.

[0192] Under the standard nomenclature used throughout this disclosure, the terminal portion of a given side chain is listed first, followed by the adjacent functional groups toward the bond point. For example, C 1-5 Alkylcarbonylamino C1-6 Alkyl substituents are equivalent to the following: [ka]

[0193] In selecting the compound of the present invention, those skilled in the art can choose from a variety of substituents (i.e., R 1 , R 2 It should be recognized that compounds such as these should be selected according to well-known principles regarding the bonding and stability of chemical structures.

[0194] The term "substituted" should be understood to encompass multiple substitutions by the specified substituents. If multiple substituent parts are disclosed or requested, the substituted compound may be independently substituted, once or multiple times, by one or more of the disclosed or requested substituent parts. Independent substitution means that the substituents may be identical or different.

[0195] The expression “pharmaceutically acceptable” is used herein to indicate a compound, material, composition, salt and / or dosage form that is safe and suitable for administration to humans and animals, when sound medical judgment is used and all applicable government regulations are followed.

[0196] Compounds represented by formula I may contain one or more chiral centers. Therefore, compounds represented by formula I may exist as racemic compounds and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. The present invention is intended to encompass all such isomeric forms of compounds represented by formula I.

[0197] The independent synthesis of optical isomers and diastereoisomers, or their chromatographic separation, can be achieved as known in the Art by appropriately modifying the methodologies disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates (which are, if necessary, derivatized with reagents containing chiral centers of known absolute configuration or reagents containing atoms heavy enough to perform absolute assignment).

[0198] If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are isolated. This separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereoisomer mixture, and then separating the individual diastereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivative can then be converted back to the pure enantiomer by cleavage of an added chiral residue. The racemic mixture of the compound can also be separated directly by chromatography using a chiral stationary phase, a method well known in the art.

[0199] Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents with known configurations in methods well known in the art.

[0200] Some of the compounds described herein contain olefin double bonds and, unless otherwise specified, are intended to encompass both E and Z geometric isomers.

[0201] A tautomer is defined as a compound that undergoes a rapid proton shift from one atom to another. Some of the compounds described herein may exist as tautomers with different hydrogen bonding sites. Such examples may be ketones and their enol forms, known as keto-enol tautomers. Individual tautomers and mixtures thereof are encompassed by the compound represented by formula I.

[0202] In compounds represented by general formula I, the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in specific isotopes having the same atomic number but different atomic masses or mass numbers from those primarily found in nature. The present invention is intended to encompass all appropriate isotopic variants of compounds represented by structural formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H) is included. Protium is the major hydrogen isotope found in nature. Enriching deuterium may provide certain therapeutic benefits, such as extending the half-life in vivo or reducing the required dosage, or it may provide compounds that are useful as standards for characterizing biological samples. Tritium is radioactive and therefore can provide radiolabeled compounds that are useful as tracers in metabolic or kinetic studies. Isotopically enriched compounds within the range of structural formula I can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by preparation methods similar to those described herein in the schemes and examples, using appropriate isotope-enriched reagents and / or intermediates.

[0203] Furthermore, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and are themselves intended to be included within the scope of the present invention. Additionally, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are included within the scope of the present invention.

[0204] It is generally preferable to administer the compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of many conventional methods. These methods include chiral chromatography, derivatization with chiral auxiliaries followed by separation by chromatography or crystallization, and fractional crystallization of diastereomer salts.

[0205] salt Where used herein, references to the compounds of the present invention are intended to include pharmaceutically acceptable salts, as well as pharmaceutically unacceptable salts when used as precursors to the free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[0206] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds included in the term "pharmaceutically acceptable salt" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, camusylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate. Salts such as nitrates, lactates, lactobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl sulfates, mucinates, napsylates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonic acid salts, salicylates, stearates, sulfates, acetates, succinates, tannates, tartrates, theoclates, tosylates, triethoidides, trifluoroacetates, and valersates. Furthermore, if the compound of the present invention has an acidic portion, suitable pharmaceutically acceptable salts therefor include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.Examples of salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary and tertiary amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0207] Furthermore, if a carboxylic acid (-COOH) group or an alcohol group is present in the compound of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl may also be used. This includes esters and acyl groups known in the art for modifying solubility or hydrolysis properties for use as a sustained-release formulation or prodrug formulation.

[0208] The term “prodrug” means a compound that is rapidly converted in vivo to a parent compound, for example, by hydrolysis in the blood (e.g., conversion from a prodrug of formula I to a compound of formula I or a salt thereof); a full discussion is provided in “T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series” and “Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987” (both of which are incorporated herein by reference). The present invention encompasses prodrugs of the novel compounds of the present invention.

[0209] Furthermore, solvates and especially hydrates of the compounds of the present invention are also included in the present invention.

[0210] usefulness The compound of the present invention is ethylene Na v 1.8 A selective inhibitor of sodium ion channel activity, or Na v 1.8 It has selective activity as a sodium ion channel blocker. In one embodiment, the compound of the present invention has functional efficacy (IC) for each channel in the Qube® assay system. 50 Based on the value, Na v 1.5 Sodium channel v It exhibits at least 10 times selectivity for 1,8 sodium channels, and in some embodiments, Na v 1.5 Sodium channel v The compound of the present invention exhibits at least 100 times selectivity for 1,8 sodium channels. v 1.8 It is a potent inhibitor of channel activity. The compound and its pharmaceutically acceptable salts are Na v 1.8 Sodium ion channel activity and / or Na v1.8 Receptor inhibition may be effective in treating diseases, disorders, and conditions.

[0211] Na v 1.8 Sodium ion channel activity and / or Na v 1.8 Diseases, disorders, or conditions mediated by receptors include, but are not limited to, nociception, osteoarthritis, peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, pruritus, acute pruritus, chronic pruritus, migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, perioperative pain, postoperative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, phantom limb pain, pain due to cancer and chemotherapy, chronic pelvic pain, pain syndromes, and complex regional pain syndrome.

[0212] One or more of these conditions or disorders can be treated, managed, prevented, alleviated, mitigated, improved or controlled by administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of treatment. Furthermore, the compounds of the present invention can be used to manufacture agents that may be useful in treating, preventing, managing, alleviating, improving or controlling one or more of these conditions, disorders or disorders (nociception, osteoarthritis, peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, pruritus, acute pruritus, chronic pruritus, migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, perioperative pain, postoperative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, phantom limb pain, pain from cancer and chemotherapy, chronic pelvic pain, pain syndromes, and complex regional pain syndromes).

[0213] A preferred use of the compound may be to treat one or more of the following diseases by administering a therapeutically effective dose to patients in need of treatment. The compound is suitable for 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.

[0214] In one embodiment of the present invention, the pain condition is either an acute pain disorder or a chronic pain disorder. In another embodiment of the present invention, the pain condition is an acute pain disorder.

[0215] The compounds of the present invention may be effective in treating nociception. Nociception, or pain, is essential for survival and often serves a protective function. However, pain associated with surgical procedures and current treatments to alleviate it can delay postoperative recovery and prolong hospital stays. 80% of surgical patients experience postoperative pain resulting from tissue damage, peripheral nerve damage, and subsequent inflammation. Approximately 10–50% of surgical patients develop chronic pain after surgery, as nerve damage often leads to persistent neuropathic pain once the wound heals.

[0216] The compounds of the present invention may be effective in the treatment of osteoarthritis. Osteoarthritis is a type of arthritis caused by inflammation, destruction, and eventual loss of cartilage within the joint. The standard treatment for pain associated with osteoarthritis is nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., celecoxib and diclofenac (as outlined in "Zeng et al, 2018"). Patients who do not respond to NSAID therapy are typically treated with low doses of opioids (e.g., hydrocodone). Patients who are resistant to the above treatments are usually treated with total arthroplasty.

[0217] The compounds of the present invention may be effective in the treatment of peripheral neuropathy. Peripheral neuropathy is nerve damage caused by chronic hyperglycemia and diabetes. It causes numbness, loss of sensation, and, in some cases, pain in the distal limbs (e.g., feet, legs, or hands). It is the most common complication of diabetes. The standard treatment for painful diabetic neuropathy is gabapentinoids, e.g., gabapentin and pregabalin. Some patients respond well to tricyclic antidepressants such as amitriptyline, while others are significantly relieved with SRI / NRI drugs such as duloxetine (Schreiber et al., World J Diabetes. 2015 Apr 15;6(3):432-44). Many options are available, but side effects (e.g., dizziness, nausea) are common and limit their maximum potential.

[0218] The compounds of the present invention may be effective in the treatment of hereditary erythromelalgia. Hereditary erythromelalgia (IEM) is a chronic pain syndrome associated with mutations in several voltage-gated sodium channels, including Nav1.8 (Kist et al., PLoS One. 2016 Sep 6; 11(9):e0161789). Patients exhibit a classic "glove and stocking" redness pattern in distal areas such as the hands and feet, which is typically triggered by warm temperatures and exercise. Some patients find relief from the burning pain associated with the redness by immersing themselves in cold water. While drug therapies that affect voltage-gated sodium channels (e.g., lidocaine and mexiletine) are promising, there is currently no standard treatment for IEM.

[0219] The compounds of the present invention may be effective in the treatment of neuropathic pain. Neuropathic pain is pain caused by injury or disease affecting the somatosensory nervous system. In human patients and animal models of neuropathic pain, it has been demonstrated that damage to primary afferent sensory neurons can lead to the formation of neurotumors and spontaneous activity, in addition to activity induced in response to stimuli that are normally harmless (Colloca et 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. 2000 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, which is thought to be the underlying mechanism of pathological pain (Black et al., Ann Neurol. 2008 Dec;64(6):644-53; Bird et al., Br J Pharmacol. 2015 May;172(10):2654-70). Peripheral nerve damage often results in neuropathic pain that persists long after the initial injury has healed. Examples of neuropathic pain, though not limited to these, include postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, lumbar radiculopathy, phantom limb pain, cancer and chemotherapy-related pain, chronic pelvic pain, complex regional pain syndrome and related neuralgia, and pain conditions resulting from gain-of-function mutations in Nav1.8 (Huang et al., J Neurosci. 2013 Aug 28;33(35):14087-97; Kist et al., PLoS One. 2016 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).

[0220] Ectopic activity of sensory neurons, which are normally inactive, is thought to contribute to the development and maintenance of neuropathic pain, and this is generally thought to be related to increased sodium channel activity in damaged nerves (Wood et al., Curr Opin Pharmacol. 2001 Feb; 1(1):17-21; Baker et al., TRENDS in Pharmacological Sciences, 2001, 22(1): 27-31). Standard treatment for neuropathic pain varies greatly depending on the specific condition, but first-line treatment is typically pregabalin, gabapentin, tricyclic antidepressants (e.g., amitriptyline), and SRI / NRI drugs (e.g., duloxetine). Patients who are resistant to these treatments are usually prescribed low doses of opioids (e.g., hydrocodone).

[0221] The compounds of the present invention may be effective in the treatment of multiple sclerosis. Recent evidence indicates a potential role of Nav1.8 in multiple sclerosis. Expression of Nav1.8 in the cerebellum has been confirmed in tissues taken from animal models of multiple sclerosis (EAE models) 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 Acad Sci US A. 2000 Oct 10;97(21):11598-602). Furthermore, two types of SCN10A polymorphisms have shown a significant association with MS (Roostaei et al., Neurology. 2016 Feb 2; 86 (5):410-7). Overexpression of Nav1.8 in the cerebellum induced ataxia-related motor impairments in mice, which were ameliorated by oral delivery of a selective small molecule Nav1.8 antagonist (Shields et al., PLoS One. 2015 Mar 6; 10(3)). These studies suggest that Nav1.8 antagonists may be a useful treatment for symptoms associated with multiple sclerosis.

[0222] The compounds of the present invention may be effective in the treatment of asthma. Asthma is caused by inflammation of the airways, where the human airways become hypersensitive, narrowed, and swollen, thereby making breathing difficult. These symptoms are typically caused by an allergic reaction (Nair P et al., J Allergy Clin Immunol Pract. 2017 May-Jun; 5(3):649-659). In preclinical models of asthma, airway inflammation and immune cell infiltration are reduced by removing Nav1.8-containing neurons or by inhibiting nerve fibers with small molecules (Talbot et al., Neuron. 2015 Jul 15;87(2):341-54). Selective Nav1.8 antagonists may be useful therapeutic agents for preventing airway hypersensitivity caused by immune cell infiltration.

[0223] The compounds of the present invention may be effective in the treatment of pruritus. Pruritus, also commonly known as itching, affects about 4% of the world's population and is considered an unpleasant sensation that triggers a desire or reflex to scratch and is closely related to pain (Luo et al., Cell Mol Life Sci. 2015 Sep;72 (17): 3201-23). ​​Theories regarding the origin of itching suggest the activation of subtle low frequencies in nociceptors (neurons that sense pain); however, it has been described that some afferent nerves preferentially respond to histamine, which induces itching (Schmelz et al., J Neurosci. 1997 Oct 15; 17(20):8003-8). At the same time, it has been found that histamine-responsive neurons also respond to capsaicin, which causes pain (McMahon et al., Trends in Neuroscience 1992, 15:497-501). Members of the transient receptor potential (TRP) family and nerve growth factor (NGF) are both known to play a role in itching and pain, and clinically, both disorders are treated with therapeutic agents such as gabapentin and antidepressants. Therefore, it remains accepted that the underlying mechanisms of pain and itching are highly interwoven and complex, and the distinction between panselective and pruritic pathways remains ambiguous (Ikoma et al., Nat Rev Neurosci. 2006 Jul; 7(7):535-47). The role of Nav1.8 in pruritus was studied using mice genetically modified to express a constitutively active form of serine / threonine kinase BRAF, where BRAF was expressed in neurons expressing Nav1.8. This increased the excitability of pruritus receptors and enhanced induced spontaneous scratching behavior (Zhao et al, 2013). In the skin, pruritogens are released from keratinocytes, lymphocytes, mast cells, and eosinophils during inflammation.These molecules induce itching by directly acting on free nerve endings that express Nav1.8 (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, and can be classified as cutaneous or pruriceptive, neurological, neuropathic, or psychogenic; itching can arise from both systemic diseases, skin diseases, and physical or chemical damage to the dermis. Pathologically, conditions such as dry skin, eczema, psoriasis, varicella-zoster, urticaria, scabies, renal failure, cirrhosis, lymphoma, iron deficiency, diabetes, menopause, polycythemia, uremia, and hyperthyroidism can cause itching, as can neurological disorders such as tumors, multiple sclerosis, peripheral neuropathy, nerve compression, and delusions associated with obsessive-compulsive disorder. Opioids and other medications such as chloroquine can also cause itching (Ikoma et al., Nat Rev Neurosci. 2006 Jul;7(7):535-47). Post-burn itching is also a very serious clinical problem because it interferes with the healing process, thereby causing lasting anxiety and negatively impacting quality of life (Van Loey et al., Br J Dermatol. 2008 Jan;158(1):95-100).

[0224] The present invention further includes pharmaceutically acceptable salts of the compound, and also includes pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier.

[0225] The compound or a pharmaceutically acceptable salt thereof may be useful in the treatment of painful conditions, itchy conditions, and coughing conditions.

[0226] The compounds of the present invention or pharmaceutically acceptable salts thereof can be used in the manufacture of agents for treating pain, itchiness, and coughing conditions in human patients or other mammalian patients.

[0227] A method for treating a pain condition involves administering to a patient in need of treatment a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound.

[0228] A method for treating itching involves administering to a patient in need of treatment a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound. A method for treating cough involves administering to a patient in need of treatment a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound. Other medical uses of the compound of the present invention are described herein.

[0229] As used herein, the term “pain condition” includes, but is not limited to, the following: acute pain, perioperative pain, preoperative pain, postoperative pain, neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, phantom limb pain, chronic pelvic pain, vulvovaginal pain, complex regional pain syndrome and related neuralgia, pain associated with cancer and chemotherapy, pain associated with HIV and HIV treatment-induced neuropathy, nerve injury, avulsion injury, painful traumatic mononeuropathy, painful polyneuropathy, erythromyelalgia, paroxysmal severe pain, and small fiber neuropathy. , oral burning syndrome, central pain syndrome (which can be caused by virtually any lesion at any level of the nervous system), postoperative pain syndrome (e.g., post-mastectomy syndrome, post-thoracotomy syndrome, stump pain), bone and joint pain (osteoarthritis), repetitive pain, toothache, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, dysmenorrhea, pain associated with the angina, inflammatory pain of various causes (e.g., osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis and gout), shoulder tendinitis or bursitis, gouty arthritis, and polymyalgia rheumatica Rheumatism, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization, complex regional pain syndrome, chronic arthralgia and associated neuralgia, acute pain, migraine, migraine headache, headache, cluster headache, nonvascular headache, traumatic nerve injury, nerve compression or entrapment, and neuromic pain.

[0230] As used herein, the terms “pruritic condition” or “pruritic disorder” encompass, but are not limited to, conditions involving an unpleasant sensation that induces an urge to scratch, such as chronic itching.

[0231] As used herein, the terms “cough condition” or “cough disorder” include, but are not limited to, chronic cough, neuropathic cough, or cough resulting from a neurological condition.

[0232] Na v1.8 Sodium ion channel activity or Na v 1.8 Treatment of a receptor-mediated disease, disorder, or condition means administering the compound of the present invention to a subject having said disease, disorder, or condition. 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 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 treatment is Na v 1.8 Sodium ion channel activity or Na v 1.8 It may improve diseases, disorders, or conditions mediated by receptors. Another outcome of treatment is Na v 1.8 Sodium ion channel activity or Na v 1.8 It may suppress diseases, disorders, or conditions mediated by receptors. 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.

[0233] Another outcome of the treatment is Na v 1.8 Sodium ion channel activity or Na v 1.8 It may prevent diseases, disorders, or conditions mediated by receptors.

[0234] Na v 1.8 Sodium ion channel activity or Na v 1.8 Prevention of receptor-mediated diseases, disorders, or conditions means administration of the compounds of the present invention to subjects at risk of such diseases, disorders, or conditions. One consequence of prevention is that in subjects at risk of such diseases, disorders, or conditions, Na v 1.8 Sodium ion channel activity or Na v 1.8 It may reduce diseases, disorders, or conditions mediated by receptors. Another outcome of prevention is that in individuals at risk of such diseases, disorders, or conditions, Nav 1.8 Sodium ion channel activity or Na v 1.8 It may suppress diseases, disorders, or conditions mediated by receptors. Another outcome of prevention is that in individuals at risk of such diseases, disorders, or conditions, Na v 1.8 Sodium ion channel activity or Na v 1.8 It may improve diseases, disorders, or conditions mediated by receptors. Another outcome of prevention is that in individuals at risk of such disease, disorder, or condition, 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 prevention is that in individuals at risk of such diseases, disorders, or conditions, 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] One possible outcome of the treatment is a reduction in the amount of pain experienced by the subject compared to the pain the subject experienced immediately before administration of the compound of the present invention. Another possible outcome of the treatment is a reduction in the amount of pain experienced by the subject compared to the pain the subject experienced immediately before administration of the compound of the present invention. Another possible outcome of the treatment is an improvement in the amount of pain experienced by the subject compared to the pain the subject experienced immediately before administration of the compound of the present invention. Another possible outcome of the treatment is a suppression of the amount of pain experienced by the subject compared to the pain the subject experienced immediately before administration of the compound of the present invention. Another possible outcome of the treatment is control of the amount of pain experienced by the subject compared to the pain the subject experienced immediately before administration of the compound of the present invention. Another possible outcome of the treatment is an improvement in the amount of pain experienced by the subject compared to the pain the subject experienced immediately before administration of the compound of the present invention.

[0236] Another possible outcome of the treatment is the prevention of further pain experienced by the subject after administration of the compound of the present invention.

[0237] Pain prevention means administering the compound of the present invention to reduce pain in subjects at risk of pain. Prevention includes, but is not limited to, administration to subjects before surgery or another anticipated painful event. One outcome of prevention may be pain reduction in subjects at risk of pain. Another outcome of prevention may be suppression of pain in subjects at risk of pain. Another outcome of prevention may be improvement of pain in subjects at risk of pain. Another outcome of prevention may be alleviation of pain in subjects at risk of pain. Another outcome of prevention may be management of pain in subjects at risk of pain.

[0238] The terms “administering” and / or “giving” a compound should be understood to mean providing the compound of the present invention or a prodrug of the compound of the present invention to an individual or mammal in need of treatment.

[0239] The administration of the compound represented by structural formula I for this treatment method is carried out by administering an effective amount of the compound represented by structural formula I to a mammal requiring such treatment or prevention. The need for prophylactic administration according to the method of the present invention is determined by using well-known risk factors. The effective amount of each compound is determined in the final analysis by the physician or veterinarian in charge of the case, however, the effective amount depends on various factors, such as the exact disease being treated, the severity of that disease and any other diseases or conditions the patient is suffering from, the chosen route of administration, any other drugs and treatments the patient may simultaneously require, and other factors at the physician's discretion.

[0240] The usefulness of this compound in these diseases or disorders can be demonstrated in animal disease models reported in the literature.

[0241] Dosage and dosage range To provide an effective dose of the compound of the present invention to mammals (especially humans), any suitable route of administration can be used. For example, it can be administered orally, intravenously, by infusion, subcutaneously, percutaneously, intramuscularly, intradermally, permucosally, intramucosally, rectally, topically, parenterally, orally, in the lungs, orally. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, and aerosols. Preferably, the compound of the present invention is administered orally.

[0242] Na v1.8 In the treatment or prevention of disorders, diseases and / or conditions requiring inhibition of sodium ion channel activity, appropriate dosage levels are generally about 0.0001 to 500 mg per kg of patient body weight per day, which can be administered as a single or multiple doses. In one embodiment, appropriate dosage levels may be about 0.001 to 500 mg per kg of patient body weight per day. In another embodiment, appropriate dosage levels may be about 0.001 to 250 mg / kg per day. In another embodiment, appropriate dosage levels may be about 0.01 to 250 mg / kg per day. In another embodiment, appropriate dosage levels may be about 0.1 to 100 mg / kg per day. In another embodiment, appropriate dosage levels may be about 0.05 to 100 mg / kg per day. In another embodiment, appropriate dosage levels may be about 0.1 to 50 mg / kg per day. In another embodiment, an appropriate dosage level may be about 0.05 to 0.5 mg / kg per day. In yet another embodiment, an appropriate dosage level may be about 0.5 to 5 mg / kg per day. In yet another embodiment, an appropriate dosage level may be about 5 to 50 mg / kg per day. For oral administration, the composition is supplied in the form of tablets containing preferably 0.01 to 1000 mg of the active ingredient, particularly 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, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient, in order to adjust the dosage for the patient being treated according to their symptoms. The compound can be administered in a regimen of 1 to 8 times per day (preferably 1 to 4 times per day, more preferably 1 or 2 times per day). This administration regimen can be adjusted to provide an optimal therapeutic response.

[0243] However, it is understood that specific dosage levels and frequencies for any particular patient may be modified and depend on a variety of factors, including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, general health, sex, diet, method and timing of administration, elimination rate, drug combinations, severity of the particular condition, and the recipient being treated.

[0244] The compounds of the present invention can be used in pharmaceutical compositions comprising (a) the compound or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compounds of the present invention can be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients. The compounds of the present invention can further be used in pharmaceutical compositions in which the compound of the present invention or a pharmaceutically acceptable salt thereof is the sole active ingredient.

[0245] In pharmaceutical compositions, the term "composition" is intended to encompass products containing one or more active ingredients and one or more inactive ingredients that constitute the individual components. Furthermore, it is intended to encompass any products directly or indirectly arising from any combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from another type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any compositions produced by mixing the compounds of the present invention with pharmaceutically acceptable carriers.

[0246] The compounds of the present invention can be used in combination with other drugs that may be equally useful in treating or improving diseases or conditions for which the compounds of the present invention are useful. Such other drugs may be administered simultaneously with or sequentially with the compounds of the present invention, in the routes and amounts commonly used for them. In the treatment of patients with painful, itchy, and coughing conditions, two or more drugs are commonly administered. The compounds of the present invention can generally be administered to patients who are already taking one or more other drugs for these conditions. Often, the compounds are administered to patients who are already being treated with one or more anti-pain compounds when the patient's pain is not responding adequately to the treatment.

[0247] Combination therapy further includes therapies in which the compound of the present invention and one or more other drugs are administered on different schedules that overlap. When used in combination with one or more other active ingredients, it is also intended that the compound of the present invention and the other active ingredients can be used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include pharmaceutical compositions that contain one or more other active ingredients in addition to the compound of the present invention.

[0248] Examples of other active ingredients that can be administered in combination with the compounds of the present invention, and that can be administered separately or in the same pharmaceutical composition, include, but are not limited to, the following: (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.

[0249] In another embodiment of the present invention, the pharmaceutical composition comprises 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 a pharmaceutically acceptable salt thereof: (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.

[0250] Nav1.7 biological agents refer to proteins that inhibit the function of the Nav1.7 channel (this includes, but is not limited to, antibodies, nanobodies, and peptides). Nav1.8 biological agents refer to proteins that inhibit the function of the Nav1.8 channel (this includes, but is not limited to, antibodies, nanobodies, and peptides).

[0251] Specific compounds used in combination with the compounds of the present invention include, but are not limited to, sodium channel inhibitors (including lidocaine such as lidocaine patches); tricyclic antidepressants (including amitriptyline, but are not limited to); and SRI / NRI drugs (including duloxetine, but are not limited to).

[0252] Appropriate opioid agonists include, but are not limited to, codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, buprenorphine, butorphanol, dezosin, nalbufine, pentazocine, and tramadol.

[0253] Appropriate opioid antagonists include, but are not limited to, naltrexone and naloxone.

[0254] Suitable calcium channel antagonists include, but are not limited to, amlodipine, diltiazem, felodipine, gabapentin, islazipine, nicardipine, nifedipine, nisoldipine, pregabalin, verapamil, and diconitide.

[0255] Appropriate NMDA receptor antagonists include, but are not limited to, ketamine, methadone, memantine, amantadine, and dextromethorphan.

[0256] Appropriate COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, and parecoxib.

[0257] Appropriate NSAIDs or nonsteroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, and tolmetin.

[0258] Appropriate pain relievers include, but are not limited to, acetaminophen and duloxetine.

[0259] The above combinations include not only combinations of the compound of the present invention with one other active compound, but also combinations with two or more other active compounds. Non-limiting examples include combinations of the compound with two or more active compounds selected from the following: opioid agonists; opioid antagonists; calcium channel antagonists; NMDA receptor agonists; NMDA receptor antagonists; COX-2 selective inhibitors; NSAIDs (nonsteroidal anti-inflammatory drugs); and analgesics.

[0260] The compounds of the present invention or pharmaceutically acceptable salts thereof may also be used in combination with spinal cord stimulation therapy and skin stimulation therapy.

[0261] The present invention further includes Na v 1.8 We also provide methods for treating or preventing diseases, disorders, or conditions mediated by sodium ion channel activity, wherein the method is used to treat patients who require such treatment or Na v 1.8 Therapeutic dose of sodium in patients at risk of developing sodium-mediated diseases. v 1.8 The administration of a sodium ion channel inhibitor and a specific amount of one or more active ingredients, thereby providing effective relief together.

[0262] In a further embodiment of the present invention, Na v 1.8 A pharmaceutical composition is provided which contains a sodium ion channel activity inhibitor and one or more active ingredients together with at least one pharmaceutically acceptable carrier or excipient.

[0263] Therefore, according to a further aspect of the present invention, Na v 1.8 Na for the manufacture of drugs for treating or preventing diseases, disorders, or conditions mediated by sodium ion channel activity. v 1.8 The use of a sodium ion channel activity inhibitor and one or more active ingredients is provided. Therefore, in further or alternative embodiments of the present invention, Na v 1.8 Na as a combination preparation for simultaneous, separate, or sequential use in the treatment or prevention of diseases, disorders, or conditions mediated by sodium ion channel activity. v Products containing a 1,8 sodium ion channel activity inhibitor and one or more active ingredients are provided. Such combined preparations may be available, for example, in the form of a twin pack.

[0264] It is understood that the compounds of the present invention may be used in conjunction with other pharmaceuticals effective in treating the disease, disorder, or condition in order to treat or prevent pain, itchiness, and coughing.

[0265] The present invention also provides a method for treating or preventing pain, itching, and coughing conditions, wherein the method involves administering to a patient in need of such treatment a specific amount of the compound of the present invention and a specific amount of another agent that is effective in treating (threat) the disorder, disease, or condition, thereby resulting in effective relief when they are combined.

[0266] The present invention also provides a method for treating or preventing pain, itching, and coughing conditions, wherein the method involves administering to a patient in need of such treatment a specific amount of the compound of the present invention and a specific amount of another agent useful in treating the particular condition, disorder, or disease, thereby resulting in effective relief when they work together.

[0267] The term "therapeutic dose" means the amount of a compound represented by structural formula I that elicits a biological or medical response in a cell, tissue, system, animal, or human (which includes alleviation of symptoms of the disorder being treated) as determined by a researcher, veterinarian, physician, or other clinician. The novel therapeutic methods of the present invention are for disorders known to those skilled in the art. The term "mammal" includes humans and companion animals (e.g., dogs and cats).

[0268] The weight ratio of the compound represented by formula I to the second active ingredient can be varied and depends on the effective dose of each ingredient. Generally, the effective dose of each is used. For example, when the compound represented by formula I is combined with a COX-2 inhibitor, the weight ratio of the compound represented by formula I to the COX-2 inhibitor is generally in the range of about 1000:1 to about 1:1000, preferably in the range of about 200:1 to about 1:200. The combination of the compound represented by formula I with another active ingredient is also generally within the aforementioned range, but in any case, the effective dose of each active ingredient should be used.

[0269] Synthesis method The following reaction schemes and examples illustrate methods that may be used for the synthesis of the compound represented by structural formula I as described in the present invention. These reaction schemes and examples are provided for illustrative purposes and should not be construed as limiting the present invention in any way. All substituents are as defined above unless otherwise indicated. Several strategies based on synthetic transformations known in the organic synthesis literature can be used for the preparation of the compound represented by structural formula I. The scope of the present invention is defined by the attached "Claims".

[0270] device Reverse-phase chromatography was performed on a Gilson GX-281 with columns selected from the following: Phenomenex Synergi C18 (150mm-30mm-4micron), YMC-Actus Pro C18 (150mm-30mm-5micron), Xtimate C18 (150mm-25mm-5micron), Boston Green ODS (150mm-30mm-5micron), XSELECT C18 (150mm-30mm-5micron), and Waters XSELECT C18 (150mm-30mm-5micron). Conditions included either high pH (0-100% acetonitrile / water eluent containing 0.1% v / v 10mM NH4CO3 or 0.05% NH4OH) or low pH (0-95% acetonitrile / water eluent containing 0.1% v / v TFA), as noted in some examples.

[0271] SFC chiral partitioning was performed using Sepiate Prep SFC 100, Multigram II (MG II), THAR80 prep SFC, or Waters SFC (80, 200, or 350).

[0272] LC / MS measurements were performed using one of the following conditions on a Waters Classing Aquity system with TUV and MS detectors and a Waters SQD mass spectrometer, a Shimadzu 20UV254 and 220nM with a Shimadzu 2010 or 2020 mass spectrometer, or an Agilent 1200 HPLC with DAD / ELSD and G6110 MSD: (1) Ascentis Express C18 (3-50 mm) 2.7 μm column, using mobile phases containing A: 0.05% TFA in water and B: 0.05% TFA in acetonitrile [gradient flow rate of 1.8 mL / min, 90:10 (A:B) → 5:95 (A:B) over 6 minutes], UV detection 210 nm; (2) Aquity BEH C18 (1.0-50 mm) 1.7 μm column, (1) Mobile phases containing A: 0.05% TFA in water and B: 0.05% TFA in acetonitrile [gradient flow rate of 0.3 mL / min, 90:10 (A:B) → 5:95 (A:B) over 2 minutes], UV detection at 215 nm; (2) Agilent YMC J'Sphere H-80 (3-50 mm) 5 μm column, mobile phases containing A: 0.1% TFA in water and B: acetonitrile [gradient flow rate of 1.4 mL / min, 95:5 (A:B) → 0:100 (A:B) over 3.6 minutes, and 0:100 (A:B) over 0.4 minutes], UV detection at 254 nm and 220 nm, and Agilent 1100 quadrupole mass spectrometer; (3) Agilent TC-C18 (2.1-50 mm) A 5 μm column was used, with mobile phases containing A: 0.0375% TFA in water and B: 0.01875% TFA in acetonitrile [gradient flow rate of 0.8 mL / min, 90:10 (A:B) for 0.4 minutes, then 90:10 → 0:100 (A:B) over 3 minutes, and 10:90 (A:B) for 0.6 minutes], UV detection at 254 nm and 220 nm, and an Agilent 6110 quadrupole mass spectrometer.

[0273] Proton NMR or 1Unless otherwise specified, ¹H NMR spectra were acquired according to standard analytical techniques using a Varian Unity-Inova 400 MHz NMR spectrometer with a Varian 400 ATB PFG 5mm, Nalorac DBG 400-5, or Nalorac IDG 400-5 probe; a Varian-400 MHz MR spectrometer with an Auto X ID PFG Probe 5mm; a Varian 400 MHz VNMRS spectrometer with a PFG 4Nuc Probe 5mm; or a Bruker AvanceIII 500 MHz spectrometer with a PABBO Probe 5mm. The results of the spectral analysis are reported. Chemical shift (δ) values ​​are reported in delta (δ) units, parts per million (ppm). Chemical shifts in the 1H NMR spectrum are given relative to the signals of residual non-deuterated solvents (CDCl3 (referenced at δ 7.26 ppm), DMSO d-6 (referenced at δ 2.50 ppm), and CD3OD (referenced at δ 3.31 ppm)). Multiplets are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, m = multiplet or overlap of non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz).

[0274] Abbreviation AcOH is acetic acid; BAST is bis(2-methoxyethyl)aminosulfur trifluoride; Boc is tert-butoxycarbonyl; Calc'd is the calculated value; CDI is 1,1'-carbonyldiimidazole; DAST is diethylaminosulfur trifluoride; DIBAL-H is diisobutylaluminum hydride; DCE is dichloroethane; DCM is dichloromethane; DEA is diethanolamine; DIPEA or DIEA is N,N-diisopropylethylamine; DMA is dimethylacetamide; DME is dimethoxyethane; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et3N is triethylamine; Et2O is diethyl ether; Depositphotos is ethyl acetate; EtOH is ethanol; g is grams; h or hr(s) is hours (s); HATU is 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexa-fluorophosphate; Hex is hexane; HOAt is 1-hydroxy-7-azabenzotriazole; HPLC is high-performance liquid chromatography; IPA is isopropyl alcohol; iPrMgCl is isopropyl magnesium chloride; iPrMgCl-LiCl is isopropyl magnesium chloride lithium chloride complex; L is liter; LAH is lithium aluminum hydride; LC / MS is liquid chromatography-mass spectrometry; LRMS is low-resolution mass spectrometry; M is mole; Me is methyl; MeOH is methanol; MeCN is acetonitrile; mg is milligrams; mL is milliliters; mmol is millimoles; MPLC is medium-pressure liquid chromatography; N is normal;NaHMDS is sodium bis(trimethylsilyl)amide; NH4OAc is ammonium acetate; NMO is 4-methylmorpholine N-oxide; NMP is N-methylpyrrolidone; PCC is pyridinium chlorochromate; Pd / C is carbon-supported palladium; Pd(dppf)Cl2 is [1,1-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II); Pd(OAc)2 is palladium(II) acetate; Pd(PPh3)4 is tetrakis(triphenylphosphine)-palladium(O); Pd(t-Bu3P)2 is bis(tri-tert-butylphosphine)-palladium(O); Pet.ether or PE is petroleum ether; PG is a protecting group; ppm is milligrams per liter; Prep. or prep is preparative; psi is pounds per square inch; rt or RT is room temperature; SFC is supercritical fluid chromatography; TBAF is tetrabutylammonium fluoride; TLC is thin-layer chromatography; tBuXPhosPd G2 is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); tBuXPhos Pd G3 is [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; 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 is ultraviolet light; v / v is volume / volume; and xantphos is 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0275] As shown in Scheme A, the compounds of the present invention can be prepared by condensing a appropriately functionalized aldehyde A-1 with a tert-butansulfinamide using a dehydrating agent such as Ti(OEt)4 or Ti(OiPr)4 to obtain intermediate A-2. Intermediate A-2 can then be reacted with various organometallic nucleophiles A-3 to obtain intermediate A-4, which can be deprotected under acidic conditions to obtain the amine represented by formula A-5. Then, amine A-5 can be coupled with piperazine A-6 using urea coupling conditions (using triphosgene or CDI as the coupling reagent) to obtain the compound represented by formula A-7. In some embodiments, protecting groups such as Boc may need to be removed during the synthesis process. Aldehydes of type A-1 and organometallic compounds of type A-3 are commercially available or can be synthesized from suitable starting materials and reagents.

[0276] Scheme A [ka]

[0277] As shown in Scheme B, the compounds of the present invention can be prepared by activating a appropriately functionalized carboxylic acid B-1 with (COCl)2 or by amide coupling it with amine B-2 to obtain an intermediate represented by B-3. These intermediates are suitable for reaction with various organometallic nucleophiles A-3 to obtain intermediate B-4. Intermediate B-4 can then be subjected to reductive amination in the presence of an amine source and a reducing agent to produce intermediate A-5. In some cases, tert-butansulfinamide may be used as the amine source, and deprotection (in an acidic environment) may be required after reductive amination. Amine A-5 can then be reacted with piperazine A-6 under urea coupling conditions (using triphosgene or CDI as the coupling reagent) to obtain the compound represented by formula A-7. In some embodiments, protecting groups such as Boc may need to be removed during the synthesis process. Type B-1 carboxylic acids and type A-3 organometallics are commercially available or can be synthesized from suitable starting materials and reagents.

[0278] Scheme B [ka] [Examples]

[0279] Examples Examples 1A and 1B (2R)-N-((R)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0280] Step 1: (E)-2-methyl-N-((6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methylene)propan-2-sulfinamide Titanium(IV) isopropoxide (6 mL, 20.27 mmol) was added to a solution prepared by dissolving 6-(2,2,2-trifluoroethoxy)nicotinaldehyde (1.98 g, 9.65 mmol) and 2-methylpropan-2-sulfinamide (1.228 g, 10.13 mmol) in CH2Cl2 (8 mL). The mixture was stirred at room temperature for 20 hours, and then H2O (30 mL) and ethyl acetate (40 mL) were added. The mixture was stirred at room temperature for 20 minutes, and then filtered through a Celite® pad. The separated organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0281] LRMS m / z (M+H): Calculated value 308.3, Measured value 309.2. Step 2: N-((3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide 1-Bromo-3-chloro-2,4-difluorobenzene (277 mg, 1.218 mmol) was dissolved in anhydrous THF and purged with N2 for 5 minutes. Subsequently, 1.3 M isopropylmagnesium chloride-lithium chloride complex (0.938 mL, 1.220 mmol) in THF was added. The mixture was stirred at room temperature for 5 hours, and (E)-2-methyl-N-((6-(2,2,2-trifluoroethoxy)-pyridine-3-yl)methylene)propan-2-sulfinamide (200 mg, 0.649 mmol) was added in small amounts. The reaction was continued at room temperature for 20 hours. The reaction was then quenched with saturated aqueous solution (NH4Cl) and extracted with diethyl ether. The separated organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0282] LRMS m / z (M+H): Calculated value 456.9, Measured value 457.2. Stage 3: (3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methanamine hydrochloride N-((3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)-pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (296 mg, 0.648 mmol) was dissolved in CH2Cl2 (2 mL) and MeOH (1 mL), and HCl (4 M, 2 mL, 8.00 mmol) from 1,4-dioxane was added to the solution. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The resulting residue was treated with diethyl ether (15 mL), filtered, and the solid was collected. The solid was washed with diethyl ether and dried under reduced pressure to obtain the title compound.

[0283] LRMS m / z (M+H): Calculated value 352.7, Measured value 353.2. Stage 4: Examples 1A and 1B (3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methaneamine was dissolved in HCl (98 mg, 0.252 mmol) in CH2Cl2 (3 mL). Et3N (0.176 mL, 1.259 mmol) and triphosgene (74.7 mg, 0.252 mmol) were added to this solution at 0°C. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one (43.1 mg, 0.378 mmol) was added. After stirring at 0°C for 1 hour, the reaction product was heated to room temperature, stirred for 1 hour, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution with 0-4% MeOH / DCM) to obtain a mixture of isomers. The mixture of isomers was further separated using SFC (AD-H column, 35% MeOH cosolvent) to obtain Example 1A (first eluted fraction) and Example 1B (second eluted fraction).

[0284] Example 1A: LRMS m / z (M+H): Calculated 492.8, Example 493.3. 1H NMR δ (ppm) (500 MHz, Chloroform-d): 8.05 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.29 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.32 (d, J = 6.3 Hz, 2H), 5.53 ? 5.31 (m, 1H), 4.77 (q, J = 8.5 Hz, 2H), 4.49 (s, 1H), 4.23 (d, J = 12.5 Hz, 1H), 3.33 (s, 1H), 3.20 (s, 1H), 1.50 (d, J = 5.8 Hz, 3H). Example 1B: LRMS m / z (M+H): calculated 492.8, Example 493.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.04 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 7.1 Hz, 1H), 6.23 (s, 1H), 5.25 (d, J = 7.0 Hz, 1H), 4.76 (q, J = 8.5 Hz, 2H), 4.45 (q, J = 6.7 Hz, 1H), 4.23 (d, J = 12.9 Hz, 1H), 3.57 ? 3.47 (m, 1H), 3.34 (d, J = 10.9 Hz, 1H), 3.23 (t, J = 10.9 Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H). Table 1: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 1A and 1B. [Table 1] TIFF0007846132000024.tif213168TIFF0007846132000025.tif241168TIFF0007846132000026.tif41167

[0285] Examples 12A and 12B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0286] Stage 1: (3-Chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methanone 870 mg, 3.92 mmol of 2-(2,2,2-trifluoroethoxy)pyrimidine-5-carboxylic acid was dissolved in 15.00 mL of DCM. At 0°C, 3.92 mL, 7.83 mmol of 2 M (COCl)2 in DCM and one drop of DMF were added. The reaction mixture was heated to room temperature for 4 hours, then heated to 40°C and stirred for 30 minutes. The mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (4 mL, Solution A). In a separate reaction flask, 1397 mg, 5.09 mmol of 2-chloro-1,3-difluoro-4-iodobenzene (1397 mg, 5.09 mmol) in anhydrous tetrahydrofuran (15 mL) was mixed with 3.92 mL, 5.09 mmol of 1.3 M isopropylmagnesium chloride-lithium chloride complex in THF at 0°C. The mixture was stirred at 0°C for 2 hours, followed by the addition of copper(I) cyanide (526 mg, 5.88 mmol). The mixture was stirred at 0°C for 30 minutes, and then solution A was added. The reaction mixture was maintained at 0°C for 2 hours, then heated to room temperature and stirred for 20 hours. The reaction product was quenched with 40 mL of saturated aqueous solution (NH4Cl) and extracted with ethyl acetate (2 × 40 mL). The organic phases were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0287] LRMS m / z (M+H): Calculated value 352.6, Example 353.1. Step 2: (E)-N-((3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)-methylene)-2-methylpropane-2-sulfinamide 2-methyl-propane-2-sulfinamide (0.516 g, 4.25 mmol), (3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methanone (1.0 g, 2.84 mmol), and titanium(iv) ethoxide (3 mL, 14.31 mmol) were charged into a microwave tube. The mixture was heated in a microwave oven at 110°C for 40 minutes, then cooled to room temperature, poured into brine and ethyl acetate, and filtered through a Celite® pad. The organic phase was separated, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-50% ethyl acetate / hexane) to obtain the title compound.

[0288] LRMS m / z (M+H): Calculated value 455.8, Example 456.2. Step 3: I-((3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methylpropane-2-sulfinamide (E)-N-((3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methylene)-2-methylpropane-2-sulfinamide (800 mg, 1.755 mmol) was dissolved in EtOH (8 mL), and NaBH4 (66.4 mg, 1.755 mmol) was added at 0°C. The mixture was stirred at 0°C for 10 minutes, quenched with H2O, and extracted with diethyl ether. The separated organic phase was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0289] LRMS m / z (M+H): Calculated value 457.8, Example 458.3. Stage 4: (3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methaneamine N-((3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)-methyl)-2-methylpropane-2-sulfinamide (800 mg, 1.747 mmol) was dissolved in CH2Cl2 (8 mL), and 4 M HCl (3 mL, 12.00 mmol) in 1,4-dioxane was added at 0°C. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in 10 mL of DCM, and then NH3 (7N, 5 mL) in MeOH was added. The mixture was stirred for 1 minute and then concentrated. The resulting residue was purified by silica gel column chromatography (eluted with 0-5% MeOH / DCM) to obtain the title compound.

[0290] LRMS m / z (M+H): Calculated value 353.7, Example 354.2. Stage 5: Examples 12A and 12B (3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methaneamine (110 mg, 0.311 mmol) was dissolved in CH2Cl2 (4 mL) and Et3N (0.173 mL, 1.244 mmol) and triphosgene (92 mg, 0.311 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one (53.3 mg, 0.467 mmol) was added. After stirring at 0°C for 1 hour, the reaction product was raised to room temperature and maintained at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (elution with 0-4% MeOH / DCM) to obtain a mixture of isomers. The mixture of isomers was further separated using SFC (OD-H column, 30% EtOH cosolvent) to obtain Example 12A (first eluted fraction) and Example 12B (second eluted fraction).

[0291] Example 12A: LRMS m / z (M+H): calculated 493.8, example 494.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.51 (s, 2H), 7.37 (td, J = 8.3, 5.9 Hz, 1H), 7.07 (t, J = 8.4 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.20 (s, 1H), 6.14 (d, J = 6.6 Hz, 1H), 4.83 (qd, J = 8.3, 2.3 Hz, 2H), 4.62 (q, J = 6.9 Hz, 1H), 4.31 (d, J = 13.3 Hz, 1H), 3.45 (td, J = 11.7, 4.3 Hz, 1H), 3.37 ? 3.27 (m, 1H), 3.22 ? 3.07 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H). Example 12B: LRMS m / z (M+H): calculated 493.8, Example 494.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.48 (s, 2H), 7.32 (q, J = 8.2 Hz, 1H), 7.06 (t, J = 8.3 Hz, 1H), 6.36 (d, J = 7.4 Hz, 1H), 6.31 (s, 1H), 5.85 (s, 1H), 4.82 (q, J = 8.3 Hz, 2H), 4.57 (q, J = 6.8 Hz, 1H), 4.26 (d, J = 13.0 Hz, 1H), 3.49 (td, J = 11.6, 4.1 Hz, 1H), 3.33 (d, J = 11.9 Hz, 1H), 3.27 ? 3.15 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H). Table 2: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 12A and 12B. [Table 2]

[0292] Examples 15A and 15B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0293] Step 1: (E)-2-methyl-N-((6-(trifluoromethyl)pyridine-3-yl)methyl)propan-2-sulfinamide 6-(trifluoromethyl)nicotinaldehyde (447 mg, 2.55 mmol), 2-methylpropane-2-sulfinamide (325 mg, 2.68 mmol), and titanium(IV) isopropoxide (2.5 mL, 8.44 mmol) were combined in a microwave tube. The mixture was heated in a microwave oven at 90°C for 20 minutes, then cooled to room temperature and poured into 30 mL of brine and 50 mL of ethyl acetate. The mixture was filtered through a Celite® pad. The separated organic phase was dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-100% ethyl acetate / hexane) to obtain the title compound.

[0294] LRMS m / z (M+H): Calculated value 278.3, Example 279.2. Stage 2: N-((3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide 1-Bromo-3-chloro-2,4-difluorobenzene (490 mg, 2.156 mmol) was dissolved in anhydrous THF (8 mL), purged with N2 for 5 minutes, and then isopropylmagnesium chloride-lithium chloride complex (1.3 M, 1.658 mL, 2.156 mmol) in THF was added. The mixture was stirred at room temperature for 5 hours, and then (E)-2-methyl-N-((6-(trifluoromethyl)pyridine-3-yl)methylene)propan-2-sulfinamide (300 mg, 1.078 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 20 hours, then quenched with saturated aqueous solution (NH4Cl), and extracted with diethyl ether. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0295] LRMS m / z (M+H): Calculated value 426.8, Example 427.3. Stage 3: (3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methanamine hydrochloride N-((3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (460 mg, 1.078 mmol) was dissolved in CH2Cl2 (1.5 mL) and MeOH (0.5 mL). HCl (4 M, 2 mL, 8.00 mmol) from 1,4-dioxane was added to the solution. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was washed with diethyl ether (2 × 10 mL) and filtered to obtain the title compound.

[0296] LRMS m / z (M+H): Calculated value 322.7, Example 323.2. Stage 4: Examples 15A and 15B (3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methaneamine was dissolved in HCl (120 mg, 0.334 mmol) in CH2Cl2 (4 mL). Et3N (0.233 mL, 1.671 mmol) and triphosgene (99 mg, 0.334 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour, followed by the addition of (R)-3-methylpiperazine-2-one (57.2 mg, 0.501 mmol). The reaction product was stirred at 0°C for 1 hour, then heated 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 of isomers. The mixture of isomers was further separated using SFC (AD-H column, 25% MeOH cosolvent) to obtain Example 15A (first eluted fraction) and Example 15B (second eluted fraction).

[0297] Example 15A: LRMS m / z (M+H): calculated 462.8, Example 463.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.77 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.36 (q, J = 8.2 Hz, 1H), 7.06 (t, J = 8.3 Hz, 1H), 6.51 (d, J = 7.5 Hz, 1H), 6.25 (s, 1H), 6.12 (s, 1H), 4.61 (q, J = 6.7 Hz, 1H), 4.30 (d, J = 12.6 Hz, 1H), 3.44 (td, J = 11.6, 3.9 Hz, 1H), 3.29 (d, J = 11.8 Hz, 1H), 3.22 ? 3.03 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H). Example 15B: LRMS m / z (M+H): calculated 462.8, Example 463.3. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.70 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.05 (t, J = 8.3 Hz, 1H), 6.46 (d, J = 7.3 Hz, 1H), 6.30 (s, 1H), 5.67 (d, J = 7.1 Hz, 1H), 4.52 (q, J = 7.0 Hz, 1H), 4.26 (d, J = 13.7 Hz, 1H), 3.58 ? 3.44 (m, 1H), 3.38 ? 3.30 (m, 1H), 3.27 ? 3.14 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H). Table 3: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 15A and 15B. [Table 3] TIFF0007846132000031.tif212165TIFF0007846132000032.tif244165TIFF0007846132000033.tif178165

[0298] Example 28A (2R)-N-((R or S)-(3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0299] Step 1: (R,E)-2-methyl-N-((2-(trifluoromethyl)pyrimidine-5-yl)methylene)propan-2-sulfinamide 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (1.5 g, 8.52 mmol), (R)-2-methylpropane-2-sulfinamide (1.239 g, 10.22 mmol), and tetraethoxytitanium (5.83 g, 25.6 mmol) were placed in a microwave tube. The mixture was heated in a microwave oven at 90°C for 25 minutes, then cooled to room temperature, and 30 mL of H2O and 50 mL of ethyl acetate were added. The reaction mixture was stirred for 10 minutes and then filtered through a Celite® pad. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-50% ethyl acetate / hexane) to obtain the title compound.

[0300] LRMS m / z (M+H): Calculated value 279.3, Example 280.3. Stage 2: (R)-N-((3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methylpropan-2-sulfinamide (isomer A), and (R)-N-((3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methylpropan-2-sulfinamide (isomer B) (R,E)-2-methyl-N-((2-(trifluoromethyl)pyrimidine-5-yl)methylene)propan-2-sulfinamide (300 mg, 1.074 mmol) was dissolved in THF (8 mL), and 3,4-dichlorophenylmagnesium bromide (1 M, 1.611 mL, 1.611 mmol) in THF was added at -20°C. The reaction mixture was stirred at -20°C for 2 hours, then heated to 0°C and quenched with saturated aqueous solution NH4Cl. The mixture was extracted with diethyl ether, and the separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (eluted with 30% ethyl acetate / hexane) to obtain two fractions: Isomer A (polar fraction); LRMS m / z (M+H): Calculated value 425.0, Example 426.3. And, Isomer B (weakly polar fraction): LRMS m / z (M+H): Calculated value 425.0, Example 426.3. Stage 3: (3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methanamine hydrochloride (R)-N-((3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methylpropane-2-sulfinamide (isomer A, 190 mg, 0.446 mmol) was dissolved in DCM (2 mL), and HCl (4 M, 2 mL, 8.00 mmol) in 1,4-dioxane was added to the solution. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was washed with 2 × 10 mL of diethyl ether and filtered to obtain the title compound.

[0301] LRMS m / z (M+H): Calculated value 321.0, Example 322.2. Stage 4: Example 28A ((3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methaneamine, HCl (55 mg, 0.153 mmol) was dissolved in CH2Cl2 (2 mL) to a solution to which Et3N (0.107 mL, 0.767 mmol) and triphosgene (45.5 mg, 0.153 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one (26.3 mg, 0.230 mmol) was added. The reaction product was stirred at 0°C for 1 hour, and then the temperature was raised to room temperature over 1 hour and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution with 0-4% MeOH / DCM) to obtain Example 28A.

[0302] LRMS m / z (M+H): calculated 461.1, example 462.2. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.91 (s, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 6.59 (s, 1H), 6.34 (d, J = 7.8 Hz, 1H), 6.12 (s, 1H), 4.67 (q, J = 6.8 Hz, 1H), 4.37 (dd, J = 13.7, 3.1 Hz, 1H), 3.44 (td, J = 11.8, 4.3 Hz, 1H), 3.30 (d, J = 12.0 Hz, 1H), 3.20 ? 3.09 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H). Table 4: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedure for Example 28A. [Table 4] TIFF0007846132000036.tif190167

[0303] Example 34 (2R)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0304] Stage 1: (R,E)-N-((5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide (R)-2-methylpropane-2-sulfinamide (1.378 g, 11.37 mmol), 5-fluoro-6-(trifluoromethyl)nicotinaldehyde (1.83 g, 9.48 mmol), titanium(IV) ethoxide (3.97 mL, 18.95 mmol), and toluene (5 mL) were charged into a microwave tube. The mixture was heated in a microwave oven at 100°C for 20 minutes, cooled to room temperature, and then 30 mL of H2O and 100 mL of ethyl acetate were added. The reaction mixture was stirred for 10 minutes and then filtered through a Celite® pad. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-40% ethyl acetate / hexane) to obtain the title compound.

[0305] LRMS m / z (M+H): Calculated value 296.3, Example 279.3. Stage 2: N-((3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (isomer A), and N-((3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (isomer B) 915 mg of 2-chloro-1,3-difluoro-4-iodobenzene (3.33 mmol) was dissolved in 15 mL of anhydrous THF. To this solution, isopropylmagnesium chloride-lithium chloride complex (1.3 M, 1.973 mL, 2.57 mmol) in THF was added at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and then stirred at -20°C for 1 hour. The reaction mixture was cooled again to -78°C, and then (R,E)-N-((5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide (760 mg, 2.57 mmol) was added. The mixture was stirred at -78°C for 1 hour, and then slowly heated to 0°C over 1 hour. The reaction mixture was then quenched with saturated aqueous solution (NH4Cl) and extracted with ethyl acetate. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-40% ethyl acetate / hexane) to obtain a mixture. This mixture was further separated by SFC (AD-H column, 5% MeOH cosolvent) to obtain isomer A (first fraction) and isomer B (second fraction).

[0306] Isomer A: LRMS m / z (M+H): Calculated value 444.8, Example 445.4. Isomer B: LRMS m / z (M+H): Calculated value 444.8, Example 445.4. Stage 3: (3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methanamine hydrochloride N-((3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (isomer A) (800 mg, 1.798 mmol) was dissolved in CH2Cl2 (2 mL) and HCl (4 M, 1 mL, 4.00 mmol) from 1,4-dioxane was added at 0°C. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was washed with 2 × 10 mL of diethyl ether and filtered to obtain the title compound.

[0307] LRMS m / z (M+H): Calculated value 340.6, Example 341.3. Stage 4: Example 34 (3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methaneamine, HCl (129 mg, 0.342 mmol) was dissolved in CH2Cl2 (3 mL). To this solution, Et3N (0.191 mL, 1.368 mmol) and triphosgene (81 mg, 0.274 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one (54.7 mg, 0.479 mmol) was added. The reaction product was stirred at 0°C for 1 hour, then heated to room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution with 0-4% MeOH / DCM) to obtain Example 34.

[0308] LRMS m / z (M+H): calculated value 480.8, example 481.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 8.52 (s, 1H), 7.58 (d, J = 10.4 Hz, 1H), 7.37 ? 7.30 (m, 1H), 7.07 (t, J = 8.3 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 6.13 (s, 1H), 4.65 (q, J = 6.7 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H), 3.48 (td, J = 11.6, 3.9 Hz, 1H), 3.32 (d, J = 11.9 Hz, 1H), 3.23 ? 3.12 (m, 1H), 1.48 (d, J = 7.0 Hz, 3H). Table 5: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedure for Example 34. [Table 5]

[0309] Examples 38A and 38B N-((R or S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide, and N-((R or S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide [ka]

[0310] Stage 1: (R,E)-2-methyl-N-((6-(trifluoromethyl)pyridine-3-yl)methylene)propan-2-sulfinamide 6-(trifluoromethyl)nicotinaldehyde (2.04 g, 11.65 mmol), (R)-2-methylpropane-2-sulfinamide (1.694 g, 13.98 mmol), and tetraisopropoxytitanium (8.62 mL, 29.1 mmol) were combined in a microwave tube. The mixture was heated in a microwave oven at 90°C for 20 minutes, then cooled to room temperature and poured into 30 mL of brine and 100 mL of ethyl acetate. The mixture was filtered through a Celite® pad. The separated organic layer was dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-100% ethyl acetate / hexane) to obtain the title compound.

[0311] LRMS m / z (M+H): Calculated value 278.3, Example 279.2. Stage 2: (R)-N-((3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (isomer A), and (R)-N-((3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (isomer B) To a solution of 2-chloro-1,3-difluoro-4-iodobenzene (4.17 g, 15.20 mmol) dissolved in THF (20 mL), isopropylmagnesium chloride-lithium chloride complex (1.3 M, 11.69 mL, 15.20 mmol) in THF was added at -20°C. The mixture was stirred at -20°C for 2 hours, followed by the addition of (R,E)-2-methyl-N-((6-(trifluoromethyl)pyridine-3-yl)methylene)propan-2-sulfinamide (2.82 g, 10.13 mmol). The reaction mixture was stirred at -20°C for 2 hours, then heated to room temperature, quenched with saturated aqueous solution NH4Cl, and extracted with diethyl ether. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the mixture. The mixture was further separated using SFC (OD-H column, 20% MeOH cosolvent) to obtain isomer A (first fraction) and isomer B (second fraction).

[0312] Stage 3: (3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methanamine hydrochloride (R)-N-((3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide (isomer B, 1.80 g, 4.22 mmol) was dissolved in DCM (8 mL) and MeOH (2 mL), to which HCl (4 M, 6 mL, 24.00 mmol) from 1,4-dioxane was added. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was washed with diethyl ether (2 × 20 mL) and filtered to obtain the title compound.

[0313] LRMS m / z (M+H): Calculated value 322.7, Example 323.2. Stage 4: Examples 38A and 38B (3-chloro-2,4-difluorophenyl)(6-(trifluoro-methyl)pyridine-3-yl)methaneamine was dissolved in HCl (118 mg, 0.329 mmol) in CH2Cl2 (4 mL). Et3N (0.229 mL, 1.643 mmol) and triphosgene (97 mg, 0.329 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour, and then 3-cyclopropylpiperazine-2-one (69.1 mg, 0.493 mmol) was added. After stirring at 0°C for 1 hour, the reaction product was heated to room temperature over 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 the mixture. The mixture was further separated using SFC (OJ-H column, 30% MeOH cosolvent) to obtain Example 38A (first eluted fraction) and Example 38B (second eluted fraction).

[0314] Example 38A: LRMS m / z (M+H): Calculated 488.8, Example 489.5. 1H NMR δ (ppm) (500 MHz, Chloroform-d): 8.78 ? 8.62 (m, 1H), 7.82 ? 7.73 (m, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.30 ? 7.24 (m, 1H), 7.05 (t, J = 8.3 Hz, 1H), 6.57 ? 6.33 (m, 2H), 5.72 (s, 1H), 4.21 (d, J = 6.3 Hz, 1H), 4.14 (d, J = 12.0 Hz, 1H), 3.54 ? 3.37 (m, 3H), 1.30 ? 1.21 (m, 1H), 0.69 (p, J = 9.1 Hz, 1H), 0.59 (dq, J = 17.5, 9.6, 7.4 Hz, 2H), 0.46 (d, J = 5.3 Hz, 1H). Example 38B: LRMS m / z (M+H): Calculated value 488.8, Example 489.5. ¹H NMR δ (ppm) (500 MHz, chloroform-d): 8.73 (s, ¹H), 7.78 (d, J = 8.1 Hz, ¹H), 7.68 (d, J = 8.1 Hz, ¹H), 7.36 - 7.29 (m, ¹H), 7.07 (t, J = 8.3 Hz, ¹H), 6.47 (d, J = 7.6 Hz, ¹H), 6.28 (s, ¹H), 5.78 (s, ¹H), 4.28 (d, J = 6.1 Hz, ¹H), 4.19 - 4.10 (m, ¹H), 3.53 ? 3.35 (m, 3H), 1.24 (d, J = 6.1 Hz, 1H), 0.73 ? 0.66 (m, 1H), 0.59 (ddt, J = 13.0, 9.0, 4.8 Hz, 2H), 0.47 (dt, J = 10.4, 5.3 Hz, 1H). Table 6: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 38A and 38B. [Table 6] TIFF0007846132000041.tif61170

[0315] Example 42 N-((R or S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide [ka]

[0316] Stage 1: (R,E)-N-(3-chloro-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide Titanium(IV) ethoxide (1476 µg, 6.99 mmol), 3-chloro-4-fluorobenzaldehyde (554 mg, 3.49 mmol), and (R)-2-methylpropane-2-sulfinamide (423 mg, 3.49 mmol) were combined in a microwave tube. The mixture was heated in a microwave oven at 70°C for 20 minutes, then cooled to room temperature and poured into 30 mL of brine and 50 mL of ethyl acetate. The mixture was filtered through a Celite® pad, and the separated organic layer was dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound.

[0317] LRMS m / z (M+H): Calculated value 261.7, Example 262.2. Stage 2: (R)-N-((3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (isomer B) To a solution of 2-iodo-6-(trifluoromethyl)pyridine (993 mg, 3.64 mmol) dissolved in THF (15 mL), isopropylmagnesium chloride-lithium chloride complex (1.3 M, 2.97 mL, 3.87 mmol) in THF was added at -78°C. The mixture was stirred at -78°C for 2 hours, followed by the addition of (R,E)-N-(3-chloro-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (880 mg, 3.36 mmol). The mixture was heated to 0°C for 2 hours, then to room temperature, quenched with saturated aqueous solution (NH4Cl), and extracted with diethyl ether. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the mixture. The mixture was further separated using SFC (Whelk-1 column, 15% MeOH cosolvent) to obtain isomer A (the first fraction to elute) and isomer B (the second fraction to elute).

[0318] Stage 3: (3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methanamine hydrochloride (R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (isomer B, 706 mg, 1.727 mmol) was dissolved in CH2Cl2 (10 mL), and HCl (4 M, 2 mL, 8.00 mmol) from dioxane was added to the solution. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was washed with diethyl ether (2 × 10 mL) and filtered to obtain the title compound.

[0319] LRMS m / z (M+H): Calculated value 304.7, Example 305.6. Stage 4: Example 42 (R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methaneamine was dissolved in HCl (15 mg, 0.044 mmol) in CH2Cl2 (1.5 mL). To this solution, Et3N (0.037 mL, 0.264 mmol) and triphosgene (13.05 mg, 0.044 mmol) were added at 0°C. The mixture was stirred at 0°C for 1 hour, followed by the addition of piperazine-2-one (8.80 mg, 0.088 mmol). After stirring at 0°C for 1 hour, the reaction product was heated to room temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-4% MeOH / DCM) to obtain Example 42.

[0320] LRMS m / z (M+H): calculated 430.8, example 431.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.88 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 6.9 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 6.09 (d, J = 4.4 Hz, 1H), 4.23 ? 4.04 (m, 2H), 3.80 ? 3.71 (m, 1H), 3.67 ? 3.58 (m, 1H), 3.42 (s, 2H). Table 7: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedure for Example 42. [Table 7]

[0321] Examples 48A and 48B (2R)-N-((R)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0322] Stage 1: 3-Fluoro-2-(trifluoromethyl)-6-vinylpyridine To a solution prepared by dissolving 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine (2.20 g, 11.03 mmol) in 1,4-dioxane (15 mL), Cs2CO3 (7.18 g, 22.05 mmol), vinylboronic acid pinacol ester (2.81 mL, 16.54 mmol), and water (200 μL) were added. The mixture was purged with N2 for 10 minutes, followed by the addition of 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.359 g, 0.551 mmol). The reaction product was heated to 80°C, stirred for 20 hours, then quenched with H2O and extracted with diethyl ether. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0323] LRMS m / z (M+H): Calculated value 191.1, Example 192.3. Stage 2: 5-Fluoro-6-(trifluoromethyl)picolinealdehyde To a solution of 3-fluoro-2-(trifluoromethyl)-6-vinylpyridine (2000 mg, 10.46 mmol) dissolved in THF (10 mL), water (1 mL), 2.5% osmium tetroxide in t-butanol (3.28 mL, 0.262 mmol), 2,6-dimethylpyridine (2.438 mL, 20.93 mmol), and sodium periodate (8953 mg, 41.9 mmol) were sequentially added at 0°C. The resulting mixture was then heated to room temperature, stirred for 3 hours, diluted with 30 mL of diethyl ether, and filtered. The filtrate was partitioned between diethyl ether and water. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0324] Stage 3: (R,E)-N-((5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide 5-Fluoro-6-(trifluoromethyl)picoline aldehyde (2.0 g, 10.36 mmol) and (R)-2-methylpropane-2-sulfinamide (2.008 g, 16.57 mmol) were dissolved in CH2Cl2 (20 mL), and Cs2CO3 (5.40 g, 16.57 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours, and the solution was filtered through a Celite® pad to remove the solid. After washing with CH2Cl2, the filtrates were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-20% ethyl acetate / hexane) to obtain the title compound.

[0325] LRMS m / z (M+H): Calculated value 296.3, Example 297.3. Stage 4: (R)-N-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide 3-Fluoro-5-iodo-2-(2,2,2-tri-fluoroethoxy)pyridine (399 mg, 1.242 mmol) was dissolved in anhydrous THF (4 mL) and cooled to -78°C. Subsequently, isopropylmagnesium chloride-lithium chloride complex (1.3 M, 1.015 mL, 1.320 mmol) in THF was added. The mixture was stirred at -78°C for 30 minutes and then raised to 0°C. Next, (R,E)-N-((5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (230 mg, 0.776 mmol) in THF (1 mL) was added, and the reaction was stirred at 0°C for 1 hour and then stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous solution NH4Cl. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-20% ethyl acetate / hexane) to obtain the title compound.

[0326] LRMS m / z (M+H): Calculated value 491.4, Example 492.5. Stage 5: (5-Fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-Fluoro-6-(trifluoromethyl)pyridine-2-yl)methanamine hydrochloride (R)-N-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (180 mg, 0.366 mmol) was dissolved in CH2Cl2 (1 mL), and the solution was cooled to 0°C. Subsequently, HCl (4 M, 1 mL, 4.00 mmol) in 1,4-dioxane was added. The reaction mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The resulting residue was washed with 2 × 5 mL of hexane and filtered to obtain the title compound.

[0327] LRMS m / z (M+H): Calculated value 387.2, Example 388.4. Stage 5: Examples 48A and 48B (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methaneamine, HCl (70 mg, 0.165 mmol) was dissolved in CH2Cl2 (2 mL). Et3N (92.14 mL, 0.661 mmol) and triphosgene (49.0 mg, 0.165 mmol) were added to this solution at 0°C. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one (28.3 mg, 0.248 mmol) was added. The reaction product was stirred at 0°C for 1 hour, then heated to room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution with 0-4% MeOH / DCM) to obtain the mixture. The mixture was further separated using SFC (OJ-H column, 10% EtOH + 0.2% DIPEA cosolvent) to obtain Example 48A (first eluted fraction) and Example 48B (second eluted fraction).

[0328] Example 48A: LRMS m / z (M+H): Calculated value 527.4, Example 528.5. 1H NMR δ (ppm) (500 MHz, Chromo-d): 7.96 (d, J = 2.0 Hz, 1H), 7.65 (t, J = 8.9 Hz, 1H), 7.46 (dd, J = 8.7, 3.4 Hz, 1H), 7.35 (dd, J = 10.1, 2.0 Hz, 1H), 6.68 (d, J = 5.9 Hz, 1H), 6.16 (d, J = 5.7 Hz, 1H), 5.94 (s, 1H), 4.83 (dddd, J = 20.9, 12.5, 8.4, 4.0 Hz, 2H), 4.55 ? 4.49 (m, 1H), 4.24 (d, J = 12.2 Hz, 1H), 3.56 ? 3.48 (m, 1H), 3.35 (s, 1H), 3.29 ? 3.20 (m, 1H), 1.52 (d, J = 6.8 Hz, 3H). Example 48B: LRMS m / z (M+H): Calculated value 527.4, Example 528.5. 1H NMR δ (ppm) (500 MHz, Chromo-d): 7.97 (d, J = 2.0 Hz, 1H), 7.65 (t, J = 8.9 Hz, 1H), 7.49 (dd, J = 8.6, 3.4 Hz, 1H), 7.37 (dd, J = 10.1, 2.0 Hz, 1H), 6.64 (d, J = 5.9 Hz, 1H), 6.11 (d, J = 5.8 Hz, 1H), 6.08 (s, 1H), 4.90–4.75 (m, 2H). 4.53 (q, J = 7.0 Hz, 1H), 4.11 (d, J = 13.6 Hz, 1H), 3.52 (td, J = 11.2, 3.7 Hz, 1H), 3.36 (dq, J = 11.6, 3.5 Hz, 1H), 3.28 (ddd, J = 14.1, 10.8, 3.6 Hz, 1H), 1.56 (d, J = 7.1 Hz, 3H). Table 8:The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 48A and 48B. [Table 8] TIFF0007846132000046.tif244168TIFF0007846132000047.tif240168TIFF0007846132000048.tif145167

[0329] Examples 61A and 61B (2R)-N-((R)-(5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0330] Stage 1: 5-Chloro-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide To a solution prepared by dissolving 5-chloro-6-(trifluoromethyl)picolinic acid (1.0 g, 4.43 mmol) in CH2Cl2 (15 mL), N,O-dimethylhydroxylamine HCl (0.649 g, 6.65 mmol), HATU (2.53 g, 6.65 mmol), and DIPEA (2.323 mL, 13.30 mmol) were added. The resulting mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-3% MeOH / DCM) to obtain the title compound.

[0331] LRMS m / z (M+H): Calculated value 268.6, Example 269.3. Step 2: 5-Cyano-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide 5-Chloro-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide (320 mg, 1.191 mmol) was dissolved in DMA (5 mL). Zinc cyanide (280 mg, 2.383 mmol) and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii)methanesulfonate (93 mg, 0.119 mmol) were added under N2. The mixture was heated to 100°C, stirred for 20 hours, then cooled to room temperature and partitioned between ethyl acetate and water. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-40% ethyl acetate / hexane) to obtain the title compound.

[0332] LRMS m / z (M+H): Calculated value 259.2, Example 260.3. Stage 3: 6-(3-fluoro-4-(trifluoromethoxy)benzoyl)-2-(trifluoromethyl)nicotinonitrile A solution of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (385 mg, 1.487 mmol) dissolved in anhydrous THF (5 mL) was purged with N2 for 10 minutes, and then isopropylmagnesium chloride-lithium chloride complex (1.3 M, 1.144 mL, 1.487 mmol) in THF was added. The mixture was heated to 40°C under N2 and stirred for 1 hour. The mixture was then cooled to 0°C, and 5-cyano-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide (257 mg, 0.992 mmol) was added in small amounts. The reaction product was stirred at 0°C under N2 for 3 hours, then quenched with 30 mL of saturated aqueous solution NH4Cl, and extracted with diethyl ether (2 × 20 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0333] LRMS m / z (M+H): Calculated value 378.2, Example 379.0. Stage 4: (R,E)-N-((5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide 6-(3-fluoro-4-(trifluoromethoxy)-benzoyl)-2-(trifluoromethyl)nicotinonitrile (370 mg, 0.978 mmol) and (R)-2-methylpropane-2-sulfinamide (237 mg, 1.957 mmol) were dissolved in toluene (1 mL), and titanium(IV) ethoxide (0.410 mL, 1.957 mmol) was added to the solution. The mixture was heated to 100 °C, stirred for 1 hour, and then cooled to room temperature. H₂O (20 mL) and diethyl ether (50 mL) were added, and the resulting mixture was stirred for 10 minutes, then filtered through a Celite® pad. The organic layer was separated, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound.

[0334] LRMS m / z (M+H): Calculated value 481.4, Example 482.4. Step 5: (R)-N-((5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide (R,E)-N-((5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (471 mg, 0.978 mmol) was dissolved in THF (8 mL) and water (0.5 mL). The solution was cooled to 0°C, and then NaBH4 (111 mg, 2.94 mmol) was added. The mixture was stirred at 0°C for 3 hours and then partitioned between diethyl ether and saturated aqueous solution NaHCO3. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 0-50% ethyl acetate / hexane) to obtain the title compound.

[0335] LRMS m / z (M+H): Calculated value 483.4, Example 484.4. Stage 6: 6-(amino(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-2-(trifluoromethyl)nicotinonitrile hydrochloride (R)-N-((5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide (100 mg, 0.207 mmol) was dissolved in CH2Cl2 (500 μL), and HCl (4 M, 500 μL, 2.000 mmol) from 1,4-dioxane was added to the solution. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was washed with hexane (2 × 5 mL) and filtered to obtain the title compound.

[0336] LRMS m / z (M+H): Calculated value 379.2, Example 380.2. Stage 7: Examples 61A and 61B 6-(amino(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-(trifluoromethyl)nicotinonitrile HCl (80 mg, 0.192 mmol) was dissolved in anhydrous acetonitrile (1.5 mL), and CDI (62.4 mg, 0.385 mmol) was added to the solution. The reaction mixture was stirred under N2 at room temperature for 1 hour, followed by the addition of (R)-3-methylpiperazine-2-one (43.9 mg, 0.385 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative silica gel TLC (eluted with 4% MeOH / DCM) to obtain two fractions.

[0337] Example 61A (weak polarity analysis): LRMS m / z (M+H): Calculated value 519.4, Example 520.5. 1H NMR δ (ppm) (500 MHz, Chromo-holm-d): 8.19 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.22 (dd, J = 10.2, 2.0 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 5.9 Hz, 1H), 6.42 (s, 1H), 6.27 (d, J = 6.1 Hz, 1H). 4.53 (q, J = 7.0 Hz, 1H), 4.23 (d, J = 13.6 Hz, 1H), 3.51 (td, J = 12.1, 11.4, 3.9 Hz, 1H), 3.41 ? 3.30 (m, 1H), 3.24 (ddd, J = 14.1, 11.1, 3.5 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H); And, Example 61B (polarity differentiation): LRMS m / z (M+H): Calculated value 519.4, Example 520.5. 1H NMR δ (ppm) (500 MHz, Chromo-d): 8.20 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.21 (dd, J = 10.2, 1.9 Hz, 1H), 7.19–7.16 (m, 1H), 6.46 (d, J = 5.2 Hz, 1H), 6.26 (s, 1H), 6.21 (d, J = 5.9 Hz, 1H). 4.53 (q, J = 7.0 Hz, 1H), 4.12 (d, J = 13.3 Hz, 1H), 3.52 (td, J = 12.0, 11.4, 3.9 Hz, 1H), 3.41 ? 3.34 (m, 1H), 3.29 (ddd, J = 14.0, 10.8, 3.5 Hz, 1H), 1.56 (d, J = 7.1 Hz, 3H). Examples 62A and 62B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0338] Stage 1: (R,E)-2-methyl-N-((2-(trifluoromethyl)thiazole-5-yl)methylene)propan-2-sulfinamide (R)-(+)-2-methyl-2-propanesulfinamide (0.803 g, 6.62 mmol) and 2-(trifluoromethyl)-1,3-thiazole-5-carbaldehyde (1.0 g, 5.52 mmol) were dissolved in toluene (4 mL), to which titanium(IV) ethoxide (2.315 mL, 11.04 mmol) was added. The mixture was heated to 80°C for 3 hours, then cooled to room temperature, and subsequently H2O (30 mL) and ethyl acetate (50 mL) were added. The mixture was stirred for 10 minutes and then filtered through a Celite® pad. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0339] LRMS m / z (M+H): Calculated value 284.3, Example 285.3. Step 2: (R)-N-((3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methylpropane-2-sulfinamide 2-chloro-1,3-difluoro-4-iodobenzene (420 mg, 1.530 mmol) was dissolved in anhydrous THF (3 mL) and isopropylmagnesium chloride-lithium chloride complex (1.3 M, 1.177 mL, 1.530 mmol) in THF was added at 0°C. The mixture was stirred at 0°C for 1 hour, and then (R,E)-2-methyl-N-((2-(trifluoromethyl)thiazole-5-yl)methylene)propan-2-sulfinamide (290 mg, 1.020 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, and then heated to room temperature for 1 hour. The reaction product was then quenched with saturated aqueous solution NH4Cl and extracted with diethyl ether. The separated organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0340] LRMS m / z (M+H): Calculated value 432.9, Example 433.4. Stage 3: (3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methanamine hydrochloride (R)-N-((3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methylpropane-2-sulfinamide (442 mg, 1.021 mmol) was dissolved in CH2Cl2 (1 mL) and MeOH (0.2 mL), to which HCl (4 M, 1 mL, 4.00 mmol) from 1,4-dioxane was added. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting residue was washed with 2 × 5 mL of diethyl ether and filtered to obtain the title compound.

[0341] LRMS m / z (M+H): Calculated value 328.7, Example 329.3. Stage 4: Examples 62A and 62B (3-chloro-2,4-difluorophenyl)(2-(trifluoro-methyl)thiazole-5-yl)methaneamine was dissolved in CH2Cl2 (8 mL) at 0°C. Triphosgene (146 mg, 0.493 mmol) and Et3N (0.069 mL, 0.493 mmol) were added to the solution. The mixture was stirred at 0°C for 1 hour, and then (R)-3-methylpiperazine-2-one (73.2 mg, 0.641 mmol) was added. After stirring at 0°C for another 1 hour, the reaction product was raised to room temperature and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution with 0-4% MeOH / DCM) to obtain the mixture. The mixture was further separated using SFC (OJ-H column, 10% MeOH cosolvent) to obtain Example 62A (first eluted fraction) and Example 62B (second eluted fraction).

[0342] Example 62A: LRMS m / z (M+H): Calculated value 468.8, Example 469.4. ¹H NMR δ (ppm) (500 MHz, chloroform-d): 7.59 (s, ¹H), 7.36 (q, J = 8.0 Hz, ¹H), 7.08 (t, J = 8.3 Hz, ¹H), 6.62 (d, J = 7.9 Hz, ¹H), 6.32 (s, ¹H), 5.81 (s, ¹H), 4.48 (s, ¹H), 4.24 (d, J = 13.0 Hz, ¹H), 3.63 (s, ¹H), 3.49 (d, J = 15.6 Hz, ¹H), 3.35 (d, J = 10.8 Hz, 1H), 1.53 (d, J = 6.1 Hz, 3H). Example 62B: LRMS m / z (M+H): Calculated value 468.8, Example 469.4. 1H NMR δ (ppm) (500 MHz, chloroform-d): 7.64 (s, 1H), 7.43 - 7.35 (m, 1H), 7.12 - 7.04 (m, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.28 (s, 1H), 6.06 (s, 1H), 4.55 (q, J = 7.0 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 3.54 - 3.45 (m, 1H), 3.37 - 3.28 (m, 1H), 3.19 (ddd, J = 14.3, 11.3, 3.7 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H). Table 9: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 62A and 62B. [Table 9]

[0343] Examples 66A and 66B (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0344] Stage 1: 1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (1.4 g, 8.64 mmol) was dissolved in DCM (30 mL), and CDI (1.400 g, 8.64 mmol) was added at 20 °C. The reaction mixture was stirred for 1 hour, and then TEA (2.408 mL, 17.27 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.842 g, 8.64 mmol) were added. The resulting mixture was stirred for a further 12 hours at 20 °C, and then water (30 mL) was added. The mixture was extracted with DCM (2 × 5 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent 38% ethyl acetate / petroleum ether) to obtain the title compound.

[0345] LRMS m / z (M+H): Calculated value 205.1, Example 206.0. Stage 2: (3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methanone 1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (500 mg, 2.437 mmol) was dissolved in THF (10 mL). To this solution, (4-chloro-3-fluorophenyl)magnesium bromide (0.5 M, 14.62 mL, 7.31 mmol) from THF was added over 5 minutes at -78°C. The mixture was then stirred at 20°C for 1 hour, followed by the addition of saturated aqueous solution NH4Cl (5 mL), and extraction with ethyl acetate. The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column; eluent 2.9% ethyl acetate / petroleum ether) to obtain the title compound.

[0346] 1H NMR (500 MHz, CD3OD) δ 8.44-8.50 (m, 1H), 8.31-8.39 (m, 1H), 8.20-8.26 (m, 1H), 7.55-7.81 (m, 1H), 7.42 (t, J=9.0 Hz, 1H), 7.09-7.15 (m, 1H). Stage 3: (3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methaneamine A mixture of (3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methanone (500 mg, 1.821 mmol) and ammonium acetate (2105 mg, 27.3 mmol) in EtOH (8 mL) was mixed with sodium borohydride (172 mg, 2.73 mmol) at 20 °C. The mixture was stirred at 130 °C for 10 minutes under microwave (biotage initiator). The reaction mixture was then concentrated to remove most of the EtOH, treated with 2N NaOH until pH > 10, and extracted with ethyl acetate (3 × 15 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound.

[0347] LRMS m / z (M+H): Calculated value 275.6, Example 276.3. Stage 4: Examples 66A and 66B A mixture of CDI (176 mg, 1.088 mmol) and (3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methaneamine (150 mg, 0.544 mmol) in DMF (2 mL) was stirred at 20°C for 1 hour. Then, (R)-3-methylpiperazine-2-one (74.5 mg, 0.653 mmol) was added. The resulting mixture was stirred at 20°C for 1 hour. The resulting solid was then filtered off, and the filtrate was purified by Prep-HPLC (64:36 → 34:66; water (0.1% TFA): MeCN (0.1% TFA)) to obtain the mixture. The mixture was further separated using Chiral-SFC (OJ-H column, 25% (0.1% NH3H2O ​​+ EtOH) cosolvent) to obtain Example 66A (first eluted fraction) and Example 66B (second eluted fraction).

[0348] Example 66A: LRMS m / z (M+H): calculated value 415.8, Example 416.1. 1H NMR δ (ppm) (400 MHz, CD3CN0): 7.88-7.94 (m, 1H), 7.13-7.50 (m, 4H), 6.31-6.43 (m, 2H), 6.05-6.13 (m, 2H), 4.34-4.44 (m, 1H), 3.88-3.99 (m, 1H), 3.25-3.36 (m, 1H), 3.14-3.24 (m, 2H), 1.31-1.37 (m, 3H). Example 66B: LRMS m / z (M+H): calculated value 415.8, Example 416.1. 1H NMR δ (ppm) (400 MHz, CD3CN): 7.88-7.94 (m, 1H), 7.11-7.51 (m, 4H), 6.35-6.41 (m, 2H), 6.01-6.16 (m, 2H), 4.41 (q, J=7.2 Hz, 1H), 3.93-4.01 (m, 1H), 3.25-3.34 (m, 1H), 3.13-3.23 (m, 2H), 1.33-1.39 (m, 3H). Table 10: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 66A and 66B. [Table 10]

[0349] Examples 68A and 68B (2R)-N-((R)-(4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0350] Step 1: (E)-2-methyl-N-((2-(trifluoromethyl)pyrimidine-4-yl)methylene)propan-2-sulfinamide A mixture of 2-(trifluoromethyl)pyrimidine-4-carbaldehyde (400 mg, 2.271 mmol) and 2-methylpropane-2-sulfinamide (330 mg, 2.73 mmol) in THF (8 mL) was mixed with tetraisopropoxy-titanium (1291 mg, 4.54 mmol) at 20°C. The resulting mixture was stirred at 20°C for 2 hours, then poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and washed with brine (10 mL), dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column; eluent 18% petroleum ether / ethyl acetate) to obtain the title compound.

[0351] 1 H NMR (400M Hz, CDCl3) δ 9.06 (d, J=5.2 Hz, 1H), 8.72 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 1.29 (s, 9H). Stage 2: N-((4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methylpropane-2-sulfinamide (E)-2-methyl-N-((2-(trifluoromethyl)pyrimidine-4-yl)methylene)propan-2-sulfinamide (300 mg, 1.074 mmol) was dissolved in THF (15 mL). While stirring, (4-chlorophenyl)magnesium bromide (1 M, 2.6 mL, 2.60 mmol) from THF was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours, then quenched with saturated NH4Cl aqueous solution (10 mL), and extracted with ELISA (2 × 10 mL). The organic layers were combined, dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound.

[0352] LRMS m / z (M+H): Calculated value 391.1, Example 392.1. Stage 3: (4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methanamine hydrochloride N-((4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methylpropane-2-sulfinamide (100 mg, 0.255 mmol) was dissolved in MeOH (1.0 mL). While stirring the solution, HCl MeOH (4 M, 1.0 mL) was added at 20°C. The reaction mixture was stirred at 20°C for 12 hours, and then the solvent was removed under reduced pressure to obtain the title compound.

[0353] LRMS m / z (M+H): Calculated value 287.0, Example 288.0. Stage 4: Examples 68A and 68B A solution of CDI (51 mg, 0.315 mmol) dissolved in DMF (2.0 mL) was stirred, and (4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methaneamine hydrochloride (60 mg, 0.209 mmol) from DMF (1.0 mL) was added at 20°C. The reaction mixture was then stirred at 20°C for 30 minutes, and (R)-3-methylpiperazine-2-one (36 mg, 0.315 mmol) was added. The reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was then purified by Prep-HPLC (60:40 → 30:70; water (0.1% TFA): MeCN (0.1% TFA)) to obtain the mixture. The mixture was further separated using a chiral SFC (OD-H column, co-solvent: 30% EtOH + 0.1% NH3H2O) to obtain Example 68A (first eluted fraction) and Example 68B (second eluted fraction).

[0354] Example 68A: LRMS m / z (M+H): calculated value 427.8, Example 428.2. 1H NMR δ (ppm) (400 MHz, CD3OD): 8.88 (d, J=5.2 Hz, 1H), 7.64 (d, J=5.2 Hz, 1H), 7.32-7.39 (m, 4H), 6.15 (s, 1H), 4.60 (q, J=7.2 Hz, 1H), 4.03-4.11 (m, 1H), 3.37-3.45 (m, 2H), 3.21-3.28 (m, 1H), 1.47 (d, J=6.8 Hz, 3H). Example 68B: LRMS m / z (M+H): calculated value 427.8, Example 428.2. 1H NMR δ (ppm) (400 MHz, CD3OD): 8.89 (d, J=5.2 Hz, 1H), 7.68 (d, J=5.2 Hz, 1H), 7.31-7.37 (m, 4H), 6.14 (s, 1H), 4.60 (q, J=7.2 Hz, 1H), 4.02-4.09 (m, 1H), 3.33-3.37 (m, 2H), 3.22-3.29 (m, 1H), 1.40 (d, J=6.8 Hz, 3H). Table 11: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 68A and 68B. [Table 11]

[0355] Examples 70A and 70B (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0356] Stage 1: 6-Chloro-5-fluoro-N-methoxy-N-methylpicorinamide CDI (5.54 g, 34.2 mmol) was added at 20°C to a mixture of 6-chloro-5-fluoropicolinic acid (5 g, 28.5 mmol) in DCM (20 mL). The mixture was stirred under N2 at 20°C for 1 hour. Then, N,O-dimethylhydroxylamine hydrochloride (3.33 g, 34.2 mmol) and triethylamine (12.35 mL, 85 mmol) were added, and the mixture was stirred under N2 at 20°C for 16 hours. The reaction mixture was then diluted with water (50 mL) and extracted with DCM (3 × 30 mL). The organic layers were combined and washed with brine (50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent [0~30]% ethyl acetate / petroleum ether) to obtain the title compound.

[0357] LRMS m / z (M+H): Calculated value 218.1, Example 219.0. Step 2: 5-Fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)picolinamide A mixture of 6-chloro-5-fluoro-N-methoxy-N-methylpicolinamide (3 g, 13.72 mmol), tBuXPhosPd G2 (1.068 g, 1.372 mmol), and Cs2CO3 (9.39 g, 28.8 mmol) in toluene (20 mL) was mixed with 2,2,2-trifluoroethanol (1.098 g, 10.98 mmol) at 20 °C. The mixture was stirred under N2 at 80 °C for 16 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent [0~30]% ethyl acetate / petroleum ether) to obtain the title compound.

[0358] LRMS m / z (M+H): Calculated value 282.1, Example 283.1. Stage 3: (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methanone A solution of 4-bromo-2-chloro-1-fluorobenzene (2.449 g, 11.69 mmol) dissolved in THF (5 mL) was added at 0°C to the THF containing isopropyl magnesium chloride (1.3 M, 6.54 mL, 8.50 mmol), and the mixture was stirred at 20°C for 1 hour. Next, a solution of 5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)picolinamide (1.5 g, 5.32 mmol) dissolved in THF (5 mL) was added, and the resulting mixture was stirred at 20°C for 16 hours. Then, saturated aqueous solution NH4Cl (20 mL) was added to the reaction product, and the mixture was extracted with ELISA (3 × 50 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent 30% ethyl acetate / petroleum ether) to obtain the title compound.

[0359] LRMS m / z (M+H): Calculated value 351.0, Example 352.1. Stage 4: (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methaneamine In a 30 mL microwave vial, (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methanone (300 mg, 0.853 mmol) was dissolved in EtOH (5 mL), to which NH4OAc (986 mg, 12.80 mmol) and NaBH3CN (80 mg, 1.280 mmol) were added. The mixture was stirred and heated in a microwave reactor at 130 °C for 10 minutes. The reaction mixture was then concentrated to remove most of the EtOH, treated with 2N NaOH until pH > 10, and extracted with ELISA (2 × 20 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent [0-30]% ethyl acetate / petroleum ether) to obtain the title compound.

[0360] 1 H NMR (500 MHz, CD3OD-d4) δ 7.61-7.71 (m, 2H), 7.43-7.45 (m, 1H), 7.33 (t, J=8.5 Hz, 1H), 7.07 (dd, J=2.5, 8.0 Hz, 1H), 5.63 (s, 1H), 4.98-5.24 (m, 2H). Stage 5: Examples 70A and 70B A mixture of CDI (101 mg, 0.624 mmol) and (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methanamine (220 mg, 0.624 mmol) in DCM (2 mL) was stirred at 20°C for 1 hour. Then, (R)-3-methylpiperazine-2-one (71.2 mg, 0.624 mmol) was added. The resulting mixture was stirred at 20°C for 16 hours, and then dissolved in water (20 mL) and DCM (20 mL). The organic layer was separated, and the aqueous layer was back-extracted with DCM (3 × 20 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by Prep-HPLC (73:27 → 43:57; water (0.1% TFA): MeCN (0.1% TFA)) to obtain a mixture of isomers. This mixture of isomers was further purified by Chiral-SFC (co-solvent: 0-43% EtOH + 0.05% DEA) to obtain Example 70A (first eluted fraction) and Example 70B (second eluted fraction).

[0361] Example 70A: LRMS m / z (M+H): Calculated value 492.1, Example 493.1. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 7.57 (dd, J=8.0, 10.0 Hz, 1H), 7.45 (dd, J=2.0, 7.2 Hz, 1H), 7.28-7.29 (m, 1H), 7.16-7.24 (m, 1H), 7.07 (dd, J=2.8, 8.4 Hz, 1H), 6.06 (s, 1H), 4.91-4.98 (m, 2H), 4.61 (q, J=7.2 Hz, 1H), 4.02-4.14 (m, 1H), 3.24-3.43 (m, 3H), 1.43 (d, J=7.2 Hz, 3H). Example 70B: LRMS m / z (M+H): Calculated value 492.1, Example 493.1. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 7.57 (dd, J=8.0, 10.0 Hz, 1H), 7.46 (dd, J=2.4, 7.04 Hz, 1H), 7.28-7.29 (m, 1H), 7.16-7.24 (m, 1H), 7.05 (dd, J=2.4, 8.0 Hz, 1H), 6.06 (s, 1H), 4.91-4.98 (m, 2H), 4.61 (q, J=7.2 Hz, 1H), 4.01-4.15 (m, 1H), 3.22-3.43 (m, 3H), 1.44 (d, J=7.2 Hz, 3H). Table 12: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 70A and 70B. [Table 12]

[0362] Examples 72A and 72B (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0363] Step 1: 2-Chloro-6-(difluoromethoxy)pyridine Sodium hydride (0.617 g, 15.44 mmol) was added at 0°C to a mixture of 6-chloropyridine-2-ol in MeCN (15 mL). The reaction mixture was stirred for 1 hour, and then 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.062 g, 11.58 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 12 hours, and then water (40 mL) was added. The mixture was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column; eluent 2.5% petroleum ether / ethyl acetate) to obtain the title compound.

[0364] LRMS m / z (M+H): Calculated value 179.5, Example 180.0. Stage 2: 6-(difluoromethoxy)-N-methoxy-N-methylpicolinamide A mixture of 2-chloro-6-(difluoromethoxy)pyridine (2 g, 11.14 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.630 g, 16.71 mmol) in toluene (15 mL) was mixed with triethylamine (3.38 g, 33.4 mmol), xanthophos (0.645 g, 1.114 mmol), and Pd(OAc)2 (0.150 g, 0.668 mmol). The reaction vessel was degassed and refilled with CO (3 times). The resulting mixture was stirred under CO (pressure: 15 atm) at 80°C for 18 hours, and then cooled to room temperature. Water (250 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and washed with brine (50 mL), dehydrated with Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent 1% petroleum ether / ethyl acetate) to obtain the title compound.

[0365] LRMS m / z (M+H): Calculated value 232.1, Example 233.2. Stage 3: 6-(difluoromethoxy)picolinealdehyde A mixture of 6-(difluoromethoxy)-N-methoxy-N-methylpicolinamide (400 mg, 1.723 mmol) in THF (5 mL) was mixed with DIBAL-H (1 M, 3.45 mL, 3.45 mmol) in toluene at 0°C. The resulting mixture was stirred at 0°C for 1 hour. Water (30 mL) was then added, and the mixture was extracted with DCM (4 × 15 mL). The organic layers were combined and washed with brine (30 mL), dehydrated with Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure to obtain the title compound.

[0366] LRMS m / z (M+H): Calculated value 173.1.0, Example 174.1. Stage 4: (R,E)-N-((6-(difluoromethoxy)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide A mixture of 6-(difluoromethoxy)picoline aldehyde (200 mg crude) in THF (5 mL) was mixed with titanium(IV) ethoxide (0.570 mL, 2.77 mmol) at 0°C. The resulting mixture was stirred at 20°C for 1 hour, then diluted with ethyl acetate (20 mL) and brine (100 mL), and filtered. The filtrate was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined and evaporated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column; eluent 28% petroleum ether / ethyl acetate) to obtain the title compound.

[0367] LRMS m / z (M+H): Calculated value 276.1, Example 277.0. Step 5: (R)-N-((3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide A mixture of (R,E)-N-((6-(difluoromethoxy)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (100 mg, 0.362 mmol) in toluene (1 mL) was mixed with (3-chloro-4-fluorophenyl)magnesium bromide (0.5 M, 2.172 mL, 1.086 mmol) in THF at -45°C. The resulting mixture was stirred at -45°C for 90 minutes. Saturated aqueous solution NH4Cl (10 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (3 × 8 mL). The organic layers were combined and dehydrated with Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain the title compound.

[0368] LRMS m / z (M+H): Calculated value 406.1, Example 407.1. Stage 6: (3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methanamine hydrochloride HCl / MeOH (3 mL, 0.246 mmol) was added to a mixture of (R)-N-((3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide (100 mg, 0.246 mmol) in MeOH (2 mL). The resulting mixture was stirred at 15°C for 1 hour, and then evaporated under reduced pressure to obtain the title compound.

[0369] LRMS m / z (M+H): Calculated value 302, Example 303. Stage 7: Examples 72A and 72B A mixture of (3-chloro-4-fluorophenyl)(6-(difluoro-methoxy)pyridine-2-yl)methaneamine hydrochloride (100 mg crude) and CDI (96 mg, 0.590 mmol) in DMF (1.5 mL) was mixed with DIEA (0.103 mL, 0.590 mmol). The reaction mixture was stirred at 20°C for 2 hours, and then (R)-3-methylpiperazine-2-one (40.4 mg, 0.354 mmol) was added. The resulting mixture was stirred at 20°C for 1 hour, and then purified by reverse-phase HPLC (55:45 → 25:75; water (0.1% TFA): MeCN (0.1% TFA)), followed by lyophilization to obtain a mixture of isomers. The mixture was further separated using Chiral-SFC (column AS-H, cosolvent: 0-43%EtOH + 0.1%NH3H2O) to obtain Example 72A (first eluted fraction) and Example 72B (second eluted fraction).

[0370] Example 72A: LRMS m / z (M+H): Calculated value 442.8, Example 443.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.86 (t, J=8.0 Hz, 1H), 7.49 (dd, J=2.0, 7.0 Hz, 1H), 7.40-7.74 (m, 1H), 7.29-7.35 (m, 1H), 7.19-7.26 (m, 2H), 6.91 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.63 (q, J=7.0 Hz, 1H), 4.05-4.14 (m, 1H), 3.37-3.46 (m, 1H), 3.27-3.33 (m, 2H), 1.46 (d, J=7.0 Hz, 3H). Example 72B: LRMS m / z (M+H): Calculated value 442.8, Example 443.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 7.86 (t, J=8.0 Hz, 1H), 7.44-7.77 (m, 2H), 7.29-7.36 (m, 1H), 7.17-7.26 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.64 (q, J=7.0 Hz, 1H), 4.05-4.17 (m, 1H), 3.37-3.45 (m, 1H), 3.26-3.33 (m, 2H), 1.47 (d, J = 7.0 Hz, 3H). Table 13: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 72A and 72B. [Table 13]

[0371] Examples 75A and 75B (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0372] Step 1: 5-Bromo-2-(1,1-difluoroethyl)pyridine A solution of 1-(5-bromopyridine-2-yl)ethane-1-one (6 g, 30.0 mmol) dissolved in BAST (60 mL) was stirred at 70°C for 2 hours. The reaction mixture was quenched by adding saturated aqueous solution NaHCO3 (100 mL) and extracted with DCM (3 × 50 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column; eluent 0-2% siRNA / petroleum ether) to obtain the title compound.

[0373] 1H NMR (CD3OD, 400MHz) δ 8.71 (d, J=4.0 Hz, 1H), 8.13 (dd, J=8.0 Hz, 8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 1.97 (t, J=8.0 Hz, 3H). Step 2: 2-(1,1-difluoroethyl)-5-vinylpyridine To a mixture of 5-bromo-2-(1,1-difluoroethyl)-pyridine (2.8 g, 12.61 mmol) and 1,4-dioxane (60 mL) in water (12 mL), K2CO3 (3.49 g, 25.2 mmol), potassium trifluoro(vinyl)borate (3.38 g, 25.2 mmol), and Pd(dppf)Cl2 (0.923 g, 1.261 mmol) were added. The reaction mixture was stirred under N2 at 80°C for 18 hours. The reaction product was then quenched with water (100 mL) and extracted with DCM (3 × 80 mL). The organic layers were combined, dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was obtained. The title compound was obtained by purification with 0-1% HCl / petroleum ether.

[0374] LRMS m / z (M+H): Calculated value 169.2, Example 170.1. Stage 3: 6-(1,1-difluoroethyl)nicotinaldehyde 2-(1,1-difluoroethyl)-5-vinylpyridine (1.7 g, 10.05 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL). Sodium periodate (4.30 g, 20.10 mmol) and osmium(VIII) oxide (0.128 g, 0.502 mmol) were added to this solution. The reaction mixture was stirred at 20°C for 18 hours. The mixture was then diluted with water (50 mL) and extracted with SiO2 (3 × 50 mL). The organic layers were combined and washed with brine (50 mL), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with Prep.MPLC (ISCO®; 20 g SepaFlash® Silica Flash Column; eluent 0-1% SiO2 / petroleum ether) to obtain the title compound.

[0375] 1 H NMR (CD3OD, 400MHz) δ 10.15 (s, 1H), 8.69 (s, 1H), 8.02 (dd, J=1.6 Hz, 8.0 Hz, 1H), 7.68-7.71 (m, 1H), 1.97 (t, J=18.0 Hz, 3H). Stage 4: (R,E)-N-((6-(1,1-difluoroethyl)pyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of 6-(1,1-difluoroethyl)nicotinaldehyde (1.7 g, 9.93 mmol) dissolved in THF (30 mL), tetraethoxytitanium (2.266 g, 9.93 mmol) and (R)-2-methylpropane-2-sulfinamide (1.204 g, 9.93 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours and then cooled to room temperature. The mixture was then diluted with ethyl acetate (20 mL) and brine (100 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 50 mL), the organic layers were combined and dehydrated with Na₂SO₄, and filtered. The filtrate was evaporated under reduced pressure to obtain the title compound.

[0376] 1H NMR (CD3OD, 400MHz): δ 9.09 (s, 1H), 8.71 (s, 1H), 8.45 (dd, J=8.0 Hz, 4.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 2.02 (t, J=18.0 Hz, 3H), 1.29 (d, J=4.0 Hz, 9H). Step 5: (R)-N-((3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methylpropane-2-sulfinamide A solution of isopropyl magnesium chloride in THF (2M, 3.83 mL, 7.66 mmol) was mixed with 1-bromo-3-chloro-2,4-difluorobenzene (1741 mg, 7.66 mmol) over 3 hours at 0°C. The resulting mixture was added to a solution of (R,E)-N-((6-(1,1-difluoroethyl)pyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide (700 mg, 2.55 mmol) dissolved in THF (5 mL). The reaction mixture was stirred at 25°C for 18 hours, then water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography (ISCO; 12 g Agela Silica Flash Column; eluent 0-50% siRNA / petroleum ether) to obtain the title compound.

[0377] LRMS m / z (M+H): Calculated value 422.8, Example 423.4. Stage 6: (3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methanamine hydrochloride (R)-N-((3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)-pyridine-3-yl)methyl)-2-methylpropan-2-sulfinamide (140 mg, 0.331 mmol) was dissolved in MeOH (1 mL), and HCl-MeOH (2 M, 1 mL) was added to the solution. The reaction mixture was stirred at 25°C for 2 hours, and then evaporated under reduced pressure to obtain the title compound.

[0378] Stage 7: Examples 75A and 75B (3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methanamine hydrochloride (118 mg crude) was dissolved in DMF (2 mL) and CDI (108 mg, 0.664 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour, and then (R)-3-methylpiperazine-2-one (49.3 mg, 0.432 mmol) was added. The reaction mixture was stirred at 25°C for 18 hours, and then purified by prep-HPLC (80:20 → 50:50; water (0.1% TFA): MeCN (0.1% TFA)) to obtain a mixture of isomers. The mixture of isomers was further separated using Chiral-SFC (column AD-H, cosolvent: 0-30% EtOH + 0.1% NH3H2O) to obtain Example 75A (first eluted fraction) and Example 75B (second eluted fraction).

[0379] Example 75A: LRMS m / z (M+H): Calculated value 458.8, Example 459.1. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 8.52 (s, 1H), 7.80 (dd, J=2.0, 8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.31 (dt, J=6.4, 8.4 Hz, 1H), 7.17 (dt, J=1.6, 8.8 Hz, 1H), 6.47 (s, 1H), 4.59 (q, J=6.8 Hz, 1H), 4.02-4.11 (m, 1H), 3.34-3.43 (m, 1H), 3.21-3.30 (m, 2H), 1.97 (t, J=18.8 Hz, 3H), 1.42 (d, J=7.2 Hz, 3H). Example 75B: LRMS m / z (M+H): Calculated value 458.8, Example 459.1. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 8.54 (d, J=2.0 Hz, 1H), 7.84 (dd, J=2.0, 8.0 Hz, 1H), 7.72 (d. 1H), 3.25-3.32 (m, 2H), 1.99 (t, J=18.4 Hz, 3H), 1.45 (d, J=6.8 Hz, 3H). Examples 76A and 76B (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0380] Stage 1: 3-Chloro-2-(trifluoromethyl)-6-vinylpyridine A mixture of 3,6-dichloro-2-(trifluoromethyl)pyridine (2 g, 9.26 mmol), potassium trifluoro(vinyl)borate (1.861 g, 13.89 mmol), and K2CO3 (2.56 g, 18.52 mmol) in THF (30 mL) and water (3 mL) was mixed with Pd(dppf)Cl2 (0.339 g, 0.463 mmol) under N2 at 20 °C. The reaction mixture was stirred at 80 °C for 12 hours, then water (3 mL) was added, and the mixture was extracted with DCM (3 × 15 mL). The organic layers were combined, dehydrated with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound.

[0381] LRMS m / z (M+H): Calculated value 207.5, Example 208.0. Stage 2: 5-Chloro-6-(trifluoromethyl)picolinealdehyde A mixture of 3-chloro-2-(trifluoromethyl)-6-vinylpyridine (1.922 g, 9.26 mmol), NMO (2.169 g, 18.52 mmol), and OsO4 (4.63 mL, 0.463 mmol) in THF (10 mL) and water (5 mL) was stirred at 20 °C for 12 hours. Then, NaIO4 (5.94 g, 27.8 mmol) was added, and the mixture was stirred at 20 °C for 2 hours. Then, water (60 mL) was added, and the mixture was extracted with DCM (3 × 40 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound.

[0382] LRMS m / z (M+H): Calculated value 209.6, Example 210.0. Stage 3: (R,E)-N-((5-chloro-6-(trifluoromethyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide A mixture of 5-chloro-6-(trifluoromethyl)picolinealdehyde (1.5 g crude) and (R)-2-methylpropane-2-sulfinamide (1.041 g, 8.59 mmol) in THF (5 mL) was mixed with Ti(OEt)4 (2.94 mL, 14.32 mmol) at 15 °C. The reaction mixture was stirred at 80 °C for 1 hour, then diluted with ethyl acetate (60 mL) and brine (150 mL), and filtered. The filtrate was extracted with ELISA (75 mL). The organic layer was dehydrated with Na2SO4, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column; eluent 15% ethyl acetate / petroleum ether) to obtain the title compound.

[0383] 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 1.30 (s, 9H). Stage 4: (R)-N-((5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide A solution of 4-bromobenzonitrile (640 mg, 3.52 mmol) was dissolved in THF (3 mL), to which isopropylmagnesium lithium chloride (1.3 M, 2.460 mL, 3.20 mmol) in THF was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour, and then added to a mixture of (R,E)-N-((5-chloro-6-(trifluoromethyl)pyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 1.599 mmol) in THF (2 mL). The resulting mixture was stirred at 20°C for 1 hour, and then saturated aqueous solution NH4Cl (5 mL) was added, and the mixture was extracted with ELISA (3 × 5 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column; eluent 60% ethyl acetate / petroleum ether) to obtain the title compound.

[0384] LRMS m / z (M+H): Calculated value 415.1, Example 416.1. Stage 5: 4-(amino(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)benzonitrile hydrochloride (R)-N-((5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide (570 mg, 1.371 mmol) was dissolved in MeOH (2 mL), and HCl / MeOH (2 M, 5 mL) was added to the solution. The resulting mixture was stirred at 20°C for 2 hours, and then concentrated under reduced pressure to obtain the title compound.

[0385] LRMS m / z (M+H): Calculated value 311.0, Example 312.0. Stage 6: Examples 76A and 76B A mixture of CDI (104 mg, 0.642 mmol) and 4-(amino(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)benzonitrile hydrochloride (100 mg, 0.321 mmol) in DMF (2 mL) was stirred at 20°C for 1 hour. Then, (R)-3-methylpiperazine-2-one (40.3 mg, 0.353 mmol) was added, and the resulting mixture was stirred at 20°C for 1 hour. The resulting solid was filtered off, and the filtrate was purified by prep-HPLC (80:20 → 50:50; water (0.1% TFA): MeCN (0.1% TFA)) to obtain a mixture of isomers. The mixture of isomers was further separated using Chiral-SFC (column OJ-H, cosolvent: 0-30%EtOH + 0.1%NH3H2O) to obtain Example 76A (first eluted fraction) and Example 76B (second eluted fraction).

[0386] Example 76A: LRMS m / z (M+H): calculated value 451.1, Example 452.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 8.03-8.09 (m, 1H), 7.69-7.75 (m, 2H), 7.58-7.64 (m, 1H), 7.51-7.57 (m, 2H), 6.27 (s, 1H), 4.60 (q, J=7.0 Hz, 1H), 4.05-4.11 (m, 1H), 3.36-3.44 (m, 1H), 3.25-3.30 (m, 2H), 1.44-1.50 (m, 3H). Example 76B: LRMS m / z (M+H): Calculated value 451.1, Example 452.2. 1H NMR δ (ppm) (500 MHz, CD3OD-d4): 8.04-8.10 (m, 1H), 7.69-7.75 (m, 2H), 7.63-7.69 (m, 1H), 7.49-7.55 (m, 2H), 6.26 (s, 1H), 4.59 (q, J=6.5 Hz, 1H), 4.03-4.11 (m, 1H), 3.34-3.40 (m, 1H), 3.25-3.30 (m, 2H), 1.41-1.47 (m, 3H). Table 14:The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 76A and 76B. [Table 14] TIFF0007846132000063.tif75165

[0387] Examples 82A and 82B ((2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and ((2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0388] Stage 1: 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine 3-chloro-2-(trifluoromethyl)pyridine (2.0 g, 11.02 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.20 g, 16.53 mmol) were dissolved in hexane (30 mL). To this solution, 4,4'-di-tert-butyl-2,2'-bipyridine (0.296 g, 1.102 mmol) and bis(1,5-cyclooctadiene)rhodium(i)tetrafluoroborate (0.365 g, 0.551 mmol) were added. The mixture was stirred at 65 °C for 18 hours, then diluted with water (30 mL) and extracted with DCM (3 × 10 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with MPLC (ISCO®; 12 g SepaFlash® Silica Flash Column; eluent 0-8% petroleum ether / siRNA) to obtain the title compound.

[0389] 1 H NMR (400MHz, CDCl3) δ 8.84 (s, 1H), 8.21 (s, 1H), 1.37 (s, 12H). Stage 2: 3-Chloro-5-iodo-2-(trifluoromethyl)pyridine To a solution prepared by dissolving 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (1 g, 3.25 mmol) in DME (15 mL), 1-iodopyrrolidine-2,5-dione (2.195 g, 9.76 mmol), copper(I) iodide (0.062 g, 0.325 mmol), 1,10-phenanthroline (0.059 g, 0.325 mmol), and K2CO3 (0.905 g, 6.50 mmol) were added under N2 conditions. The mixture was stirred at 50°C for 12 hours, then cooled to room temperature, diluted with water (20 mL), and extracted with DCM (3 × 10 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with Prep.TLC (ISCO®; 12 g SepaFlash® Silica Flash Column; eluent 0-1% petroleum ether / siRNA) to obtain the title compound.

[0390] LRMS m / z (M+H): Calculated value 306.9, Example 307.9. Stage 3: (R)-N-((5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methylpropane-2-sulfinamide 3-chloro-5-iodo-2-(trifluoromethyl)pyridine (280 mg, 0.911 mmol) was dissolved in toluene (3 mL), and isopropyl-magnesium lithium chloride (1.3 M, 0.654 mL, 0.851 mmol) in THF was added at -40°C. The mixture was stirred at -40°C for 1 hour, and then (R,E)-N-((5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methylene)-2-methylpropan-2-sulfinamide (intermediate from step 3 of Examples 48A and 48B, 180 mg, 0.608 mmol) in toluene (2 mL) was added. The mixture was stirred at -40°C and then slowly heated to 29°C. The reaction mixture was then stirred at 29°C for 4 hours, quenched with saturated aqueous solution NH4Cl (10 mL), and extracted with siRNA (2 × 10 mL). The organic layers were combined, washed with brine (20 mL), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with Prep.TLC (SiO2, petroleum ether:siRNA = 2:1) to obtain the title compound.

[0391] LRMS m / z (M+H): Calculated value 477.1, Example 478.1 Stage 4: (5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methanamine hydrochloride (R)-N-((5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methylpropan-2-sulfinamide (240 mg, 0.502 mmol) was dissolved in MeOH (2 mL), and HCl / MeOH (4N, 2 mL) was added to the solution. The mixture was stirred at 27°C for 11 hours, and then concentrated under reduced pressure to obtain the title compound.

[0392] LRMS m / z (M+H): Calculated value 373.1, Example 374.1 Stage 5: Examples 82A and 82B (5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methanamine hydrochloride (100 mg crude) was dissolved in DMF (3 mL) and CDI (56.8 mg, 0.351 mmol) was added. The mixture was stirred at 27°C for 1 hour, and then (R)-3-methylpiperazine-2-one (22.01 mg, 0.193 mmol) was added. The reaction mixture was stirred at 27°C for 2 hours, then diluted with MeCN (1 mL), and purified by prep-HPLC (62:38 → 32:68; water (0.1% TFA): MeCN (0.1% TFA)) to obtain a mixture of isomers. The mixture of isomers was further separated by chiral-SFC (column OJ-H, cosolvent: 0-30%EtOH + 0.1%NH3H2O) to obtain Example 82A (first eluted fraction) and Example 82B (second eluted fraction).

[0393] Example 82A: LRMS m / z (M+H): Calculated value 513.8.1, Example 514.2. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 8.61 (d, J=1.6 Hz, 1H), 8.08 (s, 1H), 7.83-7.93 (m, 2H), 6.36 (s, 1H), 4.54-4.62 (m, 1H), 4.00-4.08 (m, 1H), 3.32-3.43 (m, 2H), 3.25-3.29 (m, 1H), 1.44 (d, J=7.2 Hz, 3H). Example 82B: LRMS m / z (M+H): Calculated value 513.8.1, Example 514.2. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 8.61 (d, J=2.0 Hz, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.86-7.93 (m, 1H), 7.79-7.84 (m, 1H), 6.37 (s, 1H), 4.57-4.62 (m, 1H), 3.97-4.18 (m, 1H), 3.32-3.43 (m, 2H), 3.24-3.29 (m, 1H), 1.45 (d, J=7.2 Hz, 3H). Table 15: The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 82A and 82B. [Table 15]

[0394] Examples 85A and 85B (2R)-N-((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide, and (2R)-N-((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide [ka]

[0395] Step 1: N-Methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (1.5 g, 8.33 mmol) was dissolved in DMF (30 mL), and DIEA (4.36 mL, 24.99 mmol) and HATU (6.33 g, 16.66 mmol) were added over 30 minutes at 0°C. N,O-dimethylhydroxylamine hydrochloride (1.219 g, 12.49 mmol) was added, and the resulting mixture was stirred at 25°C for 2 hours. Then, water (150 mL) was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined and washed with brine (100 mL), dehydrated with Na₂SO₄, filtered, and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column; eluent 9% petroleum ether / ethyl acetate) to obtain the title compound.

[0396] LRMS m / z (M+H): Calculated value 223.1, Example 223.9. Stage 2: (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methanone A mixture of N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide (600 mg, 2.69 mmol) in THF (3 mL) was mixed with (3-chloro-4-fluorophenyl)magnesium bromide (13.44 mL, 13.44 mmol, 1 M in THF). The mixture was stirred at 0°C for 2 hours, then aqueous NH4Cl (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to obtain the title compound.

[0397] 1 H NMR (400 MHz, CDCl3) δ 8.10 (dd, J=2.0, 6.8 Hz, 1H), 7.90-7.99 (m, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.08 (s, 1H). Stage 3: (R,Z)-N-((3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methylene)-2-methylpropane-2-sulfinamide Titanium(IV) ethoxide (0.562 mL, 2.73 mmol) was added to a microwave tube containing (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methanone (400 mg, 1.367 mmol), (R)-2-methylpropane-2-sulfinamide (249 mg, 2.050 mmol), and toluene (3 mL). The reaction mixture was heated in a microwave oven at 105°C for 30 minutes and then cooled to room temperature. The resulting crude product (400 mg, crude) was used directly in the next step without further purification.

[0398] Stage 4: (R)-N-((3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methylpropane-2-sulfinamide (R,Z)-N-((3-chloro-4-fluorophenyl)(5-(trifluoro-methyl)-1H-pyrazole-3-yl)methylene)-2-methylpropane-2-sulfinamide (400 mg, crude, from step 3) was dissolved in THF (5 mL) and water (0.01 mL). The solution was cooled to -78 °C, followed by the addition of NaBH4 (57.4 mg, 1.516 mmol). The reaction mixture was stirred at -78 °C for 1 hour, then slowly raised to 0 °C over 1 hour and maintained at 0 °C for 1 hour. The reaction mixture was raised to room temperature, followed by the addition of aqueous NaHCO3 (50 mL), and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and washed with brine (50 mL), dehydrated with Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified using prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain the title compound.

[0399] LRMS m / z (M+H): Calculated value 397.1, Example 398.0. Stage 5: (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methaneamine hydrochloride A mixture of (R)-N-((3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methylpropane-2-sulfinamide (300 mg, 0.754 mmol) in MeOH (1 mL) was mixed with HCl (3 M, 3 mL, 0.754 mmol) in methanol at 25°C. The resulting mixture was stirred at 25°C for 1 hour. The mixture was then evaporated under reduced pressure to obtain the title compound.

[0400] LRMS m / z (M+H): Calculated value 293.1, Example 294.0. Stage 6: Examples 85A and 85B A mixture of (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazole-3-yl)methaneamine hydrochloride (100 mg crude) and CDI (98 mg, 0.606 mmol) in DMF (1 mL) was stirred at 20°C for 10 minutes, and then (R)-3-methylpiperazine-2-one (41.5 mg, 0.364 mmol) in DMF (0.5 mL) was added. The resulting mixture was stirred at 20°C for 1 hour, then purified by reverse-phase HPLC (57:43 → 27:73; water (0.1% TFA): MeCN (0.1% TFA)), and subsequently lyophilized to obtain a mixture of isomers. The mixture of isomers was further separated using Chiral-SFC (column AD-H, cosolvent: 25% IPA + 0.1% NH3, H2O) to obtain Example 85A (first eluted fraction) and Example 85B (second eluted fraction).

[0401] Example 85A: LRMS m / z (M+H): calculated value 433.1, Example 434.1. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 7.47-51 (m, 1H), 7.22-7.35 (m, 2H), 6.31-6.35 (m, 1H), 6.26 (s, 1H), 4.60 (q, J=7.2 Hz, 1H), 3.99-4.12 (m, 1H), 3.34-3.47 (m, 1H), 3.20-3.30 (m, 2H), 1.43 (d, J=7.2 Hz, 3H). Example 85B: LRMS m / z (M+H): Calculated 433.1, Example 434.1. 1H NMR δ (ppm) (400 MHz, CD3OD-d4): 7.45-7.49 (m, 1H), 7.22-7.37 (m, 2H), 6.30-6.34 (m, 1H), 6.18-6.29 (m, 1H), 4.56 (q, J=6.8 Hz, 1H),4.04-4.09 (m, 1H), 3.94-4.19 (m, 1H), 3.33-3.43 (m, 1H), 3.22-3.30 (m, 2H), 1.42 (d, J=7.2 Hz, 3H). Table 16:The following examples were prepared using appropriate starting materials and reagents, in accordance with the synthesis procedures for Examples 85A and 85B. [Table 16]

[0402] Examples of pharmaceutical compositions As a specific embodiment of the oral pharmaceutical composition, a 100 mg tablet is composed of 100 mg of any one of the examples, 268 mg of microcrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg of magnesium stearate. The active substance, microcrystalline cellulose, and croscarmellose are first blended. The mixture is then lubricated with magnesium stearate and compressed to form a tablet.

[0403] Biological assays Qube® Assay Experimental Procedure The compounds were tested against human Nav1.8 and Nav1.5 channels stably expressed in human embryonic kidney (HEK) 293 cells. Sodium current measurements using Qube® were performed as follows: Inhibition of sodium flow through human Nav1.8 and Nav1.5 channels was measured using an automated 384-well patch-clamp assay on the Qube® platform (Sophion Biosciences). Whole cell potential fixation recordings were performed at room temperature using QChips® (Sophion Biosciences). Nav1.8 current measurements using Qube® were obtained as follows: Nav1.8 current was induced with a 10-second 1 Hz pulse train from a holding potential of -90 millivolts (mV), and this current was delivered to cells once every minute under control conditions (DMSO only) and after compound addition. A 1 Hz pulse train stimulation consisted of 10 test pulses up to 10 millivolts (mV) over 20 milliseconds (ms), followed by a 980-millisecond repolarization to -67 millivolts after each test pulse. At the end of the 10-second pulse train stimulation, a 5-second hyperpolarization step down to -100 millivolts (mV) was used to recover Nav1.8 from rapid inactivation. The peak currents induced by the 1st and 10th test pulses were used to determine IC for quiescent state inhibition and inactivation state inhibition. 50 The value was determined. Nav1.5 current measurements in Qube® were obtained as follows: Nav1.5 current was induced with a 20-second 3 Hz pulse train under control conditions (DMSO only) and after compound addition. The pulse train consisted of 60 20-millisecond test pulses from a holding potential of -80 millivolts (mV) to 0 millivolts. The average peak current induced by the last three test pulses was used to determine the IC for Nav1.5 inhibition. 50 The value was determined.

[0404] For Qube® recording, the following buffers were used: External buffer for Nav1.8 Qube® recording: 150 NaCl, 2 CaCl2, 5 KCl, 1 MgCl2, 10 HEPES, 12 Dextrose; External buffer for Qube® Nav1.5 recording: 120 N-methyl-D-glucamine, 40 NaCl, 1 KCl, 2.7 CaCl2, 5 HEPES, 0.5 MgCl2; and Internal buffer for Qube® recording: 120 CsF, 30 CsCl, 10 EGTA, 5 HEPES, 5 NaF, 2MgCl2.

[0405] In all Qube® experiments, offline analysis was used to determine inhibition (%) as a function of drug concentration. 50 The values ​​were determined by applying Hill's formula. The compounds of the present invention showed a Nav1.8 IC of less than 5 micromoles in the Qube® assay. 50 It has a value. Specific IC values ​​of compounds from Examples 1A-87B in the Qube® assay. 50 The values ​​are listed in Table I. [Table 17] TIFF0007846132000069.tif243166TIFF0007846132000070.tif153166

[0406] The scope of the "Claims" should not be limited by the preferred embodiments described above, but rather should be given the broadest interpretation consistent with the overall description.

[0407] While the present invention has been described and illustrated with reference to certain specific embodiments, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions to the procedures and protocols can be made without departing from the scope of the invention. For example, effective dosages other than those specified above may be applicable as a result of variations in the response of mammals treated with the compounds of the present invention shown above for any of the indications. The specific pharmacological response observed may vary, accordingly and in accordance with the selected specific active compound, the presence or absence of a pharmaceutical carrier, and the type of formulation and method of administration used. Such expected variations or differences in the results are intended in accordance with the purpose and practice of the invention.

Claims

1. Structural formula I: 【Chemistry 1】 [During the ceremony, A is, (1) Phenyl, (2) Pyridine, (3) Pyrazole, (4) Oxazoles, and (5) Thiazole Selected from the group consisting of, Here, A is R ａ It is substituted with 1 to 5 substituents selected from; B is, (1) Phenyl, (2) Pyridine, (3) Pyrimidine, (4) Pyrazole, (5) Thiazole, (6) imidazo[1,2-a]pyridine, (7) Oxazole, (8) Benzofuran, (9) Benzoxazole, (10) Indazole, and (11) Thiazolopyridine Independently selected from the group consisting of, Here, B is R ｂ It is substituted with 1 to 5 substituents selected from; R １ , R ２ , R ３ , R ４ and R ５ is hydrogen; R ６ is hydrogen; R ７ is hydrogen; 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 unsubstituted or R ｅ It is substituted with 1 to 5 substituents selected from; 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 substituted with 1 to 5 substituents selected from halogens; 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 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 ) ｐ -OC １－６ Alkyl, (26)-(CH ２ ) ｐ -OC ２－６ Alkenil, (27)-(CH ２ ) ｐ -OC ２－６ Alkinil, (28)-(CH ２ ) ｐ -OC ３－６ Cycloalkyl, (29)-(CH ２ ) ｐ -OC 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 Alkyl 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 ) ｐ -OC １－６ Alkyl, (26)-(CH ２ ) ｐ -OC ２－６ Alkenil, (27)-(CH ２ ) ｐ -OC ２－６ Alkinil, (28)-(CH ２ ) ｐ -OC ３－６ Cycloalkyl, (29)-(CH ２ ) ｐ -OC ２－６ Heterocycloalkyl, (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 Heterocycloalkyl, (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, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and O-C １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; R ｅ teeth, (1) Hydrogen, and (2) C １－６ Alkyl Selected from; 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 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; p is independently selected from 0, 1, 2, and 3; and, r is independently selected from 0, 1, and 2. A compound represented by, however, the following compound 【change】 Compounds other than those specified, or their pharmaceutically acceptable salts.

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

3. B is, (1) Pyridine, (2) Pyrimidine, (3) Pyrazole, (4) Thiazole, and (5) imidazo[1,2-a]pyridine Independently selected from the group consisting of, Here, B is R ｂ Substituted with 1 to 5 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ８ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or R ｅ It is substituted with 1 to 5 substituents selected from; and, R ９ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or substituted with 1 to 5 substituents selected from halogens; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ８ and R ９ It is hydrogen; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. 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 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)-OH, (17)-OC １－６ Alkyl, (18)-OC ３－６ Cycloalkyl, and, (19)-OC 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 Alkyl 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.

7. Each R ａ teeth, (1) CN, (2) Halogen, (3)-C １－６ Alkyl, (4)-C １－６ Alkenil, (5)-C ３－６ Cycloalkyl, (6) Ariel, (7) - OC １－６ Alkyl, and (8) - OC ３－６ Cycloalkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Alkyl 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.

8. 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 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 Heterocycloalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl 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.

9. Each R ｂ teeth, (1) CN, (2) Halogen, (3)-C １－６ Alkyl, (4)-C １－６ Alkenil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7) Ariel, (8) Heteroaryl, (9) - OC １－６ Alkyl, (10)-OC ３－６ Cycloalkyl, and, (11)-OC ２－６ Heterocycloalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl 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.

10. R ８ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, alkyl is either unsubstituted or R ｅ It is substituted with 1 to 5 substituents selected from; R ９ teeth, (1) Hydrogen, and (2)-C １－６ Alkyl Selected from the group consisting of, Here, each alkyl group is either unsubstituted or substituted with 1 to 5 substituents selected from halogens; 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 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)-OH, (17)-OC １－６ Alkyl, (18)-OC ３－６ Cycloalkyl, and, (19)-OC 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 Alkyl 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 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 Heterocycloalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl 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.

11. A is, (1) Phenyl, and (2) Pyridine Selected from the group consisting of, Here, phenyl and pyridine are R ａ It is substituted with 1 to 5 substituents selected from; R ８ and R ９ is hydrogen; Each R ａ teeth, (1) CN, (2) Halogen, (3)-C １－６ Alkyl, (4)-C １－６ Alkenil, (5)-C ３－６ Cycloalkyl, aryl, (6)-OC １－６ Alkyl, and (7) - OC ３－６ Cycloalkyl Independently selected from the group consisting of, Here, each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Alkyl and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; and, Each R ｂ teeth, (1) CN, (2) Halogen, (3)-C １－６ Alkyl, (4)-C １－６ Alkenil, (5)-C ３－６ Cycloalkyl, (6)-C ２－６ Cycloheteroalkyl, (7) Ariel, (8) Heteroaryl, (9) - OC １－６ Alkyl, (10)-OC ３－６ Cycloalkyl, and, (11)-OC ２－６ Heterocycloalkyl Independently selected from the group consisting of, Here, each R ｂ is either not substituted, or halogen, CF ３ OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl 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.

12. below: (1) (2R)-N-((R)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (2) (2R)-N-((S)(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (3) N-((R or S)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (4) N-((S or R)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (5) (2R)-N-((R or S)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (6) (2R)-N-((S or R)-(3-chloro-4-fluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (7) (2R)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (8) (2R)-N-((S or R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (9) (2R)-N-((R)-(4-chlorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (10) (2R)-N-((S)-(4-chlorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (11) (2R)-N-((R)-(3,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (12) (2R)-N-((S)-(3,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (13) (2R)-N-((R)-(3-chloro-4,5-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (14) (2R)-N-((S)-(3-chloro-4,5-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (15) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (16) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (17) (2R)-N-((R)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (18) (2R)-N-((S)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (19) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (20) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (21) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)imidazo[1,2-a]pyridine-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (22) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)imidazo[1,2-a]pyridine-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (23) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (24) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (25) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (26) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (27) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (28) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (29) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (30) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (31) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (32) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (33) (2R)-N-((R)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (34) (2R)-N-((S)-(4-chlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (35) (2R)-N-((R)-(3,4-dichlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (36) (2R)-N-((S)-(3,4-dichlorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (37) (2R)-N-((R)-(4-fluoro-3-(trifluoromethoxy)phenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (38) (2R)-N-((S)-(4-fluoro-3-(trifluoromethoxy)phenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (39) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (40) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (41) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (42) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (43) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(5-chloro-6-(trifluoromethylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (44) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (45) (2R)-N-((R)-(4-chloro-3-cyanophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (46) (2R)-N-((R)-(3-chloro-4-cyanophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (47) (2R)-N-((S)-(3-chloro-4-cyanophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (48) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-cyclopropoxy-3-fluorophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (49) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(4-cyclopropoxy-3-fluorophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (50) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (51) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (52) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclopropylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (53) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclopropylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (54) (2R)-N-((R)-(3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (55) (2R)-N-((S)-(3,4-dichlorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (56) (2R)-N-((R)-(3,4-dichloro-2-fluorophenyl)(6-(trifluoro-methyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (57) (2R)-N-((S)-(3,4-dichloro-2-fluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (58) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (59) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (60) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (61) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (62) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (63) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoro-methyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (64) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-cyclo-propylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (65) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-cyclo-propylpyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (66) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (67) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (68) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (69) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (70) N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (71) N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (72) N-(R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (73) N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoro-methyl)pyridine-3-yl)methyl)-(S or R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (74) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (75) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (76) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-isopropyl-3-oxopiperazine-1-carboxamide; (77) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(S or R)-2-isopropyl-3-oxopiperazine-1-carboxamide; (78) N-((R)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-ethyl-3-oxopiperazine-1-carboxamide; (79) N-((S)-(3-chloro-2,4-difluorophenyl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-(R or S)-2-ethyl-3-oxopiperazine-1-carboxamide; (80) N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-(R or S)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (81) N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-(S or R)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (82) N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (83) N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (84) N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2,2-dimethyl-3-oxopiperazine-1-carboxamide; (85) N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoromethyl)pyridine-2-yl)methyl)-2,2-dimethyl-3-oxopiperazine-1-carboxamide; (86) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (87) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (88) (2S)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (89) (2S)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (90) (3S)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-3-methyl-5-oxopiperazine-1-carboxamide; (91) (3R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-3-methyl-5-oxopiperazine-1-carboxamide; (92) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-(fluoromethyl)-5-oxopiperazine-1-carboxamide; (93) (2S)-N-((S)-(3-chloro-4-fluorophenyl)(6-(trifluoro-methyl)pyridine-2-yl)methyl)-2-(fluoromethyl)-5-oxopiperazine-1-carboxamide; (94) (2R)-N-((R)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (95) (2R)-N-((S)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (96) (2R)-N-((R)-(3,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (97) (2R)-N-((S)-(3,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (98) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (99) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (100) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoro-methoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (101) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (102) (2R)-N-((R)-(4-chloro-3-cyanophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (103) (2R)-N-((S)-(4-chloro-3-cyanophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (104) (2R)-N-((R)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (105) (2R)-N-((S)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (106) N-((R)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (107) N-((S)-(4-chloro-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (108) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (109) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (110) (2R)-N-((R)-(3-fluoro-4-(trifluoromethoxy)phenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (111) (2R)-N-((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (112) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(2,2,2-trifluoroethoxy)phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (113) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(4-(2,2,2-trifluoroethoxy)phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (114) (2R)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(3-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (115) (2R)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)(3-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (116) (2R)-N-((R)-(4-cyclopropoxy-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (117) (2R)-N-((S)-(4-cyclopropoxy-3-fluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (118) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (119) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (120) (2R)-N-((R)-(5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (121) (2R)-N-((S)-(5-cyano-6-(trifluoromethyl)pyridine-2-yl)(3-fluoro-4-(trifluoromethoxy)-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (122) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (123) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)thiazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (124) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (125) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (126) (2R)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (127) (2R)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (128) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(1-(4-fluorophenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (129) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(1-(4-fluorophenyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (130) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (131) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(difluoromethyl)-1H-pyrazole-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (132) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (133) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (134) (2R)-N-((R)-(4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (135) (2R)-N-((S)-(4-chlorophenyl)(2-(trifluoromethyl)pyrimidine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (136) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (137) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(2-(trifluoromethyl)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (138) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (139) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (140) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (141) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(2-(2,2,2-trifluoroethoxy)pyridine-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (142) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (143) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (144) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (145) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(6-(difluoromethoxy)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (146) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (147) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidine-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (148) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (149) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(1,1-difluoroethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (150)x(2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (151) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(4-cyanophenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (152) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (153) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (154) N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (155) N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (156) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (157) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (158) N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (159) N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-3-oxopiperazine-1-carboxamide; (160) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (161) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)(6-(trifluoromethyl)pyridine-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (162) ((2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (163) ((2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(5-fluoro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (164) (2R)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (165) (2R)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (166) (2R)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(2-(trifluoromethyl)thiazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (167) (2R)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridine-3-yl)(2-(trifluoromethyl)thiazole-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (168) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (169) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (170) (2R)-N-((R)-(3-chloro-4-fluorophenyl)(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (171) (2R)-N-((S)-(3-chloro-4-fluorophenyl)(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (172) (2R)-2-methyl-3-oxo-N-((R)-(4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)piperazine-1-carboxamide; And, (173) (2R)-2-methyl-3-oxo-N-((S)-(4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)-1H-pyrazole-5-yl)methyl)piperazine-1-carboxamide; A compound or a pharmaceutically acceptable salt thereof, selected from the above.

13. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. Na ｖ 1. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for preparing agents useful for the treatment of disorders, conditions or diseases in mammals that require treatment in response to inhibition of channel activity.

15. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for manufacturing an agent for treating, preventing or controlling a painful disorder, a cough disorder, an acute pruritic disorder, or a chronic pruritic disorder.

16. The use according to claim 15, wherein the disorder is a painful disorder.

17. The use according to claim 16, wherein the painful disorder is selected from acute pain, inflammatory pain, or neuropathic pain.

18. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in a therapeutic setting.

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