2-oxoimidazolidine-4-carboxamides as nav1.8 inhibitors

Abstract

The novel compounds of structural formula (I) and their pharmaceutically acceptable salts are Na v 1.8 channel activity and can be used in the treatment, prevention, management, amelioration, control and inhibition of diseases mediated by Na v 1.8 channel activity. The compounds of the present invention can be used in the treatment, prevention or management of pain conditions, cough conditions, acute itch conditions and chronic itch conditions.

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)). VGSCs are ubiquitous in the central and peripheral nervous systems, where they play a central role in the initiation and propagation of action potentials, and are also ubiquitous 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 VGSC function or expression can profoundly affect normal cellular excitability (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 an α-subunit forming an ion-conducting aqueous pore and at least one β-subunit altering the channel gating kinetics and voltage dependence. Nine distinct α-subunits, including Na+, have been identified and characterized in mammalian voltage-gated sodium channels. v 1.8, also known as SNS, PN3, or Na v 1.8 (Goldin et al., Neuron. 2000 Nov; 28(2):365-8).

[0003] Sodium channel expression can be tissue-specific. v 1.8 Voltage-gated sodium channels are primarily expressed in sensory neurons responsible for transmitting information from the peripheral nervous system (e.g., skin, muscles, and joints) through the spinal cord to the central nervous system. Sodium channels are an integral part of this process because the initiation and propagation of action potentials triggered by noxious stimuli (thermal, mechanical, and chemical) that activate peripheral nociceptors require sodium channel activity (Catterall et al., NatChem Biol. 2017 Apr 13; 13(5):455-463). Increased levels of VGSC proteins or altered VGSC channel activity at the cell surface can lead to disease states such as migraine, post-ischemic neurodegeneration, epilepsy, and chronic neuropathy and inflammatory pain states. V 1.7, Na V1.8 and Na V The acquisition of functional mutations in 1.9 manifests as 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., PLoSOne. 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 v 1.8 Voltage-gated sodium channels are believed to play a role in various diseases, including neuropathic pain, chronic pruritus, 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 ion channels are conserved across various subtypes, thus serious side effects can occur when using therapeutic agents that do not exhibit subtype selectivity. Therefore, suitable therapeutic agents for addressing nociceptive symptoms, cough, or itching require specificity of action, such as differentiation of sodium ion channels. v 1.5 The role of sodium ion channels (believed to be important in regulating cardiac function) and their effect on Na+ v 1.8 The role of sodium ion channels (considered central to inflammatory nociception), or by dysfunctional and / or upregulated Na+. v 1.8 Itching and symptoms caused by sodium ion channels.

[0006] Therefore, it is believed that Na v 1.8 Inhibitors of voltage-gated sodium ion channel activity can be used to treat or prevent sodium-related disorders. v1.8 Receptors and / or clearly derived from Na+ v 1.8 Diseases, symptoms and ailments of dysfunction of voltage-gated sodium channels (Han et al., J Neurol Neurosurg Psychiatry 2014 May; 85(5):499-505), including but not limited to migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, neuropathic pain, chronic pruritus and pruritus.

[0007] Na is still needed v 1.8 Sodium ion channels have selectively active, readily available Na+ v 1.8 Sodium ion channel activity inhibitors. Therefore, the compounds of the present invention can be used for the treatment and prevention of sodium-related ion channel activity. v 1.8 receptor and Na v 1.8 Diseases, symptoms and morbidity of voltage-gated sodium ion channels.

[0008] The role of Nav1.8 sodium ion channels has been discussed in the following literature: 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 Feb2; 86(5): 473-83; and Flaxman et al., Lancet, 380: 2163-2196 (2012).

[0009] It can be used to treat Na v 1.8 Compounds associated with sodium ion channel-related diseases have been published in the following literature: ACSMed.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 v1.8 Compounds are also disclosed in the following publications: WO 2009 / 049180, WO 2009 / 049181, WO2009 / 049183, WO 2014 / 120808; WO 2014 / 120815; WO 2014 / 120820; WO 2015 / 010065; and WO2015 / 089361; WO 2017 / 209322; US 8,519,137; US 9,051,270; US 9,108,903; US 9,163,042; US 9,783,501; WO 2020 / 092667; WO2019 / 014352; WO2018 / 213426; US 8,629,149; and WO2011 / 026240. Summary of the Invention

[0011] This invention relates to novel compounds of structural formula I:

[0012]

[0013] And its pharmaceutically acceptable salts. Compounds of structural formula I and their embodiments are Na v 1.8 Inhibitors of sodium ion channel activity (or Na+) v 1.8 inhibitors) and can be used to treat and prevent Na+-related diseases. v 1.8 Sodium ion channel activity-mediated diseases, conditions, and ailments, such as nociception, osteoarthritis, peripheral neuropathy, hereditary erythromelalgia, multiple sclerosis, asthma, pruritus, atopic dermatitis, allergic or contact dermatitis, renal failure, cholestasis, pruritus, acute pruritus, chronic pruritus, migraine, post-ischemic neurodegeneration, epilepsy, pain, inflammatory pain, spontaneous pain, acute pain, acute pain due to fracture, 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 caused by 2nd or 3rd degree burns, optic neuritis, pain caused by cancer and chemotherapy, chronic pelvic pain, pain syndromes, and complex regional pain syndromes. In one embodiment of the invention, the ailment, disease, or condition is a pain condition, an acute pain condition, or a chronic pain condition. In another embodiment of the invention, the ailment, disease, or condition is an acute pain condition.

[0014] The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable carriers.

[0015] This invention also relates to the treatment, administration, prevention, relief, improvement, inhibition, or control of potential Na+ sensitivity in subjects by administering the compounds and pharmaceutical compositions of this invention.v 1.8 Methods for inhibiting sodium ion channel activity in response to symptoms, diseases, and patients.

[0016] This invention also relates to the use of compounds of this invention in the manufacture of products that can be used to treat potential sodium allergies. v 1.8 Use of drugs that inhibit sodium ion channel activity in response to diseases, symptoms, and patients.

[0017] The present invention also relates to treating or preventing said diseases, conditions, and ailments by combining the compounds of the present invention with a therapeutically effective amount of another pharmaceutical agent that can be used to treat said diseases, conditions, and ailments. The present invention also relates to a method for preparing the compounds of the present invention. Detailed Implementation

[0018] This invention relates to novel compounds of structural formula I:

[0019]

[0020] Or its pharmaceutically acceptable salt, wherein

[0021] One of A and B is selected from:

[0022] 1) Aryl, and

[0023] 2) Mixed aromatics,

[0024] The aryl and heteroaryl groups are either unsubstituted or substituted by one to five substituents selected from Ra, and

[0025] The other option between A and B is selected from:

[0026] 1) Aryl,

[0027] 2) Mixed aromatics,

[0028] 3)-C1-6 alkyl-aryl,

[0029] 4)-C3-8 cycloalkyl-aryl,

[0030] 5)-C2-8 cyclohexaalkyl-aryl,

[0031] 6)-C1-6 alkyl-heteroaryl,

[0032] 7)-C3-8 cycloalkyl-heteroaryl,

[0033] 8)-C2-8 cycloheteroalkyl-heteroaryl,

[0034] 9)-C1-6 alkyl-O-aryl,

[0035] 10)-C1-6 alkyl-O-heteroaryl,

[0036] 11)-C3-12 cycloalkyl,

[0037] 12)-C2-12 cyclohexaalkyl,

[0038] 13)-C1-6 alkyl-C3-12 cycloalkyl,

[0039] 14)-C1-6 alkyl-C2-12 cyclohexaalkyl,

[0040] 15)-C1-6 alkyl-O-C3-12 cycloalkyl,

[0041] 16)-C1-6 alkyl-O-C2-12 cyclohexaalkyl,

[0042] 17) With C4-6 cycloalkyl groups or containing 1-3 independently selected O, S and N(R) groups. h )2 heteroatom C4-6 cyclic heteroalkyl fused -C0-6 alkyl-aryl,

[0043] 18) With C4-6 cycloalkenyl groups or containing 1-3 independently selected O, S, and N(R) groups. h The heteroatom of the C4-6 cyclohexene fused to a -C0-6 alkyl-aryl group,

[0044] 19) With C4-6 cycloalkyl groups or containing 1-3 independently selected O, S and N(R) groups. h )2 heteroatom of C4-6 cyclic heteroalkyl fused -C0-6 alkyl-heteroaryl, and

[0045] 20) with C4-6 cycloalkenyl groups or containing 1-3 independently selected O, S, and N(R) groups. h The heteroatom of the C4-6 cyclohexene fused to a -C0-6 alkyl-heteroaryl group,

[0046] Wherein, alkyl, cycloalkyl, cyclohexyl, cycloalkenyl, aryl and heteroaryl are either unsubstituted or substituted by one to five substituents selected from Rb;

[0047] R 1 Selected from:

[0048] 1) Hydrogen,

[0049] 2)-C1-6 alkyl,

[0050] 3)-C3-6 alkenyl,

[0051] 4)-C3-6 ynyl group,

[0052] 5)-C3-10 cycloalkyl,

[0053] 6)-C2-10 cyclohexane,

[0054] 7)-C1-6alkyl-O-C1-6alkyl-

[0055] 8)-(CH2)sC(O)Rj,

[0056] 9)-(CH2)sC(O)NReRj,

[0057] 10)-(CH2)nNReC(O)Rj,

[0058] 11)-(CH2)nNReC(O)ORj,

[0059] 12)-(CH2)nNReC(O)N(Re)2,

[0060] 13)-(CH2)nNReC(O)NReRj,

[0061] 14)-(CH2)nNReS(O)mRj,

[0062] 15)-(CH2)nNReS(O)mN(Re)2,

[0063] 16)-(CH2)nNReS(O)mNReRj, and

[0064] 17)-(CH2)nNReRj,

[0065] Each CH2 group, alkyl, alkenyl, ynyl, cycloalkyl, and heteroalkyl group is either unsubstituted or substituted by one to five substituents selected from Rc.

[0066] R 2 Selected from:

[0067] 1) Hydrogen,

[0068] 2)-C1-6 alkyl,

[0069] 3)-C3-6 alkenyl,

[0070] 4)-C3-6 ynyl group,

[0071] 5)-C3-10 cycloalkyl,

[0072] 6)-C2-10 cyclohexane,

[0073] 7)-C1-6alkyl-O-C1-6alkyl-

[0074] 8)-(CH2)sC(O)Rj,

[0075] 9)-(CH2)sC(O)NReRj,

[0076] 10)-(CH2)nNReC(O)Rj,

[0077] 11)-(CH2)nNReC(O)ORj,

[0078] 12)-(CH2)nNReC(O)N(Re)2,

[0079] 13)-(CH2)nNReC(O)NReRj,

[0080] 14)-(CH2)nNReS(O)mRj,

[0081] 15)-(CH2)nNReS(O)mN(Re)2,

[0082] 16)-(CH2)nNReS(O)mNReRj, and

[0083] 17)-(CH2)nNReRj,

[0084] Each CH2 group, alkyl, alkenyl, ynyl, cycloalkyl, and heteroalkyl group is either unsubstituted or substituted by one to five substituents selected from Rd;

[0085] R 3 Selected from:

[0086] 1) Hydrogen,

[0087] 2)-C1-6 alkyl,

[0088] 3)-C2-6 alkenyl,

[0089] 4)-C2-6 ynyl group,

[0090] 5)-C3-10 cycloalkyl,

[0091] 6)-C2-10 cyclohexane,

[0092] 7)-C1-6alkyl-O-C1-6alkyl-

[0093] 8)-(CH2)sC(O)Rj,

[0094] 9)-(CH2)sC(O)NReRj,

[0095] 10)-(CH2)sNReC(O)Rj,

[0096] 11)-(CH2)sNReC(O)ORj,

[0097] 12)-(CH2)sNReC(O)N(Re)2,

[0098] 13)-(CH2)sNReC(O)NReRj,

[0099] 14)-(CH2)sNReS(O)mRj,

[0100] 15)-(CH2)sNReS(O)mN(Re)2,

[0101] 16)-(CH2)sNReS(O)mNReRj, and

[0102] 17)-(CH2)sNReRj,

[0103] Each CH2 group, alkyl, alkenyl, ynyl, cycloalkyl, and cyclohexaalkyl group is either unsubstituted or substituted by one to five substituents selected from Rf, and

[0104] R3 and R4, and the carbon atoms to which they are attached, can form -C3-5 cycloalkyl rings;

[0105] R 4 Selected from:

[0106] 1) Hydrogen,

[0107] 2)-C1-6 alkyl,

[0108] 3)-C2-6 alkenyl,

[0109] 4)-C2-6 ynyl group,

[0110] 5)-C3-10 cycloalkyl,

[0111] 6)-C2-10 cyclohexane,

[0112] 7)-C1-6alkyl-O-C1-6alkyl-

[0113] 8)-(CH2)sC(O)Rj,

[0114] 9)-(CH2)sC(O)NReRj,

[0115] 10)-(CH2)sNReC(O)Rj,

[0116] 11)-(CH2)sNReC(O)ORj,

[0117] 12)-(CH2)sNReC(O)N(Re)2,

[0118] 13)-(CH2)sNReC(O)NReRj,

[0119] 14)-(CH2)sNReS(O)mRj,

[0120] 15)-(CH2)sNReS(O)mN(Re)2,

[0121] 16)-(CH2)sNReS(O)mNReRj, and

[0122] 17)-(CH2)sNReRj,

[0123] Each CH2, alkyl, alkenyl, ynyl, cycloalkyl, and cyclohexaalkyl group is either unsubstituted or substituted by one to five substituents selected from Rg;

[0124] R 5 Selected from:

[0125] 1) Hydrogen, and

[0126] 2)-C1-6 alkyl,

[0127] Each alkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0128] R 6 Selected from:

[0129] 1) Hydrogen,

[0130] 2)-C1-6 alkyl,

[0131] 3)-C3-6 cycloalkyl, and

[0132] 4)-C2-6 cyclohexane,

[0133] Each alkyl, cycloalkyl, and heteroalkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0134] R 7 Selected from:

[0135] 1) Hydrogen,

[0136] 2)-C1-6 alkyl,

[0137] 3)-C2-6 alkenyl, and

[0138] 4)-C2-6 ynyl group,

[0139] Each alkyl, alkenyl, and alkynyl group is either unsubstituted or substituted by one to five halogen substituents;

[0140] Each Ra is selected independently from:

[0141] 1)-CF3,

[0142] 2)-OCF3,

[0143] 3)-CHF2,

[0144] 4)-OCHF2,

[0145] 5)–CH2CF3,

[0146] 6)–OCH2CF3,

[0147] 7)–CF2CH3,

[0148] 8)CN,

[0149] 9) Oxygenation,

[0150] 10) Halogens,

[0151] 11)–S(O)2C1-6 alkyl,

[0152] 12)-C1-6 alkyl,

[0153] 13)-C2-6 alkenyl,

[0154] 14)-C2-6 yntylic group,

[0155] 15)-C3-6 cycloalkyl,

[0156] 16)-C2-6 cyclohexane,

[0157] 17) Aryl,

[0158] 18) Mixed aromatics,

[0159] 19)-C1-6 alkyl-aryl,

[0160] 20)-C1-6 alkyl-heteroaryl,

[0161] 21)-C1-6 alkyl-C3-6 cycloalkyl,

[0162] 22)–C1-6 alkyl-C2-6 cyclohexaalkyl,

[0163] 23)-C2-6 alkenyl-C3-6 cycloalkyl,

[0164] 24)-C2-6 alkenyl-C2-6 cyclohexaalkyl,

[0165] 25)–C2-6 alkenyl-aryl,

[0166] 26)-C2-6 alkenyl-heteroaryl,

[0167] 27)-C2-6 ynyl-C3-6 cycloalkyl,

[0168] 28)-C2-6 ynyl-C2-6 cyclohexaalkyl,

[0169] 29)-C2-6 ynyl-aryl,

[0170] 30)-C2-6 ynyl-heteroaryl,

[0171] 31)-OH,

[0172] 32)-(CH2)p-OC1-6 alkyl,

[0173] 33)-(CH2)p-OC2-6 alkenyl,

[0174] 34)-(CH2)p-OC2-6 ynyl group,

[0175] 35)–(CH2)p-OC3-6 cycloalkyl,

[0176] 36)–(CH2)p-OC2-6 heterocyclic alkyl,

[0177] 37)–(CH2)pO-aryl,

[0178] 38)–(CH2)pO-heteroaryl,

[0179] 39)-OC1-6alkyl-C3-6cycloalkyl,

[0180] 40)-OC1-6alkyl-C2-6 heterocyclic alkyl,

[0181] 41)-OC1-6alkyl-aryl,

[0182] 42)-OC1-6 alkyl-heteroaryl,

[0183] 43)-S(O)mRi,

[0184] 44)-C1-6 alkyl-S(O)mRi,

[0185] 45)-N(Rk)2, and

[0186] 46)–NRkRL,

[0187] Each Ra is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OH, C1-6 alkyl and -OC1-6 alkyl;

[0188] Each Rb is selected independently from:

[0189] 1)-CF3,

[0190] 2)-OCF3,

[0191] 3)-CHF2,

[0192] 4)-OCHF2,

[0193] 5)–CH2CF3,

[0194] 6)–OCH2CF3,

[0195] 7)–CF2CH3,

[0196] 8)CN,

[0197] 9) Oxygenation,

[0198] 10) Halogens,

[0199] 11)–S(O)2C1-6 alkyl,

[0200] 12)-C1-6 alkyl,

[0201] 13)-C2-6 alkenyl,

[0202] 14)-C2-6 yntylic group,

[0203] 15)-O-C1-6 alkyl,

[0204] 16)-C3-6 cycloalkyl,

[0205] 17)-O-C3-6 cycloalkyl,

[0206] 18)-C2-6 cyclohexane,

[0207] 19) Aryl,

[0208] 20) Mixed aryl groups,

[0209] 21)-C1-6 alkyl-aryl,

[0210] 22)-C1-6 alkyl-heteroaryl,

[0211] 23)-C1-6 alkyl-C3-6 cycloalkyl,

[0212] 24)–C1-6 alkyl-C2-6 cyclohexaalkyl,

[0213] 25)-C2-6 alkenyl-C3-6 cycloalkyl,

[0214] 26)-C2-6 alkenyl-C2-6 cyclohexaalkyl,

[0215] 27)–C2-6 alkenyl-aryl,

[0216] 28)-C2-6-enyl-heteroaryl,

[0217] 29)-C2-6 ynyl-C3-6 cycloalkyl,

[0218] 30)-C2-6 ynyl-C2-6 cyclohexaalkyl,

[0219] 31)-C2-6 ynyl-aryl,

[0220] 32)-C2-6 ynyl–heteroaryl,

[0221] 33)-OH,

[0222] 34)-(CH2)q-OC1-6 alkyl,

[0223] 35)-(CH2)q-OC2-6 alkenyl,

[0224] 36)-(CH2)q-OC2-6 ynyl group,

[0225] 37)–(CH2)q-OC3-6 cycloalkyl,

[0226] 38)–(CH2)q-OC2-6 heterocyclic alkyl,

[0227] 39)–(CH2)qO-aryl,

[0228] 40)–(CH2)qO-heteroaryl,

[0229] 41)-OC1-6alkyl-C3-6cycloalkyl,

[0230] 42)-OC1-6alkyl-C2-6 heterocyclic alkyl,

[0231] 43)-OC1-6alkyl-aryl,

[0232] 44)-OC1-6 alkyl-heteroaryl,

[0233] 45)-S(O)mRi,

[0234] 46)-C1-6 alkyl-S(O)mRi,

[0235] 47)-C(O)RL, and

[0236] 48)–NRkRL,

[0237] Each Rb is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl and -OC1-6 alkyl;

[0238] Rc is selected from:

[0239] 1)-C1-6 alkyl,

[0240] 2)OH,

[0241] 3) Halogens, and

[0242] 4)-OC1-6 alkyl,

[0243] The alkyl group may be unsubstituted or substituted with one to three halogens;

[0244] Rd is selected from:

[0245] 1)-C1-6 alkyl,

[0246] 2)OH,

[0247] 3) Halogens, and

[0248] 4)-OC1-6 alkyl,

[0249] The alkyl group may be unsubstituted or substituted with one to three halogens;

[0250] Re is selected from:

[0251] 1) Hydrogen, and

[0252] 2) C1-6 alkyl;

[0253] Rf is selected from:

[0254] 1)-C1-6 alkyl,

[0255] 2)OH,

[0256] 3) Halogens, and

[0257] 4)-OC1-6 alkyl,

[0258] The alkyl group may be unsubstituted or substituted with one to three halogens;

[0259] Rg is selected from:

[0260] 1)-C1-6 alkyl,

[0261] 2)OH,

[0262] 3) Halogens, and

[0263] 4)-OC1-6 alkyl,

[0264] The alkyl group may be unsubstituted or substituted with one to three halogens;

[0265] Rh is selected from:

[0266] 1) Hydrogen, and

[0267] 2) C1-6 alkyl;

[0268] Ri is selected from:

[0269] 1) Hydrogen,

[0270] 2) C1-6 alkyl groups

[0271] 3) C3-6 cycloalkyl groups,

[0272] 4) Aryl, and

[0273] 5) Heteroaryl;

[0274] Rj is selected from:

[0275] 1) Hydrogen,

[0276] 2) C1-6 alkyl groups

[0277] 3) C3-6 alkenyl,

[0278] 4) C3-6 yntylic group.

[0279] 5) C3-6 cycloalkyl groups,

[0280] 6) C2-5 cyclohexaalkyl groups,

[0281] 7) Aryl, and

[0282] 8) Mixed aryl groups;

[0283] Rk is selected from:

[0284] 1) Hydrogen, and

[0285] 2) C1-6 alkyl;

[0286] RL is selected from:

[0287] 1) Hydrogen,

[0288] 2) C1-6 alkyl groups

[0289] 3) C3-6 cycloalkyl groups,

[0290] 4) Aryl, and

[0291] 5) Heteroaryl;

[0292] m is independently selected from 0 to 2;

[0293] n is independently selected from 2 to 6;

[0294] p is independently selected from 0 to 3;

[0295] q is independently selected from 0 to 3;

[0296] r is independently selected from 0 to 2; and

[0297] s is independently selected from 0 to 6.

[0298] The present invention has many embodiments, summarized below. The present invention includes compounds as shown, and also includes individual diastereomers, enantiomers and epimers of the compounds, and mixtures of their diastereomers and / or enantiomers, including racemic mixtures.

[0299] In another embodiment of the invention, one of A and B is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by one to five substituents selected from Ra, and the other of A and B is selected from aryl, heteroaryl, -C1-6 alkyl-aryl, -C3-8 cycloalkyl-aryl, -C2-8 cyclohexaalkyl-aryl, -C1-6 alkyl-hexaaryl, -C3-8 cycloalkyl-hexaaryl, -C2-8 cyclohexaalkyl-hexaaryl. aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteroaryl, -C3-12 cycloalkyl, -C2-12 cycloheteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteroalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, -C1-6 alkyl-O-C2-12 cycloheteroalkyl, and C4-6 cycloalkyl or containing 1-3 independently selected from O, S and N(R) h The heteroatom of the C4-6 cyclohexyl fused -C0-6 alkyl-aryl, with C4-6 cycloalkenyl or containing 1-3 independently selected from O, S and N(R) h The heteroatom of the C4-6 cyclohexene fused with a -C0-6 alkyl-aryl group, or containing 1-3 independently selected O, S, and N(R) atoms. h The heteroatom of the C4-6 cycloheteroalkyl fused to a -C0-6 alkyl-heteroaryl group, and with a C4-6 cycloalkenyl group or containing 1-3 independently selected from O, S and N(R) h The -C0-6 alkyl-heteroaryl group fused with a heteroatom of C4-6 cycloheterenyl is characterized by the presence of an alkyl group, cycloalkyl group, cycloheterenyl group, cycloalkenyl group, aryl group, and heteroaryl group that are either unsubstituted or substituted with one to five substituents selected from Rb. In one embodiment, A and B are independently substituted with 0-4 substituents selected from Rb. In another embodiment, A and B are independently substituted with 0-3 substituents selected from Rb. In yet another embodiment, A and B are independently substituted with 0-2 substituents selected from Rb.

[0300] In another embodiment, one of A and B is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted by one to five substituents selected from Ra, and the other of A and B is selected from aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteraryl, -C3-12 cycloalkyl, -C2-12 cycloheteryl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteryl, -C1-6 alkyl-O-C3-12 cycloalkyl, and C4-6 cycloalkyl or containing 1 to 3 substituents independently selected from O, S, and N(R). hThe -C0-6 alkyl-aryl group fused with a heteroatom of C4-6 cyclohexaalkyl group, wherein the alkyl, cycloalkyl, cyclohexaalkyl, aryl, and heteroaryl groups are unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A and B are independently substituted with 0-4 substituents selected from Rb. In another type of embodiment, A and B are independently substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A and B are independently substituted with 0-2 substituents selected from Rb.

[0301] In another embodiment, one of A and B is selected from aryl and heteroaryl groups, wherein the aryl and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Ra, and the other of A and B is selected from aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteroaryl, -C3-12 cycloalkyl, -C2-12 cycloheteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteroalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, and -C0-6 alkyl-aryl fused with C4-6 cycloalkyl, wherein the alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Rb. In one type of this embodiment, A and B are independently substituted by 0 to 4 substituents selected from Rb. In another type of embodiment, A and B are independently substituted by 0-3 substituents selected from Rb. In yet another type of embodiment, A and B are independently substituted by 0-2 substituents selected from Rb.

[0302] In another embodiment, one of A and B is selected from: phenyl and pyridine, wherein the phenyl and pyridine are unsubstituted or substituted by one to five substituents selected from Ra, and the other of A and B is selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, indole, thiophene, furan, triazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyrazolopyridine, pyrazolopyridine, imidazole[pyridine]oxazolopyridine The compounds include pyridine, pyrazolopyrimidine, imidazopyrimidine, oxazolopyrimidine, thiazopyrimidine, -(CH2)2-phenyl, -CH2-O-phenyl, -CH2-O-pyridine, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentane, spiro[3.3]heptane, azacyclobutane, piperidine, tetrahydropyran, tetrahydrofuran, azabicyclo[3.1.0]hexane, -CH2-cyclohexyl, -CH2-tetrahydropyran, and bicyclo[4.2.0]octtriene, wherein the alkyl, cycloalkyl, cyclohexyl, aryl, and heteroaryl groups are unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A and B are independently substituted with 0-4 substituents selected from Rb. In another type of embodiment, A and B are independently substituted with 0-3 substituents selected from Rb. In another type of implementation, A and B are independently substituted by 0-2 substituents selected from Rb.

[0303] In another embodiment, one of A and B is selected from: phenyl and pyridine, wherein the phenyl and pyridine are unsubstituted or substituted by one to five substituents selected from Ra, and the other of A and B is selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, -(CH2)2-phenyl, - CH2-O-phenyl, -CH2-O-pyridine, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentane, spiro-[3.3]heptane, azacyclobutane, piperidine, tetrahydropyran, tetrahydrofuran, azabicyclo[3.1.0]hexane, -CH2-cyclohexyl, -CH2-tetrahydropyran, and bicyclo[4.2.0]octtriene, wherein the alkyl, cycloalkyl, cyclohexyl, aryl, and heteroaryl groups are unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A and B are independently substituted with 0-4 substituents selected from Rb. In another type of embodiment, A and B are independently substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A and B are independently substituted with 0-2 substituents selected from Rb.

[0304] In another embodiment, one of A and B is an aryl group, wherein the aryl group is unsubstituted or substituted with one to five substituents selected from Ra, and the other of A and B is selected from aryl, heteroaryl, and -C3-12 cycloalkyl groups, wherein the cycloalkyl, aryl, and heteroaryl groups are unsubstituted or substituted with one to five substituents selected from Rb. In one type of this embodiment, A and B are independently substituted with 0 to 4 substituents selected from Rb. In another type of this embodiment, A and B are independently substituted with 0 to 3 substituents selected from Rb. In yet another type of this embodiment, A and B are independently substituted with 0 to 2 substituents selected from Rb.

[0305] In another embodiment, one of A and B is phenyl, wherein the phenyl is unsubstituted or substituted with one to five substituents selected from Ra, and the other of A and B is selected from phenyl, pyridine, thiazole, and cyclobutene, wherein the phenyl, pyridine, thiazole, and cyclobutene are unsubstituted or substituted with one to five substituents selected from Rb. In one type of this embodiment, A and B are independently substituted with 0-4 substituents selected from Rb. In another type of this embodiment, A and B are independently substituted with 0-3 substituents selected from Rb. In yet another type of this embodiment, A and B are independently substituted with 0-2 substituents selected from Rb.

[0306] In another embodiment of the invention, A is selected from aryl and heteroaryl groups, wherein A is unsubstituted or substituted by one to five substituents selected from Ra. In one type of embodiment, A is substituted by 0-4 substituents selected from Ra. In another type of embodiment, A is substituted by 0-3 substituents selected from Ra. In yet another type of embodiment, A is substituted by 0-2 substituents selected from Ra.

[0307] In another embodiment, A is selected from phenyl and pyridine, wherein A is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, A is substituted with 0-4 substituents selected from Ra. In another type of embodiment, A is substituted with 0-3 substituents selected from Ra. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Ra.

[0308] In another embodiment, A is an aryl group, wherein the aryl group is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, the aryl group is substituted with 0-4 substituents selected from Ra. In another type of embodiment, the aryl group is substituted with 0-3 substituents selected from Ra. In yet another type of embodiment, the aryl group is substituted with 0-2 substituents selected from Ra.

[0309] In another embodiment, A is phenyl, wherein the phenyl group is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, the phenyl group is substituted with 0-4 substituents selected from Ra. In another type of embodiment, the phenyl group is substituted with 0-3 substituents selected from Ra. In yet another type of embodiment, the phenyl group is substituted with 0-2 substituents selected from Ra.

[0310] In another embodiment, A is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C3-8 cycloalkyl-aryl, -C2-8 cycloheteroalkyl-aryl, -C1-6 alkyl-heteroaryl, -C3-8 cycloalkyl-heteroaryl, -C2-8 cycloheteroalkyl-heteroaryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteroaryl, -C3-12 cycloalkyl, -C2-12 cycloalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, -C1-6 alkyl-O-C2-12 cycloalkyl, and C4-6 cycloalkyl or containing 1-3 independently selected from O, S, and N(R) h The heteroatom of the C4-6 cyclohexyl fused -C0-6 alkyl-aryl, with C4-6 cycloalkenyl or containing 1-3 independently selected from O, S and N(R) h The heteroatom of the C4-6 cyclohexene fused with a -C0-6 alkyl-aryl group, or containing 1-3 independently selected O, S, and N(R) atoms. h The heteroatom of the C4-6 cycloheteroalkyl fused to a -C0-6 alkyl-heteroaryl group, and with a C4-6 cycloalkenyl group or containing 1-3 independently selected from O, S and N(R) h The heteroatom of 2 is a C4-6 cyclohexene fused to a -C0-6 alkyl-heteroaryl group, wherein A is unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Rb.

[0311] In another embodiment, A is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C3-8 cycloalkyl-aryl, -C2-8 cycloheteroalkyl-aryl, -C1-6 alkyl-heteroaryl, -C3-8 cycloalkyl-heteroaryl, -C2-8 cycloheteroalkyl-heteroaryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteroaryl, -C3-12 cycloalkyl, -C2-12 cycloheteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1- The following are alkyl-C2-12 cycloheteroalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, -C1-6 alkyl-O-C2-12 cycloheteroalkyl, -C0-6 alkyl-aryl fused with C4-6 cycloalkyl, -C0-6 alkyl-aryl fused with C4-6 cycloalkenyl, -C0-6 alkyl-heteroaryl fused with C4-6 cycloalkyl, and -C0-6 alkyl-heteroaryl fused with C4-6 cycloalkenyl, wherein A is unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Rb.

[0312] In another embodiment, A is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteraryl, -C3-12 cycloalkyl, -C2-12 cycloheteryl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteryl, -C1-6 alkyl-O-C3-12 cycloalkyl, and C4-6 cycloalkyl or containing 1-3 independently selected from O, S, and N(R) h The -C0-6 alkyl-aryl group fused with a heteroatom of C4-6 cyclohexaalkyl group, wherein A is unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Rb.

[0313] In another embodiment, A is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteraryl, -C3-12 cycloalkyl, -C2-12 cycloheteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteroalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, and -C0-6 alkyl-aryl fused with C4-6 cycloalkyl, and wherein A is unsubstituted or substituted by one to five substituents selected from Rb. In one type of this embodiment, A is substituted by 0-4 substituents selected from Rb. In another type of this embodiment, A is substituted by 0-3 substituents selected from Rb. In yet another type of this embodiment, A is substituted by 0-2 substituents selected from Rb.

[0314] In another embodiment, A is independently selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, indole, thiophene, furan, triazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyrazolopyridine, pyrazolopyridine, imidazole[pyridine], oxazolopyridine, pyrazolopyrimidine, imidazole[pyrimidine], -(C The following compounds are used: H2)2-phenyl, -CH2-O-phenyl, -CH2-O-pyridine, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, spiro[3.3]heptane, azacyclobutane, piperidine, tetrahydropyran, tetrahydrofuran, azabicyclo[3.1.0]hexane, -CH2-cyclohexane, -CH2-tetrahydropyran, -CH2-O-cyclohexane, and bicyclo[4.2.0]octtriene, wherein A is unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Rb.

[0315] In another embodiment, A is independently selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, -(CH2)2-phenyl, -CH2-O-phenyl, -CH2-O-pyridine, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, spiro[3.3]heptane, azacyclobutane, piperidine, tetrahydropyran, tetrahydrofuran, azabicyclo[3.1.0]hexane, -CH2-cyclohexane, -CH2-tetrahydropyran, -CH2-O-cyclohexane, and bicyclo[4.2.0]octtriene, and wherein A is unsubstituted or substituted by one to five substituents selected from Rb. In one type of embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Rb.

[0316] In another embodiment, A is independently selected from aryl, heteroaryl, and -C3-12 cycloalkyl groups, wherein the cycloalkyl, aryl, and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Rb. In one type of this embodiment, A is substituted by 0-4 substituents selected from Rb. In another type of this embodiment, A is substituted by 0-3 substituents selected from Rb. In yet another type of this embodiment, A is substituted by 0-2 substituents selected from Rb.

[0317] In another embodiment, A is independently selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, and spiro[3.3]heptane, and wherein A is unsubstituted or substituted with one to five substituents selected from Rb. In one type of this embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of this embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of this embodiment, A is substituted with 0-2 substituents selected from Rb.

[0318] In another embodiment, A is independently selected from phenyl, pyridine, thiazole, and cyclobutane, wherein A is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, A is substituted with 0-4 substituents selected from Rb. In another type of embodiment, A is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, A is substituted with 0-2 substituents selected from Rb.

[0319] In another embodiment of the invention, B is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C3-8 cycloalkyl-aryl, -C2-8 cyclo-heteroalkyl-aryl, -C1-6 alkyl-heteroaryl, -C3-8 cycloalkyl-heteroaryl, -C2-8 cyclo-heteroalkyl-heteroaryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteroaryl, -C3-12 cycloalkyl, -C2-12 cyclo-heteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cyclo-heteroalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, -C1-6 alkyl-O-C2-12 cyclo-heteroalkyl, and C4-6 cycloalkyl or containing 1-3 independently selected from O, S and N(R). h The heteroatom of the C4-6 cyclohexyl fused -C0-6 alkyl-aryl, with C4-6 cycloalkenyl or containing 1-3 independently selected from O, S and N(R) h The heteroatom of the C4-6 cyclohexene fused with a -C0-6 alkyl-aryl group, or containing 1-3 independently selected O, S, and N(R) atoms. h The heteroatom of the C4-6 cycloheteroalkyl fused to a -C0-6 alkyl-heteroaryl group, and with a C4-6 cycloalkenyl group or containing 1-3 independently selected from O, S and N(R) h The heteroatom of B is a C4-6 cyclohexene-fused -C0-6 alkyl-heteroaryl group, wherein the alkyl, cycloalkyl, cyclohexene, cycloalkenyl, aryl, and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Rb. In one type of embodiment, B is substituted by 0-4 substituents selected from Rb. In another type of embodiment, B is substituted by 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted by 0-2 substituents selected from Rb.

[0320] In another embodiment, B is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C3-8 cycloalkyl-aryl, -C2-8 cycloheteroalkyl-aryl, -C1-6 alkyl-heteroaryl, -C3-8 cycloalkyl-heteroaryl, -C2-8 cycloheteroalkyl-heteroaryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteroaryl, -C3-12 cycloalkyl, -C2-12 cycloheteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteroalkyl Alkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, -C1-6 alkyl-O-C2-12 cyclo-heteroalkyl, -C0-6 alkyl-aryl fused with C4-6 cycloalkyl, -C0-6 alkyl-aryl fused with C4-6 cycloalkenyl, -C0-6 alkyl-heteroaryl fused with C4-6 cycloalkyl, and -C0-6 alkyl-heteroaryl fused with C4-6 cyclo-alkenyl, wherein the alkyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, aryl, and heteroaryl groups are unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, B is substituted with 0-4 substituents selected from Rb. In another type of embodiment, B is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted with 0-2 substituents selected from Rb.

[0321] In another embodiment, B is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteraryl, -C3-12 cycloalkyl, -C2-12 cycloheteryl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteryl, -C1-6 alkyl-O-C3-12 cycloalkyl, and contains 0-3 independently selected from O, S, and N(R). h The heteroatom of B is a C4-6 cycloalkyl-fused -C0-6 alkyl-aryl group, wherein the alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Rb. In one type of embodiment, B is substituted by 0-4 substituents selected from Rb. In another type of embodiment, B is substituted by 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted by 0-2 substituents selected from Rb.

[0322] In another embodiment, B is independently selected from: aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-O-aryl, -C1-6 alkyl-O-heteraryl, -C3-12 cycloalkyl, -C2-12 cycloheteroalkyl, -C1-6 alkyl-C3-12 cycloalkyl, -C1-6 alkyl-C2-12 cycloheteroalkyl, -C1-6 alkyl-O-C3-12 cycloalkyl, and -C0-6 alkyl-aryl fused with a C4-6 cycloalkyl group, wherein the alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Rb. In one type of this embodiment, B is substituted by 0-4 substituents selected from Rb. In another type of this embodiment, B is substituted by 0-3 substituents selected from Rb. In yet another type of this embodiment, B is substituted by 0-2 substituents selected from Rb.

[0323] In another embodiment, B is independently selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, indole, thiophene, furan, triazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyrazolopyridine, pyrazolopyridine, imidazole[pyridine], oxazolopyridine, pyrazolopyrimidine, imidazole[pyrimidine], -(C The following compounds are used: (H2)2-phenyl, -CH2-O-phenyl, -CH2-O-pyridine, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, spiro[3.3]heptane, azacyclobutane, piperidine, tetrahydropyran, tetrahydrofuran, azabicyclo[3.1.0]hexane, -CH2-cyclohexane, -CH2-tetrahydropyran, -CH2-O-cyclohexane, and bicyclo[4.2.0]octtriene, wherein B is unsubstituted or substituted with one to five substituents selected from Rb. In one type of embodiment, B is substituted with 0-4 substituents selected from Rb. In another type of embodiment, B is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted with 0-2 substituents selected from Rb.

[0324] In another embodiment, B is independently selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, -(CH2)2-phenyl, -CH2-O-phenyl, -CH2-O-pyridine, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, spiro[3.3]heptane, azacyclobutane, piperidine, tetrahydropyran, tetrahydrofuran, azabicyclo[3.1.0]hexane, -CH2-cyclohexane, -CH2-tetrahydropyran, -CH2-O-cyclohexane, and bicyclo[4.2.0]octtriene, and wherein B is unsubstituted or substituted by one to five substituents selected from Rb. In one type of embodiment, B is substituted with 0-4 substituents selected from Rb. In another type of embodiment, B is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted with 0-2 substituents selected from Rb.

[0325] In another embodiment, B is independently selected from aryl, heteroaryl, and C3-12 cycloalkyl groups, wherein the cycloalkyl, aryl, and heteroaryl groups are unsubstituted or substituted by one to five substituents selected from Rb. In one type of embodiment, B is substituted by 0-4 substituents selected from Rb. In another type of embodiment, B is substituted by 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted by 0-2 substituents selected from Rb.

[0326] In another embodiment, B is independently selected from: phenyl, pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, and spiro[3.3]heptane, and wherein B is unsubstituted or substituted with one to five substituents selected from Rb. In one type of this embodiment, B is substituted with 0-4 substituents selected from Rb. In another type of this embodiment, B is substituted with 0-3 substituents selected from Rb. In yet another type of this embodiment, B is substituted with 0-2 substituents selected from Rb.

[0327] In another embodiment, B is independently selected from phenyl, pyridine, thiazole, and cyclobutane, wherein B is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, B is substituted with 0-4 substituents selected from Rb. In another type of embodiment, B is substituted with 0-3 substituents selected from Rb. In yet another type of embodiment, B is substituted with 0-2 substituents selected from Rb.

[0328] In one embodiment, B is selected from aryl and heteroaryl groups, wherein B is unsubstituted or substituted by one to five substituents selected from Ra. In one type of embodiment, B is substituted by 0-4 substituents selected from Ra. In another type of embodiment, B is substituted by 0-3 substituents selected from Ra. In yet another type of embodiment, B is substituted by 0-2 substituents selected from Ra.

[0329] In another embodiment, B is selected from phenyl and pyridine, wherein B is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, B is substituted with 0-4 substituents selected from Ra. In another type of embodiment, B is substituted with 0-3 substituents selected from Ra. In yet another type of embodiment, B is substituted with 0-2 substituents selected from Ra.

[0330] In another embodiment, B is an aryl group, wherein the aryl group is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, the aryl group is substituted with 0-4 substituents selected from Ra. In another type of embodiment, the aryl group is substituted with 0-3 substituents selected from Ra. In yet another type of embodiment, the aryl group is substituted with 0-2 substituents selected from Ra.

[0331] In another embodiment, B is phenyl, wherein the phenyl group is unsubstituted or substituted with one to five substituents selected from Ra. In one type of embodiment, the phenyl group is substituted with 0-4 substituents selected from Ra. In another type of embodiment, the phenyl group is substituted with 0-3 substituents selected from Ra. In yet another type of embodiment, the phenyl group is substituted with 0-2 substituents selected from Ra.

[0332] In another embodiment of the invention, R 1 Selected from: hydrogen, -C1-6 alkyl, -C3-6 alkenyl, -C3-6 ynyl, -C3-10 cycloalkyl, -C2-10 cyclohexaalkyl, and -C1-6 alkyl-O-C1-6 alkyl-, wherein each alkyl, alkenyl, ynyl, cycloalkyl, and cyclohexaalkyl group is unsubstituted or substituted by one to five substituents selected from Rc. In another embodiment, R 1 Selected from: hydrogen, -C1-6 alkyl, -C3-6 alkenyl and -C3-6 ynyl, wherein each alkyl, alkenyl and ynyl group is unsubstituted or substituted by one to five substituents selected from Rc.

[0333] In another implementation, R 1 Selected from: hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted by one to five substituents selected from Rc. In another embodiment, R 1 Selected from: hydrogen and -CH3. In another embodiment, R 1It is a -C1-6 alkyl group, wherein each alkyl group is unsubstituted or substituted by one to five substituents selected from Rc. In one such embodiment, R 1 For -CH3. In another implementation, R 1 It is hydrogen.

[0334] In another embodiment of the invention, R 2 Selected from: hydrogen, -C1-6 alkyl, -C3-6 alkenyl, -C3-6 ynyl, -C3-10 cycloalkyl, -C2-10 cyclohexaalkyl, and -C1-6 alkyl-O-C1-6 alkyl-, wherein each alkyl, alkenyl, ynyl, cycloalkyl, and cyclohexaalkyl group is unsubstituted or substituted by one to five substituents selected from Rd. In another embodiment, R 2 Selected from: hydrogen, -C1-6 alkyl, -C3-6 alkenyl and -C3-6 ynyl, wherein each CH2, alkyl, alkenyl and ynyl group is unsubstituted or substituted by one to five substituents selected from Rd.

[0335] In another implementation, R 2 Selected from: hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted by one to five substituents selected from Rd. In another embodiment, R 2 Selected from: -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted by one to five substituents selected from Rd. In one such embodiment, R 2 Selected from: -CH3 and -(CH2)2-OH. In another embodiment of the invention, R 2 It is hydrogen.

[0336] In another embodiment of the invention, R 3 Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-10 cycloalkyl, -C2-10 cyclohexa-alkyl, -C1-6 alkyl-O-C1-6 alkyl-, -(CH2)sC(O)Rj, -(CH2)sC(O)NReRj, -(CH2)sNReC(O)Rj, -(CH2)sNReC(O)ORj, -(CH2)sNReC(O)N(Re)2, -(CH2)sNReC(O)NReRj, -(CH2)sNReS(O)mRj, -(CH2)sNReS(O) m N(Re)2、-(CH2)sNReS(O) m NReRj and -(CH2)sNReRj, wherein each CH2, alkyl, alkenyl, ynyl, cycloalkyl and heteroalkyl group is unsubstituted or substituted by one to five substituents selected from Rf.

[0337] In another implementation, R 3Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-10 cycloalkyl, -C2-10 cycloheteroalkyl, -C1-6 alkyl-O-C1-6 alkyl-, wherein each alkyl, alkenyl, ynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted by one to five substituents selected from Rf.

[0338] In another implementation, R 3 Selected from: hydrogen, -C1-4 alkyl, -C2-4 alkenyl, -C2-4 ynyl, -C3-6 cycloalkyl and -C2-6 heteroalkyl, wherein each alkyl, alkenyl, ynyl, cycloalkyl and heteroalkyl is unsubstituted or substituted by one to five substituents selected from Rf.

[0339] In another implementation, R 3 Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl and -C2-6 ynyl, wherein each alkyl, alkenyl and ynyl group is unsubstituted or substituted by one to five substituents selected from Rf.

[0340] In another implementation, R 3 Selected from: hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted by one to five substituents selected from Rf. In another embodiment, R 3 It is a -C1-6 alkyl group. In another embodiment, R 3 It is hydrogen.

[0341] In another embodiment of the invention, R 4 Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-10 cycloalkyl, -C2-10 cyclo-heteroalkyl and -C1-6 alkyl-O-C1-6 alkyl-, wherein each alkyl, alkenyl, ynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted by one to five substituents selected from Rg.

[0342] In another implementation, R 4 Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-10 cycloalkyl and -C2-6 heteroalkyl, wherein each alkyl, alkenyl, ynyl, cycloalkyl and heteroalkyl is unsubstituted or substituted by one to five substituents selected from Rg.

[0343] In another implementation, R 4 Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-10 cycloalkyl, and -C2-10 heteroalkyl, wherein each alkyl, alkenyl, or ynyl group is unsubstituted or substituted by one to five substituents selected from Rg. In another embodiment, R 4Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl and -C2-6 ynyl, wherein each alkyl, alkenyl and ynyl group is unsubstituted or substituted by one to five substituents selected from Rg.

[0344] In another implementation, R 4 Selected from: hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted by one to five substituents selected from Rg. In another embodiment, R 4 It is a -C1-6 alkyl group, wherein each alkyl group is unsubstituted or substituted with one to five substituents selected from Rg. In another embodiment, R 4 It is hydrogen.

[0345] In another embodiment of the invention, R 5 The halogen is selected from hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted with one to three halogen substituents. In one type of embodiment, the halogen is selected from Cl and F. In another type of embodiment, the halogen is F. In yet another type of embodiment, the halogen is Cl.

[0346] In another implementation, R 5 The halogen is selected from hydrogen and -CH3, wherein each -CH3 group is unsubstituted or substituted with one to three halogen substituents. In one type of embodiment, the halogen is selected from Cl and F. In another type of embodiment, the halogen is F. In yet another type of embodiment, the halogen is Cl.

[0347] In another implementation, R 5 Selected from: hydrogen and -CH3.

[0348] In another implementation, R 5 It is a -C1-6 alkyl group, wherein each alkyl group is unsubstituted or substituted with one to three halogen substituents. In one type of embodiment, the halogen is selected from Cl and F. In another type of embodiment, the halogen is F. In another type of embodiment, the halogen is Cl. In yet another embodiment, R 5 For -CH3. In another implementation, R 5 It is hydrogen.

[0349] In another embodiment of the invention, R 6 Selected from: hydrogen, -C1-6 alkyl, -C3-6 cycloalkyl, and -C2-6 cyclohexaalkyl, wherein each alkyl, cycloalkyl, and cyclohexaalkyl group is unsubstituted or substituted by one to five halogen substituents. In another embodiment, R 6Selected from: hydrogen, -C1-6 alkyl, -C3-5 cycloalkyl, and -C2-5 heteroalkyl, wherein each alkyl, cycloalkyl, and heteroalkyl group is unsubstituted or substituted with one to five halogen substituents. In one type of embodiment, each alkyl, cycloalkyl, and heteroalkyl group is unsubstituted or substituted with one to three halogen substituents.

[0350] In another implementation, R 6 Selected from: hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted with one to five halogen substituents. In one type of embodiment, each alkyl group is unsubstituted or substituted with one to three halogen substituents. In another embodiment, R 6 It is a -C1-6 alkyl group, wherein each alkyl group is unsubstituted or substituted with one to five halogen substituents. In one type of embodiment, each alkyl group is unsubstituted or substituted with one to three halogen substituents. In another embodiment, R 6 It is hydrogen.

[0351] In another embodiment of the invention, R 7 Selected from: hydrogen, -C1-6 alkyl, -C2-6 alkenyl, and -C2-6 ynyl, wherein each alkyl, alkenyl, and ynyl group is unsubstituted or substituted by one to five halogen substituents. In another embodiment, R 7 Selected from: hydrogen, -C1-6 alkyl, -C2-4 alkenyl, and -C2-4 alkynyl, wherein each alkyl, alkenyl, and alkynyl group is unsubstituted or substituted by one to five halogen substituents. In one such embodiment, each alkyl, alkenyl, and alkynyl group is unsubstituted or substituted by one to three halogen substituents. In another embodiment, R 7 The group is selected from hydrogen, -C1-6 alkyl, and -C2-6 alkenyl, wherein each alkyl and alkenyl group is unsubstituted or substituted with one to five halogen substituents. In one type of embodiment, each alkyl and alkenyl group is unsubstituted or substituted with one to three halogen substituents.

[0352] In another implementation, R 7 Selected from: hydrogen and -C1-6 alkyl groups, wherein each alkyl group is unsubstituted or substituted with one to five halogen substituents. In one type of embodiment, each alkyl group is unsubstituted or substituted with one to three halogen substituents. In another embodiment, R 7 It is a -C1-6 alkyl group, wherein each alkyl group is unsubstituted or substituted with one to five halogen substituents. In one type of embodiment, each alkyl group is unsubstituted or substituted with one to three halogen substituents. In another embodiment, R 7 It is hydrogen.

[0353] In another embodiment of the invention, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -OCH2CF3, -CF2CH3, CN, oxo, halogen, -S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 heteroalkyl, aryl, heteroaryl, -C1-6 alkyl-aryl, -C1-6 alkyl-heteroaryl, -C1-6 alkyl-C3-6 cycloalkyl, -C1-6 alkyl-C2-6 cycloalkyl, -C2-6 alkenyl-C3-6 cycloalkyl, -C2-6 alkenyl-C2-6 cycloalkyl, -C2-6 alkenyl-aryl, -C2-6 alkenyl-aryl, -C2-6 alkenyl-heteroalkyl Aryl, -C2-6 ynyl-C3-6 cycloalkyl, -C2-6 ynyl-C2-6 cycloheteroalkyl, -C2-6 ynyl-aryl, -C2-6 ynyl-heteroaryl, -OH, -(CH2)p-OC1-6 alkyl, -(CH2)p-OC2-6 alkenyl, -(CH2)p-OC2-6 ynyl, -(CH2)p-OC3-6 cycloalkyl, -(CH2)p-OC2-6 heterocycloalkyl, -(CH2)pO-aryl, -(CH2)pO-heteroaryl, -OC1-6 alkyl-C3-6 cycloalkyl, -OC1-6 alkyl-C2-6 heterocycloalkyl, -OC1-6 alkyl-aryl, -OC1-6 alkyl-heteroaryl, -S(O)mRi, -C1-6 alkyl-S(O)mRi, -N(Rk)2 and -NRkRL, wherein each _ Ra is not substituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0354] In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 cycloheteroalkyl, aryl, heteroaryl, -C1-6 alkyl-aryl, –C1-6 alkyl -C1-6 alkyl-C3-6 cycloalkyl, -C1-6 alkyl-C2-6 cycloalkyl, -C2-6 alkenyl-C3-6 cycloalkyl, -C2-6 alkenyl-C2-6 cycloalkyl, -C2-6 alkenyl-aryl, -C2-6 alkenyl-heteroaryl, -C2-6 ynyl-C3-6 cycloalkyl, -C2-6 ynylcycloalkyl, -C2-6 ynyl-aryl, -C2-6 ynyl-heteroaryl and -OH, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0355] In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 cyclohexane. alkyl, aryl, heteroaryl, –C1-6 alkyl-aryl, –C1-6 alkyl-heteroaryl, –C1-6 alkyl-C3-6 cycloalkyl, –C1-6 alkyl-C2-6 cycloheteroalkyl, –C2-6 alkenyl-C3-6 cycloalkyl, –C2-6 alkenyl-C2-6 cycloheteroalkyl, –C2-6 alkenyl-aryl, –C2-6 alkenyl-heteroaryl and -OH, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0356] In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 heteroalkyl, aryl, heteroaryl, –C1-6 alkyl-aryl, -C1-6 alkyl-heteroaryl, –C1-6 alkyl-C3-6 cycloalkyl, –C1-6 alkyl-C2-6 heteroalkyl, and -OH, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0357] In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 heteroalkyl, and OH, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0358] In another implementation, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3 CN, oxo, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, and OH, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3. In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, -C1-6 alkyl, -C2-6 alkenyl, and OH, wherein each Ra is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0359] In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, -C1-6 alkyl, and OH, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3 and CH3.

[0360] In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -OCH2CF3, -CF2CH3, CN, halogens, and -C1-6 alkyl groups, wherein each Ra is unsubstituted or is selected from one to six halogens, CF3, OH, C 1-6 Alkyl and OC 1-6The alkyl group is substituted. In one type of embodiment, the halogen is F or Cl. In another type of embodiment, Ra is unsubstituted or substituted with one to six groups selected from halogens, CF3, and C. 1-6 The alkyl group is substituted. In another type of embodiment, Ra is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3. In another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, –OCH2CF3, CN, and halogen. In yet another embodiment, each Ra is independently selected from: -CF3, -OCF3, -CHF2, –OCH2CF3, CN, F, and Cl.

[0361] In another embodiment of the invention, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 Cycloalkyl, aryl, heteroaryl, –C1-6 alkyl-aryl, –C1-6 alkyl-heteroaryl, –C1-6 alkyl-C3-6 cycloalkyl, –C1-6 alkyl-C2-6 cycloalkyl, –C2-6 alkenyl-C3-6 cycloalkyl, –C2-6 alkenyl-C2-6 cycloalkyl, –C2-6 alkenyl-aryl, –C2-6 alkenyl-heteroaryl, –C2-6 ynyl-C3-6 cycloalkyl, –C2-6 ynyl-C2-6 cycloalkyl Alkyl, -C2-6 ynyl-aryl, -C2-6 ynyl-heteroaryl, -OH, -(CH2)q-OC1-6 alkyl, -(CH2)q-OC2-6 alkenyl, -(CH2)q-OC2-6 ynyl, -(CH2)q-OC3-6 cycloalkyl, -(CH2)q-OC2-6 heterocyclic alkyl, -(CH2)qO-aryl, -(CH2)qO-heteroaryl, -OC1-6 alkyl-C3-6 cycloalkyl -OC1-6alkyl-C2-6 heterocyclic alkyl, -OC1-6alkyl-aryl, -OC1-6alkyl-heteroaryl, -S(O)mRi, -C1-6alkyl-S(O)mRi, -C(O)RL, and –NRkRL, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0362] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 cycloheteroalkyl, aryl, heteroaryl, –C1-6 alkyl-aryl, -C1-6 alkyl-heteroaryl, –C1-6 alkyl-C3-6 cycloalkyl, – C1-6 alkyl-C2-6 cycloheteroalkyl, -C2-6 alken-C3-6 cycloalkyl, -C2-6 alken-C2-6 cycloheteroalkyl, -C2-6 alken-aryl, -C2-6 alken-heteroaryl, -C2-6 ynyl-C3-6 cycloalkyl, -C2-6 ynyl-C2-6 cycloheteroalkyl, -C2-6 ynyl-aryl, -C2-6 ynyl-heteroaryl, and -OH, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one such embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0363] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 cycloheteroalkyl, aryl, heteroaryl, –C1-6 alkyl-aryl, - C1-6 alkyl-heteroaryl, –C1-6 alkyl-C3-6 cycloalkyl, –C1-6 alkyl-C2-6 cycloheteroalkyl, –C2-6 alkenyl-C3-6 cycloalkyl, –C2-6 alkenyl-C2-6 cycloheteroalkyl, –C2-6 alkenyl-aryl, –C2-6 alkenyl-heteroaryl, and -OH, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3. In one type of embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0364] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -OCH2CF3, -CF2CH3, CN, oxo, halogen, -S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -O-C1-6 alkyl, -C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -C2-6 heteroalkyl, aryl, heteroaryl, and -OH, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0365] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -OCH2CF3, -CF2CH3, CN, oxo, halogen, -S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-6 cycloalkyl, -C2-6 heteroalkyl, aryl, heteroaryl, and -OH, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0366] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, oxo, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-6 cycloalkyl, -C2-6 heteroalkyl, and -OH, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0367] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -–OCH2CF3, -CF2CH3, CN, oxo, halogen, -S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C3-6 cycloalkyl, -C2-6 heteroalkyl and -OH, wherein each Rb is unsubstituted or substituted by one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl and O-C1-6 alkyl.

[0368] In one such embodiment, each Rb is either unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0369] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –OCH2CF3, –CF2CH3, CN, halogen, -S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 ynyl, -C3-6 cycloalkyl, and -C2-6 heteroalkyl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0370] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -OCH2CF3, -CF2CH3, CN, halogen, -S(O)2C1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, -C3-6 cycloalkyl, and -C2-6 heteroalkyl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0371] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, –CH(CF3)CH3, -OCH2CF3, -CF2CH3, CN, F, Cl, -S(O)2CH3, -CH3, and cyclopropyl, wherein each Rb is unsubstituted or substituted by one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted by one to six substituents selected from F, Cl, CF3, and CH3.

[0372] In another embodiment, each Rb is independently selected from: -CF3, -OCF3, -CHF2, -OCHF2, –CH2CF3, –CH(CF3)CH3, –OCH2CF3, CN, halogen, –S(O)2C1-6 alkyl, -C1-6 alkyl, and -C3-6 cycloalkyl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogen, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0373] In another embodiment, each Rb is independently selected from: CF3, -OCF3, -CHF2, -OCHF2, -CH2CF3, -CH(CF3)CH3, -OCH2CF3, CN, F, Cl, -S(O)2CH3, -CH3, and cyclopropyl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0374] In another embodiment, each Rb is independently selected from -CF3, -OCF3, -OCH2CF3, and halogens, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0375] In another embodiment, each Rb is independently selected from -CF3, -OCF3, -OCH2CF3, F, and Cl, wherein each Rb is unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl, and O-C1-6 alkyl. In one type of this embodiment, each Rb is unsubstituted or substituted with one to six substituents selected from F, Cl, CF3, and CH3.

[0376] In another embodiment of the invention, Rc is selected from: -C1-6 alkyl, OH, halogen, and -OC1-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rc is selected from: -C1-6 alkyl, OH, and halogen, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rc is selected from: OH and halogen. In one type of embodiment, Rc is selected from: OH and F. In another embodiment, Rc is OH. In another embodiment, Rc is a halogen. In one type of embodiment, Rc is F.

[0377] In another embodiment of the invention, Rd is selected from: -C1-6 alkyl, OH, halogen, and -OC1-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rd is selected from: -C1-6 alkyl, OH, and halogen, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rd is selected from: OH and halogen. In one type of embodiment, Rd is selected from: OH and F. In another embodiment, Rd is OH. In another embodiment, Rd is a halogen. In one type of embodiment, Rd is F.

[0378] In another embodiment of the invention, Re is selected from hydrogen and C1-6 alkyl. In another embodiment, Re is hydrogen. In yet another embodiment, Re is C1-6 alkyl.

[0379] In another embodiment of the invention, Rf is selected from: -C1-6 alkyl, OH, halogen, and -OC1-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rf is selected from: -C1-6 alkyl, OH, and halogen, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rf is selected from: OH and halogen. In one type of embodiment, Rf is selected from: OH and F. In another embodiment, Rf is OH. In another embodiment, Rf is a halogen. In one type of embodiment, Rf is F.

[0380] In another embodiment of the invention, Rg is selected from: -C1-6 alkyl, OH, halogen, and -OC1-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rg is selected from: -C1-6 alkyl, OH, and halogen, wherein the alkyl group may be unsubstituted or substituted with one to three halogens. In another embodiment, Rg is selected from: OH and halogen. In one type of embodiment, Rg is selected from: OH and F. In another embodiment, Rg is OH. In another embodiment, Rg is a halogen. In one type of embodiment, Rg is F.

[0381] In another embodiment of the invention, Rh is selected from hydrogen and C1-6 alkyl. In another embodiment, Rh is hydrogen. In yet another embodiment, Rh is C1-6 alkyl.

[0382] In another embodiment of the invention, Ri is selected from: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, and heteroaryl. In another embodiment, Ri is selected from: hydrogen, C1-6 alkyl, and C3-6 cycloalkyl. In another embodiment, Ri is selected from: hydrogen and C1-6 alkyl. In another embodiment, Ri is hydrogen. In another embodiment, Ri is C1-6 alkyl.

[0383] In another embodiment of the invention, Rj is selected from: hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 ynyl, C3-6 cycloalkyl, C2-5 heteroalkyl, aryl, and heteroaryl. In another embodiment, Rj is selected from: hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 ynyl, C3-6 cycloalkyl, and C2-5 heteroalkyl. In another embodiment, Rj is selected from: hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 ynyl, and C3-6 cycloalkyl. In another embodiment, Rj is selected from: hydrogen, C1-6 alkyl, C3-6 alkenyl, and C3-6 ynyl. In another embodiment, Rj is selected from: hydrogen, C1-6 alkyl, and C3-6 alkenyl. In another embodiment, Rj is selected from: hydrogen and C1-6 alkyl. In another embodiment, Rj is C1-6 alkyl. In another embodiment, Rj is hydrogen.

[0384] In another embodiment of the invention, Rk is selected from hydrogen and C1-6 alkyl. In another embodiment, Rk is hydrogen. In yet another embodiment, Rk is C1-6 alkyl.

[0385] In another embodiment of the invention, RL is selected from: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, and heteroaryl. In another embodiment, RL is selected from: hydrogen, C1-6 alkyl, and C3-6 cycloalkyl. In another embodiment, RL is selected from: hydrogen and C1-6 alkyl. In another embodiment, RL is hydrogen. In another embodiment, RL is C1-6 alkyl.

[0386] In one embodiment of the invention, 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.

[0387] In one embodiment of the invention, 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.

[0388] In one embodiment of the invention, 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 or 2. In another embodiment, p is 1 or 3. In another embodiment, p is 0 or 1. In another embodiment, p is 0 or 2. In another embodiment, p is 0 or 3. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3.

[0389] In one embodiment of the invention, q is 0, 1, 2, or 3. In another embodiment, q is 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 0 or 1. In another embodiment, q is 0 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3.

[0390] In one embodiment of the invention, r is 0, 1, or 2. In another embodiment, r is 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.

[0391] In one embodiment of the invention, 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.

[0392] In another embodiment of the invention, the invention relates to compounds of structural formula Ia:

[0393]

[0394] Where A is an aryl group; or a pharmaceutically acceptable salt thereof.

[0395] In another embodiment of the invention, the invention relates to compounds of structural formula Ib:

[0396]

[0397] Wherein A is a heteroaryl group; or a pharmaceutically acceptable salt thereof.

[0398] In another embodiment of the invention, the invention relates to compounds of structural formula Ic:

[0399]

[0400] Where A is a phenyl group; or a pharmaceutically acceptable salt thereof.

[0401] In another embodiment of the invention, the invention relates to compounds of structural formula Id:

[0402]

[0403] Where A is pyridine; or a pharmaceutically acceptable salt thereof.

[0404] Compounds of structural formula I include compounds of structural formulas Ia, Ib, Ic, and Id, as well as their pharmaceutically acceptable salts, hydrates, and solvates.

[0405] Another embodiment of the present invention relates to a compound of structural formula I, wherein:

[0406] A is selected from:

[0407] 1) Aryl, and

[0408] 2) Mixed aromatics,

[0409] Where A is either unsubstituted or substituted by one to five substituents selected from Ra;

[0410] B is selected independently from:

[0411] 1) Aryl,

[0412] 2) Mixed aromatics,

[0413] 3)-C1-6 alkyl-aryl,

[0414] 4)-C3-8 cycloalkyl-aryl,

[0415] 5)-C2-8 cyclohexaalkyl-aryl,

[0416] 6)-C1-6 alkyl-heteroaryl,

[0417] 7)-C3-8 cycloalkyl-heteroaryl,

[0418] 8)-C2-8 cycloheteroalkyl-heteroaryl,

[0419] 9)-C1-6 alkyl-O-aryl,

[0420] 10)-C1-6 alkyl-O-heteroaryl,

[0421] 11)-C3-12 cycloalkyl,

[0422] 12)-C2-12 cyclohexaalkyl,

[0423] 13)-C1-6 alkyl-C3-12 cycloalkyl,

[0424] 14)-C1-6 alkyl-C2-12 cyclohexaalkyl,

[0425] 15)-C1-6 alkyl-O-C3-12 cycloalkyl,

[0426] 16)-C1-6 alkyl-O-C2-12 cyclohexaalkyl,

[0427] 17) With C4-6 cycloalkyl groups or containing 1-3 independently selected O, S and N(R) groups. h )2 heteroatom C4-6 cyclic heteroalkyl fused -C0-6 alkyl-aryl,

[0428] 18) With C4-6 cycloalkenyl groups or containing 1-3 independently selected O, S, and N(R) groups. h The heteroatom of the C4-6 cyclohexene fused to a -C0-6 alkyl-aryl group,

[0429] 19) With C4-6 cycloalkyl groups or containing 1-3 independently selected O, S and N(R) groups. h )2 heteroatom of C4-6 cyclic heteroalkyl fused -C0-6 alkyl-heteroaryl, and

[0430] 20) with C4-6 cycloalkenyl groups or containing 1-3 independently selected O, S, and N(R) groups. h The heteroatom of the C4-6 cyclohexene fused to a -C0-6 alkyl-heteroaryl group,

[0431] The alkyl, cycloalkyl, cyclohexaalkyl, cycloalkenyl, aryl, and heteroaryl groups are either unsubstituted or substituted by one to five substituents selected from Rb; or pharmaceutically acceptable salts thereof.

[0432] R 1 Selected from:

[0433] 1) Hydrogen,

[0434] 2)-C1-6 alkyl,

[0435] 3)-C3-6 alkenyl,

[0436] 4)-C3-6 ynyl group,

[0437] 5)-C3-10 cycloalkyl,

[0438] 6)-C2-10 cyclohexane,

[0439] 7)-C1-6alkyl-O-C1-6alkyl-

[0440] 8)-(CH2)sC(O)Rj,

[0441] 9)-(CH2)sC(O)NReRj,

[0442] 10)-(CH2)nNReC(O)Rj,

[0443] 11)-(CH2)nNReC(O)ORj,

[0444] 12)-(CH2)nNReC(O)N(Re)2,

[0445] 13)-(CH2)nNReC(O)NReRj,

[0446] 14)-(CH2)nNReS(O)mRj,

[0447] 15)-(CH2)nNReS(O)mN(Re)2,

[0448] 16)-(CH2)nNReS(O)mNReRj, and

[0449] 17)-(CH2)nNReRj,

[0450] Each CH2 group, alkyl, alkenyl, ynyl, cycloalkyl, and heteroalkyl group is either unsubstituted or substituted by one to five substituents selected from Rc.

[0451] R 2 Selected from:

[0452] 1) Hydrogen,

[0453] 2)-C1-6 alkyl,

[0454] 3)-C3-6 alkenyl,

[0455] 4)-C3-6 ynyl group,

[0456] 5)-C3-10 cycloalkyl,

[0457] 6)-C2-10 cyclohexane,

[0458] 7)-C1-6alkyl-O-C1-6alkyl-

[0459] 8)-(CH2)sC(O)Rj,

[0460] 9)-(CH2)sC(O)NReRj,

[0461] 10)-(CH2)nNReC(O)Rj,

[0462] 11)-(CH2)nNReC(O)ORj,

[0463] 12)-(CH2)nNReC(O)N(Re)2,

[0464] 13)-(CH2)nNReC(O)NReRj,

[0465] 14)-(CH2)nNReS(O)mRj,

[0466] 15)-(CH2)nNReS(O)mN(Re)2,

[0467] 16)-(CH2)nNReS(O)mNReRj, and

[0468] 17)-(CH2)nNReRj,

[0469] Each CH2 group, alkyl, alkenyl, ynyl, cycloalkyl, and heteroalkyl group is either unsubstituted or substituted by one to five substituents selected from Rd;

[0470] R 3 Selected from:

[0471] 1) Hydrogen,

[0472] 2)-C1-6 alkyl,

[0473] 3)-C2-6 alkenyl,

[0474] 4)-C2-6 ynyl group,

[0475] 5)-C3-10 cycloalkyl,

[0476] 6)-C2-10 cyclohexane,

[0477] 7)-C1-6alkyl-O-C1-6alkyl-

[0478] 8)-(CH2)sC(O)Rj,

[0479] 9)-(CH2)sC(O)NReRj,

[0480] 10)-(CH2)sNReC(O)Rj,

[0481] 11)-(CH2)sNReC(O)ORj,

[0482] 12)-(CH2)sNReC(O)N(Re)2,

[0483] 13)-(CH2)sNReC(O)NReRj,

[0484] 14)-(CH2)sNReS(O)mRj,

[0485] 15)-(CH2)sNReS(O)mN(Re)2,

[0486] 16)-(CH2)sNReS(O)mNReRj, and

[0487] 17)-(CH2)sNReRj,

[0488] Each CH2 group, alkyl, alkenyl, ynyl, cycloalkyl, and cyclohexaalkyl group is either unsubstituted or substituted by one to five substituents selected from Rf, and

[0489] Where R 3 and R 4 And the carbon atoms to which they are attached can form -C3-5 cycloalkyl rings.

[0490] R 4 Selected from:

[0491] 1) Hydrogen,

[0492] 2)-C1-6 alkyl,

[0493] 3)-C2-6 alkenyl,

[0494] 4)-C2-6 ynyl group,

[0495] 5)-C3-10 cycloalkyl,

[0496] 6)-C2-10 cyclohexane,

[0497] 7)-C1-6alkyl-O-C1-6alkyl-

[0498] 8)-(CH2)sC(O)Rj,

[0499] 9)-(CH2)sC(O)NReRj,

[0500] 10)-(CH2)sNReC(O)Rj,

[0501] 11)-(CH2)sNReC(O)ORj,

[0502] 12)-(CH2)sNReC(O)N(Re)2,

[0503] 13)-(CH2)sNReC(O)NReRj,

[0504] 14)-(CH2)sNReS(O)mRj,

[0505] 15)-(CH2)sNReS(O)mN(Re)2,

[0506] 16)-(CH2)sNReS(O)mNReRj, and

[0507] 17)-(CH2)sNReRj,

[0508] Each CH2, alkyl, alkenyl, ynyl, cycloalkyl, and cyclohexaalkyl group is either unsubstituted or substituted by one to five substituents selected from Rg;

[0509] R 5 Selected from:

[0510] 1) Hydrogen, and

[0511] 2)-C1-6 alkyl,

[0512] Each alkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0513] R 6 Selected from:

[0514] 1) Hydrogen,

[0515] 2)-C1-6 alkyl,

[0516] 3)-C3-6 cycloalkyl, and

[0517] 4)-C2-6 cyclohexane,

[0518] Each alkyl, cycloalkyl, and heteroalkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0519] R 7 Selected from:

[0520] 1) Hydrogen,

[0521] 2)-C1-6 alkyl,

[0522] 3)-C2-6 alkenyl, and

[0523] 4)-C2-6 ynyl group,

[0524] Each alkyl, alkenyl, and alkynyl group is either unsubstituted or substituted by one to five halogen substituents;

[0525] Each Ra is selected independently from:

[0526] 1)-CF3,

[0527] 2)-OCF3,

[0528] 3)-CHF2,

[0529] 4)-OCHF2,

[0530] 5)–CH2CF3,

[0531] 6)–OCH2CF3,

[0532] 7)–CF2CH3,

[0533] 8)CN,

[0534] 9) Oxygenation,

[0535] 10) Halogens,

[0536] 11)–S(O)2C1-6 alkyl,

[0537] 12)-C1-6 alkyl,

[0538] 13)-C2-6 alkenyl,

[0539] 14)-C2-6 yntylic group,

[0540] 15)-C3-6 cycloalkyl,

[0541] 16)-C2-6 cyclohexane,

[0542] 17) Aryl,

[0543] 18) Mixed aromatics,

[0544] 19)-C1-6 alkyl-aryl,

[0545] 20)-C1-6 alkyl-heteroaryl,

[0546] 21)-C1-6 alkyl-C3-6 cycloalkyl,

[0547] 22)–C1-6 alkyl-C2-6 cyclohexaalkyl,

[0548] 23)-C2-6 alkenyl-C3-6 cycloalkyl,

[0549] 24)-C2-6 alkenyl-C2-6 cyclohexaalkyl,

[0550] 25)–C2-6 alkenyl-aryl,

[0551] 26)-C2-6 alkenyl-heteroaryl,

[0552] 27)-C2-6 ynyl-C3-6 cycloalkyl,

[0553] 28)-C2-6 ynyl-C2-6 cyclohexaalkyl,

[0554] 29)-C2-6 ynyl-aryl,

[0555] 30)-C2-6 ynyl-heteroaryl,

[0556] 31)-OH,

[0557] 32)-(CH2)p-OC1-6 alkyl,

[0558] 33)-(CH2)p-OC2-6 alkenyl,

[0559] 34)-(CH2)p-OC2-6 ynyl group,

[0560] 35)–(CH2)p-OC3-6 cycloalkyl,

[0561] 36)–(CH2)p-OC2-6 heterocyclic alkyl,

[0562] 37)–(CH2)pO-aryl,

[0563] 38)–(CH2)pO-heteroaryl,

[0564] 39)-OC1-6alkyl-C3-6cycloalkyl,

[0565] 40)-OC1-6alkyl-C2-6 heterocyclic alkyl,

[0566] 41)-OC1-6alkyl-aryl,

[0567] 42)-OC1-6 alkyl-heteroaryl,

[0568] 43)-S(O)mRi,

[0569] 44)-C1-6 alkyl-S(O)mRi,

[0570] 45)-N(Rk)2, and

[0571] 46)–NRkRL,

[0572] Each Ra is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OH, C1-6 alkyl and OC1-6 alkyl;

[0573] Each Rb is selected independently from:

[0574] 1)-CF3,

[0575] 2)-OCF3,

[0576] 3)-CHF2,

[0577] 4)-OCHF2,

[0578] 5)–CH2CF3,

[0579] 6)–OCH2CF3,

[0580] 7)–CF2CH3,

[0581] 8)CN,

[0582] 9) Oxygenation,

[0583] 10) Halogens,

[0584] 11)–S(O)2C1-6 alkyl,

[0585] 12)-C1-6 alkyl,

[0586] 13)-C2-6 alkenyl,

[0587] 14)-C2-6 yntylic group,

[0588] 15)-O-C1-6 alkyl,

[0589] 16)-C3-6 cycloalkyl,

[0590] 17)-O-C3-6 cycloalkyl,

[0591] 18)-C2-6 cyclohexane,

[0592] 19) Aryl,

[0593] 20) Mixed aryl groups,

[0594] 21)-C1-6 alkyl-aryl,

[0595] 22)-C1-6 alkyl-heteroaryl,

[0596] 23)-C1-6 alkyl-C3-6 cycloalkyl,

[0597] 24)–C1-6 alkyl-C2-6 cyclohexaalkyl,

[0598] 25)-C2-6 alkenyl-C3-6 cycloalkyl,

[0599] 26)-C2-6 alkenyl-C2-6 cyclohexaalkyl,

[0600] 27)–C2-6 alkenyl-aryl,

[0601] 28)-C2-6-enyl-heteroaryl,

[0602] 29)-C2-6 ynyl-C3-6 cycloalkyl,

[0603] 30)-C2-6 ynyl-C2-6 cyclohexaalkyl,

[0604] 31)-C2-6 ynyl-aryl,

[0605] 32)-C2-6 ynyl–heteroaryl,

[0606] 33)-OH,

[0607] 34)-(CH2)q-OC1-6 alkyl,

[0608] 35)-(CH2)q-OC2-6 alkenyl,

[0609] 36)-(CH2)q-OC2-6 ynyl group,

[0610] 37)–(CH2)q-OC3-6 cycloalkyl,

[0611] 38)–(CH2)q-OC2-6 heterocyclic alkyl,

[0612] 39)–(CH2)qO-aryl,

[0613] 40)–(CH2)qO-heteroaryl,

[0614] 41)-OC1-6alkyl-C3-6cycloalkyl,

[0615] 42)-OC1-6alkyl-C2-6 heterocyclic alkyl,

[0616] 43)-OC1-6alkyl-aryl,

[0617] 44)-OC1-6 alkyl-heteroaryl,

[0618] 45)-S(O)mRi,

[0619] 46)-C1-6 alkyl-S(O)mRi,

[0620] 47)-C(O)RL, and

[0621] 48)–NRkRL,

[0622] Each Rb is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl and -OC1-6 alkyl;

[0623] Rc is selected from:

[0624] 1)-C1-6 alkyl,

[0625] 2)OH,

[0626] 3) Halogens, and

[0627] 4)-OC1-6 alkyl,

[0628] The alkyl group may be unsubstituted or substituted with one to three halogens; Rd is selected from:

[0629] 1)-C1-6 alkyl,

[0630] 2)OH,

[0631] 3) Halogens, and

[0632] 4)-OC1-6 alkyl,

[0633] The alkyl group may be unsubstituted or substituted with one to three halogens; Re is selected from:

[0634] 1) Hydrogen, and

[0635] 2) C1-6 alkyl;

[0636] Rf is selected from:

[0637] 1)-C1-6 alkyl,

[0638] 2)OH,

[0639] 3) Halogens, and

[0640] 4)-OC1-6 alkyl,

[0641] The alkyl group may be unsubstituted or substituted with one to three halogens; Rg is selected from:

[0642] 1)-C1-6 alkyl,

[0643] 2)OH,

[0644] 3) Halogens, and

[0645] 4)-OC1-6 alkyl,

[0646] The alkyl group may be unsubstituted or substituted with one to three halogens; Rh is selected from:

[0647] 1) Hydrogen, and

[0648] 2) C1-6 alkyl;

[0649] Ri is selected from:

[0650] 1) Hydrogen,

[0651] 2) C1-6 alkyl groups

[0652] 3) C3-6 cycloalkyl groups,

[0653] 4) Aryl, and

[0654] 5) Heteroaryl;

[0655] Rj is selected from:

[0656] 1) Hydrogen,

[0657] 2) C1-6 alkyl groups

[0658] 3) C3-6 alkenyl,

[0659] 4) C3-6 yntylic group.

[0660] 5) C3-6 cycloalkyl groups,

[0661] 6) C2-5 cyclohexaalkyl groups,

[0662] 7) Aryl, and

[0663] 8) Mixed aryl groups;

[0664] Rk is selected from:

[0665] 1) Hydrogen, and

[0666] 2) C1-6 alkyl;

[0667] RL is selected from:

[0668] 1) Hydrogen,

[0669] 2) C1-6 alkyl groups

[0670] 3) C3-6 cycloalkyl groups,

[0671] 4) Aryl, and

[0672] 5) Heteroaryl;

[0673] m is independently selected from 0 to 2;

[0674] n is independently selected from 2 to 6;

[0675] p is independently selected from 0 to 3;

[0676] q is independently selected from 0 to 3; r is independently selected from 0 to 2; and

[0677] s is independently selected from 0 to 6;

[0678] Or its pharmaceutically acceptable salt.

[0679] Another embodiment of the present invention relates to a compound of structural formula I, wherein:

[0680] A is selected from:

[0681] 1) Aryl, and

[0682] 2) Mixed aromatics,

[0683] Where A is either unsubstituted or substituted by one to five substituents selected from Ra;

[0684] B is selected independently from:

[0685] 1) Aryl,

[0686] 2) Mixed aromatics,

[0687] 3)-C1-6 alkyl-aryl,

[0688] 4)-C1-6 alkyl-O-aryl,

[0689] 5)-C1-6 alkyl-O-heteroaryl,

[0690] 6)-C3-12 cycloalkyl,

[0691] 7)-C2-12 cyclohexaalkyl,

[0692] 8)-C1-6 alkyl-C3-12 cycloalkyl,

[0693] 9)-C1-6 alkyl-C2-12 cyclohexaalkyl,

[0694] 10)-C1-6 alkyl-O-C3-12 cycloalkyl, and

[0695] 11) With C4-6 cycloalkyl groups or containing 1-3 independently selected O, S and N(R) groups. h )2 of heteroatom C4-6 cyclohexaalkyl fused -C0-6 alkyl-aryl, wherein the alkyl, cycloalkyl, cyclohexaalkyl, aryl and heteroaryl are unsubstituted or substituted by one to five substituents selected from Rb;

[0696] R 1 Selected from:

[0697] 1) Hydrogen, and

[0698] 2)-C1-6 alkyl,

[0699] Each alkyl group is either unsubstituted or substituted with one to five substituents selected from Rc;

[0700] R 2 Selected from:

[0701] 1) Hydrogen, and

[0702] 2)-C1-6 alkyl,

[0703] Each alkyl group is either unsubstituted or substituted with one to five substituents selected from Rd; R 3 Selected from:

[0704] 1) Hydrogen, and

[0705] 2)-C1-6 alkyl,

[0706] Each alkyl group is either unsubstituted or substituted with one to five substituents selected from Rf; R 4 Selected from:

[0707] 1) Hydrogen, and

[0708] 2)-C1-6 alkyl,

[0709] Each alkyl group is either unsubstituted or substituted with one to five substituents selected from Rg; R 5 Selected from:

[0710] 1) Hydrogen, and

[0711] 2)-C1-6 alkyl,

[0712] Each alkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0713] R 6 Selected from:

[0714] 1) Hydrogen, and

[0715] 2)-C1-6 alkyl,

[0716] Each alkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0717] R 7 Selected from:

[0718] 1) Hydrogen, and

[0719] 2)-C1-6 alkyl,

[0720] Each alkyl group is either unsubstituted or substituted with one to five halogen substituents;

[0721] Each Ra is selected independently from:

[0722] 1)-CF3,

[0723] 2)-OCF3,

[0724] 3)-CHF2,

[0725] 4)-OCH2CF3,

[0726] 5)CN,

[0727] 6) Halogens, and

[0728] 7)-C2-6 ynyl group,

[0729] Each Ra is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OH, C1-6 alkyl and -OC1-6 alkyl;

[0730] Each Rb is selected independently from:

[0731] 1)-CF3,

[0732] 2)-OCF3,

[0733] 3)-CHF2,

[0734] 4)-OCHF2,

[0735] 5)–CH2CF3,

[0736] 6)–CH(CF3)CH3,

[0737] 7)–OCH2CF3,

[0738] 8)CN,

[0739] 9) Halogens,

[0740] 10)–S(O)2C1-6 alkyl,

[0741] 11)-C1-6 alkyl, and

[0742] 12)-C3-6 cycloalkyl,

[0743] Each Rb is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl and -OC1-6 alkyl;

[0744] Or its pharmaceutically acceptable salt.

[0745] Another embodiment of the present invention relates to a compound of structural formula I, wherein:

[0746] A is an aryl group, wherein the aryl group is either unsubstituted or substituted by one to five substituents selected from Ra;

[0747] B is selected independently from:

[0748] 1) Aryl,

[0749] 2) heteroaryl, and

[0750] 3) C3-12 cycloalkyl groups,

[0751] The cycloalkyl, aryl, and heteroaryl groups are either unsubstituted or substituted by one to five substituents selected from Rb;

[0752] R 1 R 2 R 3 R 4 R 5 R 6 and R 7 It is hydrogen;

[0753] Each Ra is selected independently from:

[0754] 1)-CF3,

[0755] 2)-OCF3, and

[0756] 3) Halogens;

[0757] Each Rb is selected independently from:

[0758] 1)-CF3,

[0759] 2)-OCF3,

[0760] 3) –OCH2CF3, and

[0761] 4) Halogens,

[0762] Each Rb is either unsubstituted or substituted with one to six substituents selected from halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C1-6 alkyl and -OC1-6 alkyl;

[0763] Or its pharmaceutically acceptable salt.

[0764] Can be used as Na v 1.8 Inhibitors of channel activity: Illustrative but non-limiting examples of the compounds of the present invention include the following compounds:

[0765] 1)(S)-N-((R)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0766] 2)(S)-N-((S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0767] 3)(R)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide and (S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide;

[0768] 4)(S)-N-((R)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0769] 5)(S)-N-((S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0770] 6)(S)-N-((R)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0771] 7)(S)-N-((S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0772] 8)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0773] 9)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0774] 10)(S)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0775] 11)(S)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0776] 12)(S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0777] 13)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0778] 14)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0779] 15)(S)-N-((R)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0780] 16)(S)-N-((S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0781] 17)(R)-N-[bis(4-chlorophenyl)methyl]-1-methyl-2-oxoimidazolidine-4-carboxamide;

[0782] 18)(S)-N-[bis(4-chlorophenyl)methyl]-1-methyl-2-oxoimidazolidine-4-carboxamide;

[0783] 19)(4S)-N-{((R)-3-chloro-4-fluorophenyl)[5-fluoro-6-(2,2,2-trifluoro-ethoxy)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0784] 20)(4S)-N-{((S)-3-chloro-4-fluorophenyl)[5-fluoro-6-(2,2,2-trifluoro-ethoxy)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0785] 21)(4S)-N-[((R)-3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0786] 22)(4S)-N-[((S)-3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0787] 23)(4S)-N-[((R)-5-chloro-6-cyclopropylpyridin-3-yl)(3-chloro-2,4-difluoro-phenyl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0788] 24)(4S)-N-[((S)-5-chloro-6-cyclo-propylpyridin-3-yl)(3-chloro-2,4-difluoro-phenyl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0789] 25)(4S)-N-{[(R)-5-chloro-6-(trifluoromethyl)pyridin-3-yl][5-fluoro-6-(trifluoro-methyl)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0790] 26)(4S)-N-{[(S)-5-chloro-6-(trifluoromethyl)pyridin-3-yl][5-fluoro-6-(trifluoro-methyl)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0791] 27)(S)-N-((R)-(3-chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0792] 28)(S)-N-((S)-(3-chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0793] 29)(S)-N-((R)-(3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazolyl-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0794] 30)(S)-N-((S)-(3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazolyl-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0795] 31)(S)-N-((R)-(4-chlorophenyl)(4-fluoro-3-(trifluoro-methyl)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0796] 32)(S)-N-((S)-(4-chlorophenyl)(4-fluoro-3-(trifluoro-methyl)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0797] 33)(S)-N-((R)-(3-chloro-4-fluoro-phenyl)(4-cyano-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0798] 34)(S)-N-((S)-(3-chloro-4-fluoro-phenyl)(4-cyano-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0799] 35)(S)-2-oxo-N-((R)-(6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methyl)imidazolidine-4-carboxamide;

[0800] 36)(S)-2-oxo-N-((S)-(6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methyl)imidazolidine-4-carboxamide;

[0801] 37)(R)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide;

[0802] 38)(S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide;

[0803] 39)(R)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide;

[0804] 40)(S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide;

[0805] 41)(S)-N-((R)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0806] 42)(S)-N-((S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0807] 43)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((cis)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0808] 44)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((trans)-4-(trifluoromethyl)cyclohexyl)-ethyl)-2-oxoimidazolidine-4-carboxamide;

[0809] 45)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((trans)-4-(trifluoromethyl)cyclohexyl)-ethyl)-2-oxoimidazolidine-4-carboxamide;

[0810] 46)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((cis)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0811] 47)(4S)-N-{(R)-(3-chloro-2,4-difluorophenyl)[6-(trifluoromethoxy)pyridin-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0812] 48)(4S)-N-{(S)-(3-chloro-2,4-difluorophenyl)[6-(trifluoromethoxy)pyridin-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0813] 49)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-(4,4-difluorocyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0814] 50)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-(4,4-difluorocyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0815] 51)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0816] 52)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0817] 53)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0818] 54)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0819] 55)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0820] 56)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0821] 57)((4S)-N-{(R)-(3-chloro-4-fluorophenyl)[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0822] 58)(4S)-N-{(S)-(3-chloro-4-fluorophenyl)[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide;

[0823] 59)(4S)-N-{1-((R)-3-chloro-4-fluorophenyl)-2-[(4,4-difluoro-cyclohexyl)oxy]ethyl}-2-oxoimidazolidine-4-carboxamide;

[0824] 60)(4S)-N-{1-((S)-3-chloro-4-fluorophenyl)-2-[(4,4-difluoro-cyclohexyl)oxy]ethyl}-2-oxoimidazolidine-4-carboxamide;

[0825] 61)(4S)-N-[(R)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0826] 62)(4S)-N-[(S)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0827] 63)(S)-N-((R)-(3-chloro-4-fluorophenyl)(1-methyl-3-(tri-fluoromethyl)-1H-pyrazol-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0828] 64)(S)-N-((S)-(3-chloro-4-fluorophenyl)(1-methyl-3-(tri-fluoromethyl)-1H-pyrazol-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0829] 65)(S)-N-((R)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0830] 66)(S)-N-((S)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0831] 67)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0832] 68)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0833] 69)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0834] 70)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0835] 71)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazolyl-5-yl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0836] 72)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazolyl-5-yl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0837] 73)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0838] 74)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0839] 75)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptane-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0840] 76)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptane-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0841] 77)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0842] 78)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0843] 79)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0844] 80)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0845] 81)(S)-N-((R)-3-chloro-4-(trifluoromethoxy)phenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0846] 82)(S)-N-((S)-3-chloro-4-(trifluoromethoxy)phenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0847] 83)(S)-N-((R)-(5-chloro-6-cyclopropylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0848] 84)(S)-N-((S)-(5-chloro-6-cyclopropylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0849] 85)(S)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazol-4-yl)-13-methyl)-2-oxoimidazolidine-4-carboxamide;

[0850] 86)(S)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazol-4-yl)-13-methyl)-2-oxoimidazolidine-4-carboxamide;

[0851] 87)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0852] 88)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0853] 89)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0854] 90)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0855] 91)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0856] 92)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0857] 93)(S)-N-((R)-(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(6-(trifluoromethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0858] 94)(S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(6-(trifluoromethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0859] 95)(S)-N-((R)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0860] 96)(S)-N-((S)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)(5-fluoro-6-(trifluoro-methyl)-pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0861] 97)(S)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide

[0862] 98)(S)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0863] 99)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0864] 100)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0865] 101)(S)-N-((R)-3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)pyrimidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0866] 102)(S)-N-((S)-3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)pyrimidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0867] 103)(4S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0868] 104)(4S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0869] 105)(4S)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0870] 106)(4S)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0871] 107)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-3-(4-chlorophenyl)propyl)-2-oxo-imidazolidine-4-carboxamide;

[0872] 108)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-3-(4-chlorophenyl)propyl)-2-oxo-imidazolidine-4-carboxamide;

[0873] 109)(4S)-N-(1-(3-chloro-4-fluorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)-2-oxoimidazolidine-4-carboxamide;

[0874] 110)(S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-cyclohexylethyl)-2-oxoimidazolidine-4-carboxamide;

[0875] 111)(S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-cyclohexylethyl)-2-oxoimidazolidine-4-carboxamide;

[0876] 112)(4S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0877] 113)(4S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0878] 114)(S)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0879] 115)(S)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0880] 116)(S)-N-((R)-(4-chloro-3-cyanophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0881] 117)(S)-N-((S)-(4-chloro-3-cyanophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0882] 118)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)((R)-1-(2,2,2-trifluoroethyl)piperidin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0883] 119)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)((S)-1-(2,2,2-trifluoroethyl)piperidin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0884] 120)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)((S)-1-(2,2,2-trifluoroethyl)piperidin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0885] 121)(S)-N-((S)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0886] 122)(S)-N-((R)-(4-chlorophenyl)(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0887] 123)(S)-N-((S)-(4-chlorophenyl)(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0888] 124)(S)-N-((R)-(4-chloro-3-(trifluoromethyl)-phenyl)(4-cyanophenyl)-methyl)-2-oxo-imidazolidine-4-carboxamide;

[0889] 125)(S)-N-((S)-(4-chloro-3-(trifluoromethyl)-phenyl)(4-cyanophenyl)-methyl)-2-oxo-imidazolidine-4-carboxamide;

[0890] 126)(S)-N-(bis(3-chloro-4-fluorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0891] 127)(S)-N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0892] 128)(S)-N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0893] 129)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)-5-fluoropyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0894] 130)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)-5-fluoropyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0895] 131)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0896] 132)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0897] 133)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((S)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0898] 134)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((R)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0899] 135)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((S)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0900] 136)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((R)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0901] 137)(S)-N-((R)-(3-chloro-4-fluorophenyl)(2-methylbenzo[d]thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0902] 138)(S)-N-((S)-(3-chloro-4-fluorophenyl)(2-methylbenzo[d]thiazolyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0903] 139)(S)-N-((R)-(3-chloro-4-fluorophenyl)(trans-2-(trifluoromethyl)cyclobutyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0904] 140)(S)-N-((S)-(3-chloro-4-fluorophenyl)(trans-2-(trifluoromethyl)cyclobutyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0905] 141)(4S)-N-((3-chloro-4-fluorophenyl)(3,3-dimethyl-2-(trifluoromethyl)cyclobutyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0906] 142)(4S)-N-((3-chloro-4-fluorophenyl)(4-fluorobicyclo[4.2.0]oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0907] 143)(S)-N-((R)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0908] 144)(S)-N-((R)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0909] 145)(S)-N-((S)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0910] 146)(S)-N-((S)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0911] 147)(S)-N-((R)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0912] 148)(S)-N-((R)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0913] 149)(S)-N-((S)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0914] 150)(S)-N-((S)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0915] 151)(4S)-N-((3-chloro-4-fluorophenyl)(4-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0916] 152)(4S)-N-((3-chloro-4-fluorophenyl)(thiazo[5,4-b]pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0917] 153)(S)-N-((R)-(3-chloro-4-fluorophenyl)(5-chlorobenzofuran-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0918] 154)(S)-N-((S)-(3-chloro-4-fluorophenyl)(5-chlorobenzofuran-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0919] 155)(S)-N-((R)-(4-chlorophenyl)(6-(difluoromethoxy)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0920] 156)(S)-N-((S)-(4-chlorophenyl)(6-(difluoromethoxy)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0921] 157)(S)-N-((R)-(4-chlorophenyl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0922] 158)(S)-N-((S)-(4-chlorophenyl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0923] 159)(4S)-N-((4-chlorophenyl)(4-methyl-2-(trifluoro-methyl)thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0924] 160)(4S)-N-((1(R))-(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethyl)-3-azabicyclo-[3.1.0]hexane-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0925] 161)(4S)-N-((1(S))-(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethyl)-3-azabicyclo-[3.1.0]-hexane-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0926] 162)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)((cis)-1-methyl-2-(trifluoro-methyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0927] 163)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)((trans)-1-methyl-2-(trifluoro-methyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0928] 164)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)((cis)-1-methyl-2-(trifluoro-methyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0929] 165)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)((trans)-1-methyl-2-(trifluoro-methyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0930] 166)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)((cis)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0931] 167)S)-N-((R)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0932] 168)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)((cis)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0933] 169)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0934] 170)(S)-N-((R)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0935] 171)(S)-N-((S)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0936] 172)(4S)-N-(benzo[d]thiazolyl-6-yl(4-chlorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0937] 173)(S)-N-((R)-(4-chlorophenyl)(1H-indazol-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0938] 174)(S)-N-((S)-(4-chlorophenyl)(1H-indazol-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0939] 175)(S)-N-((R)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0940] 176)(S)-N-((S)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0941] 177)(S)-N-((R)-(4-chlorophenyl)(2-methylbenzo[d]oxazol-6-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0942] 178)(S)-N-((S)-(4-chlorophenyl)(2-methylbenzo[d]oxazol-6-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0943] 179)(S)-N-((R)-(4-chlorophenyl)(2-methylbenzo[d]thiazolyl-6-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0944] 180)(S)-N-((S)-(4-chlorophenyl)(2-methylbenzo[d]thiazolyl-6-yl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0945] 181)(S)-N-((R)-(3-chloro-4-fluorophenyl)(4-(methylsulfonyl)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0946] 182)(S)-N-((S)-(3-chloro-4-fluorophenyl)(4-(methylsulfonyl)phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0947] 183)(4S)-N-[(3-chloro-4-fluorophenyl)(5-cyanopyridin-2-yl)methyl]-2-oxoimidazolidine-4-carboxamide;

[0948] 184)(S)-N-((R)-benzo[d]thiazolyl-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0949] 185)(S)-N-((S)-benzo[d]thiazolyl-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0950] 186)(S)-N-((R)-benzo[d]oxazol-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0951] 187)(S)-N-((S)-benzo[d]oxazol-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide;

[0952] 188)(S)-N-((R)-(8,8-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0953] 189)(S)-N-((S)-(8,8-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0954] 190)(S)-N-((R)-(4-chlorophenyl)(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0955] 191)(S)-N-((S)-(4-chlorophenyl)(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0956] 192)(4S)-N-((R)(4-chlorophenyl)((R)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0957] 193)(4S)-N-((R)(4-chlorophenyl)((S)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0958] 194)(4S)-N-((S)(4-chlorophenyl)((S)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; and

[0959] 195)(4S)-N-((S)(4-chlorophenyl)((R)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0960] Or its pharmaceutically acceptable salt.

[0961] Can be used as Na v Further illustrative but non-limiting examples of the compounds of the present invention that inhibit the activity of 1.8 channels include the following compounds:

[0962] 1)(S)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)-phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0963] 2)(S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)-phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0964] 3)(S)-N-((R)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0965] 4)(S)-N-((S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0966] 5)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0967] 6)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide;

[0968] 7)(S)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; and

[0969] 8)(S)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide;

[0970] Or its pharmaceutically acceptable salt.

[0971] While the specific stereochemistry described above is preferred, other stereoisomers, including diastereomers, enantiomers, epimers, and mixtures thereof, may also be used to treat sodium poisoning. v 1.8 mediated diseases.

[0972] The synthetic methods for preparing these compounds are disclosed in the examples shown below. Where synthetic details are not provided in the examples, those skilled in the art of medicinal chemistry or synthetic organic chemistry can readily prepare the compounds by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such compounds, individual stereoisomers, including enantiomers, diastereomers, and mixtures thereof, are also compounds of the present invention.

[0973] Definitions:

[0974] “Ac” represents the acetyl group, which is CH3C(=O)-.

[0975] "alkyl" refers to a saturated carbon chain, which can be straight-chain, branched, or a combination thereof, unless otherwise defined. Other groups with the prefix "alkane," such as alkoxy and alkanoyl, can also be straight-chain, branched, or a combination thereof, unless otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc.

[0976] "Alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, and can be straight-chain, branched, or a combination thereof, unless otherwise defined. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, etc.

[0977] "Alynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, and can be straight-chain, branched, or a combination thereof, unless otherwise defined. Examples of alkynyl groups include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptyynyl, etc. In one embodiment, the -C2-6 alkenyl group is vinyl or propenyl. In another embodiment, the -C2-6 alkenyl group is vinyl. In yet another embodiment, the -C2-6 alkenyl group is propenyl.

[0978] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, or bridged carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In one embodiment of the invention, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclohexyl. In another embodiment, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In another embodiment, the cycloalkyl group is cyclopropyl or cyclobutyl. In another embodiment, the cycloalkyl group is cyclopropyl. In another embodiment, the cycloalkyl group is cyclobutyl. In another embodiment, the cycloalkyl group is cyclopentyl. In another embodiment, the cycloalkyl group is cyclohexyl. In another embodiment, the cycloalkyl group is cycloheptyl. In one embodiment, the C3-12 cycloalkyl group is cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, or spiro[3.3]heptyl. In another embodiment, the C3-12 cycloalkyl group is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, or spiro[3.3]heptyl. In another embodiment, the C3-12 cycloalkyl group is cyclopropyl. In another embodiment, the C3-12 cycloalkyl group is cyclobutyl. In another embodiment, the C3-12 cycloalkyl group is cyclohexyl.

[0979] "Cycloalkenyl" refers to a monocyclic, bicyclic, spirocyclic, or bridged carbocyclic ring having a specified number of carbon atoms and at least one double bond. Examples of cycloalkenyl groups include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. In one embodiment, the cycloalkenyl group is cyclobutene.

[0980] "Cyclohexaalkyl" refers to 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 cyclic heteroatom selected from N, NH, S (including SO and SO2), and O. The cyclohexaalkyl ring may be substituted at the cyclic carbon and / or the cyclic nitrogen or sulfur. Examples of cyclohexaalkyl include tetrahydrofuranyl, pyrroliyl, tetrahydrothiophenyl, aziridine, piperazine, piperidinyl, morpholinyl, oxacyclobutane, and tetrahydropyranyl. In one embodiment of the present invention, the cyclohexaalkyl group is selected from: pyrrolidinyl, aziridine, piperidinyl, piperazinyl, aziridine-heptyl, aziridine-octyl, morpholinyl, thiomorpholinyl, thiomorpholinodiketone, oxaziridine-heptyl, 1,4-thioaziridine-heptyl, isoindolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, octahydroisoindolyl, aziridine-[2.2.1]heptyl, oxa-aziridine-[2.2.1]-yl, aziridine-[3.1.1]heptyl, aziridine-[4.1.0]heptyl, aziridine-[3.2.1]octyl, diaziridine-[3.2.1]octyl, oxa-aziridine-[3.2.1] Octyl, azabicyclo[3.2.0]heptyl, oxa-azabicyclo[3.2.0]heptyl, azaspiro[2.5]octyl, azaspiro[2.6]nonyl, azaspiro[3.5]nonyl, oxa-azaspiro[3.5]nonyl, oxaazaspiro-[4.5]decyl, dihydrothieno[3,2-c]pyridyl, dihydro-thiazo[4,5-c]pyridyl, dihydrooxazolo[4,5-c]pyridyl, dihydroimidazo[1,2-a]pyrazinyl, hexahydrofuran[3,2-b]pyrroleyl, hexahydrocyclopent[c]pyrroleyl, octahydrocyclopent[c]pyrroleyl and azatricyclo[4.3.1.13,8]-undecyl. In another embodiment, the cyclohexaalkyl group is selected from: pyrrolidine, azacyclobutane, piperidine, piperazine, azacycloheptane, morpholine, thiomorpholine, oxazacycloheptane, isoindoline, dihydroisoquinoline, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]-heptane, azabicyclo[4.1.0]-heptane, azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane, dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, and hexahydrofuran[3,2-b]pyrrole. In another embodiment, the cyclohexaalkyl group is selected from azacycloheptane, morpholine, and piperidine. In another embodiment, the cyclohexaalkyl group is azacycloheptane. In another embodiment, the cyclohexaalkyl group is morpholine. In another embodiment, the cyclohexaalkyl group is piperidine. In another embodiment, the cyclohexaalkyl group is aziridine, piperidine, tetrahydropyran, tetrahydrofuran, or azirbicyclo[3.1.0]hexane. In another embodiment, the cyclohexaalkyl group is aziridine, piperidinyl, tetrahydropyranyl, or tetrahydrofuranyl.In another embodiment, the C2-12 cyclohexaalkyl group is a tetrahydropyranyl group.

[0981] "Cyclohepenyl" refers to a monocyclic, bicyclic, spirocyclic, or bridging ring or ring system having a specified number of carbon atoms and containing at least one double bond and at least one heteroatom. Examples of cyclohepenyl groups include dihydropyran and dihydrofuran.

[0982] "Aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one ring is aromatic. Examples of aryl include phenyl and naphthyl. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is naphthyl. In yet another embodiment, the aryl group is phenyl.

[0983] "Heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring or ring system containing 5-14 ring atoms and at least one heteroatom selected from N, NH, S (including SO and SO2), and O, wherein at least one ring containing a heteroatom is aromatic. Examples of heteroaryl groups include pyrroleyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazoleyl, triazolyl, tetrazolyl, furanyl, triazinyl, thiopheneyl, pyrimidinyl, pyrazinyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, quinolinyl, indolyl, isoquinolinyl, quinazolinyl, dibenzofuranyl, etc. In one embodiment of the present invention, the heteroaryl group is a 5- or 6-membered heteroaryl ring. In another embodiment, the heteroaryl group is selected from: pyrazolyl, pyridyl, isoxazolyl, and thiazolyl. In another embodiment of the invention, the heteroaryl group is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazoleyl, imidazo[1,2-a]pyridyl, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 1H-[1,2,3]triazol[4,5-b]pyridyl, 1H-pyrazol[4,3-b]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[2,3-b]pyridyl, benzimidazolyl, imidazolyl, pyrazolyl, thiophene, furan, 1,2,4-oxadiazolyl, 1,3, 4-Oxadiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 4H-pyrido[2,3-e][1,2,4]thiadiazinyl 1,1-dioxide, 2H-pyrido[2,3-e][1,2]thiazinyl 1,1-dioxide, 2,3-dihydroisothiazolyl[4,5-b]pyridinyl 1,1-dioxide, and 3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazinyl 1,1-dioxide. In another embodiment of the invention, the heteroaryl group is selected from pyridinyl, pyrimidinyl, and pyridazinyl. In another embodiment of the invention, the heteroaryl group is pyridinyl.

[0984] In another embodiment, the heteroaryl group is pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, thiophene, furan, triazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyrazolopyridine, pyrazolopyridine, imidazolepyridine, oxazolopyridine, pyrazolopyrimidine, imidazolepyrimidine, oxazolopyrimidine, or thiazopyrimidine. In another embodiment, the heteroaryl group is pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, pyrazolo[1,5-a]pyridine, thiophene, furan, triazole, or indole. In another embodiment, the heteroaryl group is pyridine, thiazole, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, or pyrazolo[1,5-a]pyridine. In another embodiment, the heteroaryl group is a pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, benzofuran, benzo[d]oxazole, benzo[d]thiazole, indazole, thiazo[5,4-b]pyridine, or pyrazolo[1,5-a]pyridine.

[0985] In another embodiment of the invention, the heteroaryl group is selected from: pyridine, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, thiazole, oxazole, benzofuran, benzoxazole, benzothiazole, indole, indazole, thiazopyridine, thiophene, furan, triazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyrazolopyridine, pyrazolopyridine, imidazolepyridine, oxazolopyridine, pyrazolopyrimidine, imidazolepyrimidine, oxazolopyrimidine, and thiazopyrimidine.

[0986] In another embodiment of the invention, the heteroaryl group is selected from: pyridine, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, thiazole, oxazole, benzofuran, benzoxazole, benzothiazole, indole, indazole, and thiazopyridine.

[0987] In another embodiment of the invention, the heteroaryl group is selected from pyridine and thiazole. In another embodiment of the invention, the heteroaryl group is pyridine. In another embodiment of the invention, the heteroaryl group is thiazole.

[0988] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, the halogen is fluorine, chlorine, or bromine. In another embodiment, the halogen is fluorine or chlorine. In another embodiment, the halogen is chlorine or bromine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is chlorine. In another embodiment, the halogen is bromine.

[0989] “Me” stands for methyl.

[0990] "Oxyto" means =O.

[0991] "Saturation" refers to a structure containing only single bonds.

[0992] "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 at least one triple bond.

[0993] When any variable (e.g., R1, Ra, etc.) appears more than once in any constituent or in Formula I, its definition for each occurrence is independent of its definition for each other occurrence. Furthermore, combinations of substituents and / or variables are permitted only if such combinations produce stable compounds. The wavy lines across bonds in substituent variables indicate connection points.

[0994] Under the standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functional group toward the junction. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to:

[0995]

[0996] When selecting compounds of the present invention, those skilled in the art will recognize that various substituents, such as R1, R2, etc., must be selected in accordance with well-known principles of chemical structural connectivity and stability.

[0997] The term "substituted" should be considered to include multiple degrees of substitution of the specified substituents. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently monosubstituted or polysubstituted by one or more of the disclosed or claimed substituent moieties. Independent substitution means that (two or more) substituents may be the same or different.

[0998] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, salts, and / or dosage forms that would be safe and suitable for administration to humans or animals using reasonable medical judgment and in accordance with all applicable government regulations.

[0999] Compounds of Formula I may contain one or more asymmetric centers and thus may exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. This invention is intended to cover all such isomeric forms of compounds of Formula I.

[1000] The independent synthesis of optical isomers and diastereomers, or their chromatographic separation, can be achieved by appropriate modifications of the methods disclosed herein, as is known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or intermediate, and, if necessary, by derivatization of the crystalline product or intermediate with an asymmetric center containing a known absolute configuration or a sufficiently heavy atom to obtain an absolute classification.

[1001] If desired, racemic mixtures of compounds can be separated to isolate individual enantiomers. Separation can be performed using methods known in the art, such as coupling the racemic mixture of compounds with an enantiomerically pure compound to form a mixture of diastereomers, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction typically uses an enantiomerically pure acid or base to form a salt. The diastereomeric derivatives can then be converted to pure enantiomers by cleavage of the added chiral residues. Racemic mixtures of compounds can also be directly separated by chromatographic methods using a chiral stationary phase, methods known in the art.

[1002] Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents with known configurations, through methods known in the art.

[1003] Some of the compounds described herein contain alkene double bonds, and unless otherwise stated, both E and Z geometric isomers are intended to be included.

[1004] A tautomer is defined as a compound in which a rapid proton migration occurs from one atom of the compound to another. Some of the compounds described herein can exist as tautomers with different hydrogen connection sites. Such examples can be ketones and their enol forms, referred to as keto-enol tautomers. Individual tautomers and mixtures thereof are covered by compounds of Formula I.

[1005] In compounds of formula I, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in specific isotopes having the same atomic number but a different atomic mass or mass number than those predominantly found in nature. This invention is intended to include all suitable isotopic variants of compounds of formula I. For example, different isotopic forms of hydrogen (H) include protium (… 1 H), deuterium ( 2 H) and tritium ( 3Deuterium (H) is the main hydrogen isotope found in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. Tritium is radioactive and therefore can provide radiolabeled compounds that can be used as tracers in metabolic or kinetic studies.

[1006] Compounds enriched with isotopes in Formula I can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or using methods similar to those described in the schemes and examples herein, using suitable isotope-enriching reagents and / or intermediates.

[1007] Furthermore, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and are therefore intended to be included in the present invention. Additionally, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are covered within the scope of the present invention.

[1008] The compounds of the present invention are generally preferred to be administered in enantiomeric form. Racemic mixtures can be separated into their individual enantiomers by any of a variety of conventional methods. These include chiral chromatography, derivatization with chiral adjuvants followed by separation by chromatography or crystallization, and fractional crystallization of diastereomer salts.

[1009] Salt

[1010] It should be understood that, as used herein, references to the compounds of the present invention are also intended to include pharmaceutically acceptable salts, as well as non-pharmaceutically acceptable salts when used as precursors to free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[1011] 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, wherein the base or acid includes inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of the present invention, which are typically prepared by reacting a 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: acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, camphorsulfonates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, ethanedisulfonates, propionate ester dodecane sulfate, ethanesulfonates, fumarates, gluconate, gluconate, glutamate, glycolyllars-anilate, hexylresorcinol salts, hyaluronic acid salts, hydrobromide salts, and hydrochloride salts. Hydroxynaphthalene salts, iodides, hydroxyethyl sulfonates, lactates, lacturonates, lysine salts, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, oleates, oxalates, pyruvate (bishydroxynaphthalate), palmitate, pantothenates, phosphates, diphosphates, polygalacturonates, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, 8-chlorotheophylline salts, toluenesulfonates, triethyliodide salts, trifluoroacetate salts, and valerates. When the compounds of the present invention contain an acidic moiety, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include primary, secondary, and tertiary amines, cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[1012] Furthermore, in the presence of a carboxylic acid (-COOH) or alcohol group in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl esters, ethyl esters, or neopentyloxymethyl esters, or acyl derivatives of alcohols, such as O-acetyl, O-neopentyl, O-benzoyl, and O-aminoacyl groups, may be used. This includes esters and acyl groups known in the art for modifying solubility or hydrolytic properties for use as sustained-release or prodrug formulations.

[1013] The term "prodrug" refers to a compound that is rapidly converted into a parent compound in vivo, for example, by hydrolysis in the blood; for example, a prodrug of Formula I is converted into a compound of Formula I or into its salt; a full discussion is provided in T. Higuchi and V. Stella, *Pro-drugs as Novel Delivery Systems*, Vol. 14 of the ACSSymposium 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. This invention includes prodrugs of the novel compounds of this invention.

[1014] Solvates of the compounds of the present invention, particularly hydrates, are also included in the present invention.

[1015] Utility

[1016] The compound of this invention is Na v 1.8 Selective inhibitors of sodium ion channel activity or as Na v 1.8 Sodium ion channel blockers exhibit selective activity. Based on Determine the functional effectiveness (IC) of each channel in the system. 50 (value), in one embodiment, the compound of the present invention is effective against Na. v 1.8 Sodium channel selectivity compared to Na v The 1.5 sodium channel exhibits at least 10-fold higher selectivity, and in some embodiments, it is even more selective for Na+. v 1.8 Sodium channel selectivity comparison with Na v The selectivity of the 1.5 sodium channel is at least 100 times higher.

[1017] The compound of this invention is Na v 1.8 Channel activity potent inhibitors. The compounds and their pharmaceutically acceptable salts are effective inhibitors of Na+ channel activity. v 1.8 Sodium ion channel activity and / or Na vTreatment of diseases, symptoms, and patients mediated by 1.8 receptor inhibition.

[1018] by Na v 1.8 Sodium ion channel activity and / or Na v 1.8 Receptor-mediated diseases, conditions, or ailments 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 caused by cancer and chemotherapy, chronic pelvic pain, pain syndromes, and complex regional pain syndromes.

[1019] One or more of these patients or diseases can be treated, managed, prevented, alleviated, 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 requiring treatment. Furthermore, the compounds of the present invention can be used to manufacture drugs that can be used to treat, prevent, manage, alleviate, improve, or control one or more of these patients, diseases, or conditions: nociceptive pain, osteoarthritis, peripheral neuropathy, hereditary erythematosus limba, 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 caused by cancer and chemotherapy, chronic pelvic pain, pain syndrome, and complex regional pain syndrome.

[1020] The preferred use of the compound is to treat one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment. The compound can be used to manufacture a medicament for treating one or more of these diseases:

[1021] 1) Pain sufferers,

[1022] 2) Patients with pruritus, and

[1023] 3) Patients with cough.

[1024] In one embodiment of the invention, the pain patient suffers from either acute or chronic pain. In another embodiment of the invention, the pain patient suffers from acute pain.

[1025] The compounds of this invention are effective in treating nociception. Nociception, or pain, is essential for survival and often has a protective function. However, pain associated with surgery and current therapies for relieving this pain may delay postoperative recovery and prolong hospital stays. Up to 80% of surgical patients experience postoperative pain due to tissue damage, peripheral nerve injury, and subsequent inflammation. Approximately 10-50% of surgical patients develop chronic pain after surgery, often due to persistent neuropathic pain caused by nerve damage after wound healing.

[1026] The compounds of this invention are effective in treating osteoarthritis. Osteoarthritis is a type of arthritis caused by inflammation, breakage, and eventual loss of articular cartilage. The standard of care for pain associated with osteoarthritis is nonsteroidal anti-inflammatory drugs (NSAIDs), such as celecoxib and diclofenac (reviewed in Zeng et al., 2018). Patients unresponsive to NSAID therapy are often treated with low-dose opioids such as hydrocodone. Patients who are difficult to treat with the above therapies often opt for total joint replacement.

[1027] The compounds of this invention are effective in treating peripheral neuropathy. Peripheral neuropathy is nerve damage caused by chronic hyperglycemia and diabetes. It can cause numbness, loss of sensation, and sometimes pain in the distal extremities such as the feet, legs, or hands. It is the most common complication of diabetes. The standard of care for treating painful diabetic neuropathy is gabapentin, such as gabapentin and pregabalin. Some patients respond well to tricyclic antidepressants such as amitriptyline, while others experience significant relief with SRI / NRI drugs such as duloxetine (Schreiber et al., World JDiabetes. 2015 Apr 15; 6(3):432-44). There are many options available, however, side effects (e.g., dizziness, nausea) are common, which limits their full potential.

[1028] The compounds of this invention are effective in treating hereditary erythromelalgia (IEM). IEM is a chronic pain syndrome, associated with conditions including Na+. v Mutations in several voltage-gated sodium channels, including 1.8, are associated with this condition (Kist et al., PLoS One. 2016 Sep 6; 11(9):e0161789). Patients exhibit a classic “glove and sock” bright spot pattern in distal areas such as the hands and feet, often induced by warm temperatures and exercise. Some patients find relief from the burning sensation associated with the bright spots by immersion in cold water. Although drugs that affect voltage-gated sodium channels (e.g., lidocaine and mexiletine) show promise, there is currently no standard of care for treating IEM.

[1029] The compounds of this invention are effective in treating neuropathic pain. Neuropathic pain is pain caused by damage or disease affecting the somatic sensory nervous system. Damage to primary afferent sensory neurons has been demonstrated in human patients and in animal models of neuropathic pain to lead to neuroma formation and spontaneous activity, as well as induced activity in response to normal, harmless stimuli. (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 neurological injuries lead to increased Nav1.8 expression, which is believed to be a potential 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). Damage to the peripheral nervous system often results in neuropathic pain that persists for a long time after the initial injury has subsided. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic low back pain, lumbar radiculopathy, phantom limb pain, pain caused by cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and associated neuropathic pain, as well as pain conditions caused by 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).

[1030] Ectopic activity of normally silent sensory neurons is thought to contribute to the generation and persistence of neuropathic pain, which is generally considered to be associated with 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). Standards of care for neuropathic pain vary depending on the specific case, but first-line treatments are usually pregabalin, gabapentin, tricyclic antidepressants (e.g., amitriptyline), and SRI / NRI drugs (e.g., duloxetine). Patients who are difficult to treat with these therapies are often given low-dose opioids (e.g., hydrocodone).

[1031] The compounds of this invention are effective in treating multiple sclerosis. Recent evidence suggests a potential role for Nav1.8 in multiple sclerosis. Expression of Nav1.8 in the cerebellum has been identified in tissues from an animal model of multiple sclerosis (EAE model) and in post-mortem brains from 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 Oct10; 97(21):11598-602). In addition, two SCN10A polymorphs have shown a significant association with MS (Roostaei et al., Neurology. 2016 Feb 2; 86(5):410-7). When Nav1.8 is overexpressed in the cerebellum, mice exhibit ataxia-related motor deficits, which can be improved by oral delivery of selective small-molecule Nav1.8 antagonists (Shields et al., PLoS One. 2015 Mar 6; 10(3)). These studies suggest that Nav1.8 antagonists may be a useful therapy for treating symptoms associated with multiple sclerosis.

[1032] The compounds of this invention are effective in treating asthma. Asthma is caused by airway inflammation, in which the airways become hyperresponsive, narrowed, and swollen, leading to difficulty breathing. These symptoms are often triggered 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, deletion of Nav1.8-containing neurons or inhibition of nerve fibers via small molecules reduces airway inflammation and immune cell infiltration (Talbot et al., Neuron. 2015 Jul 15; 87(2):341-54). Selective Nav1.8 antagonists may be a useful therapy to prevent airway hyperresponsiveness caused by immune cell infiltration.

[1033] The compounds of this invention are effective in treating pruritus. Pruritus, commonly known as itching, affects approximately 4% of the global population and is an unpleasant sensation that induces a scratching urge or reflex and is considered to be closely related to pain (Luo et al., Cell Mol Life Sci. 2015 Sep; 72(17):3201-23). ​​Theories about the origin of pruritus involve subtle, low-frequency activation of nociceptors (pain-sensing neurons); however, some afferent neurons are described as preferentially responding to histamine, which induces pruritus (Schmelz et al., J Neurosci. 1997 Oct 15; 17(20):8003-8). Meanwhile, histamine-responsive neurons have also been found to respond to capsaicin, which produces 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 known to play roles in both pruritus and pain, both of which are clinically treated with agents such as gabapentin and antidepressants. Therefore, the underlying mechanisms of pain and pruritus continue to be considered highly intertwined and complex, and the distinction between pain-selective or pruritus-selective pathways remains unclear (Ikoma et al., Nat Rev Neurosci. 2006 Jul; 7(7):535-47). The role of Nav1.8 in pruritus was investigated in mice using a transgenic expression of the constitutively active form of the serine / threonine kinase BRAF expressed in Nav1.8-expressing neurons. This resulted in increased excitability of pruritus receptors and enhanced induced and spontaneous scratching behavior (Zhao et al., 2013). In the skin, pruritogens are released from keratinocytes, lymphocytes, mast cells, and eosinophils during inflammation. These molecules act directly on free nerve endings expressing Nav1.8 to induce pruritus (Riol-Blanco et al., Nature. 2014 Jun 5; 510(7503):157-61). Chronic and acute pruritus can be caused by a wide variety of injuries, diseases, and conditions, and can be classified as cutaneous or pruritogenic, neurogenic, neurological, or psychogenic: pruritus can be caused by systemic conditions, skin conditions, 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 all cause pruritus, just as neurological diseases such as tumors, multiple sclerosis, peripheral neuropathy, nerve compression, and delusions associated with obsessive-compulsive disorder may. Drugs such as opioids and chloroquine can also cause itching (Ikoma et al., Nat RevNeurosci. 2006 Jul; 7(7): 535-47).Post-burn itching is also an extremely serious clinical problem because it can hinder the healing process, leading to permanent scarring and adversely affecting quality of life (Van Loey et al., Br JDermatol. 2008 Jan; 158(1): 95-100).

[1034] The present invention also includes pharmaceutically acceptable salts of the said compound, and pharmaceutical compositions comprising the said compound and a pharmaceutically acceptable carrier.

[1035] The compound or a pharmaceutically acceptable salt thereof can be used to treat patients with pain, itching, and cough.

[1036] The compounds of the present invention or pharmaceutically acceptable salts thereof can be used to manufacture remedies for treating pain, itching, and cough in humans or other mammals.

[1037] Methods of treating pain include administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, to a patient requiring treatment. Methods of treating pruritus include administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, to a patient requiring treatment. Methods of treating cough include administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, to a patient requiring treatment. Other medical uses of the compounds of the present invention are described herein.

[1038] As used herein, the term "pain patient" includes, but is not limited to, 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, vulvar pain, complex regional pain syndrome and related neuropathic pain, pain associated with cancer and chemotherapy, HIV-related pain and neuropathy caused by HIV treatment, nerve injury, nerve root avulsion, painful traumatic mononeuropathy, painful polyneuropathy, erythromyelalgia, paroxysmal excruciating pain, small fiber neuropathy, oral burning syndrome, central pain syndrome (which may be caused by virtually any lesion at any level of the nervous system), and postoperative pain syndrome (e.g., Postoperative pain may include: post-mastectomy syndrome, post-thoracotomy syndrome, stump pain, bone and joint pain (osteoarthritis), repetitive motion pain, toothache, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, dysmenorrhea, pain associated with angina, inflammatory pain of various origins (e.g., osteoarthritis, rheumatoid arthritis, rheumatic diseases, tenosynovitis, and gout), shoulder tendinitis or bursitis, gouty arthritis and polymyalgia rheumatica, primary hyperalgesia, secondary hyperalgesia, primary anomalous pain, secondary anomalous pain, or other pain caused by central sensitization, complex regional pain syndrome, chronic arthritis pain and related neuropathic pain, acute pain, migraine, migraine headache, headache, cluster headache, nonvascular headache, traumatic nerve injury, nerve compression or entrapment, and neuroma pain.

[1039] As used herein, the terms “pruritus patient” or “pruritus condition” include, but are not limited to, patients with an unpleasant sensation that induces the urge to scratch, such as chronic pruritus.

[1040] As used herein, the terms “cough patient” or “cough condition” include, but are not limited to, chronic cough, neurological cough, or cough caused by neurological disorders.

[1041] Treatment by Na v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated disease, condition, or ailment refers to the administration of the compound of the present invention to a subject suffering from such disease, condition, or ailment. One outcome of the treatment may be the reduction of symptoms caused by Na+ receptor mediated disease, condition, or ailment. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, symptoms, or ailments. Another outcome of treatment may be the relief of symptoms caused by Na+ receptors. v 1.8 Sodium ion channel activity or Na v1.8 Receptor-mediated diseases, conditions, or ailments. Another outcome of treatment may be improvement in conditions caused by Na+ receptors. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or ailments. Another outcome of treatment may be the suppression of Na+ receptor-mediated diseases, symptoms, or ailments. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or ailments. Another outcome of treatment may be the management of Na+-mediated diseases, conditions, or ailments. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, symptoms, or illnesses.

[1042] Another outcome of the treatment may be the prevention of Na+-related diseases. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, symptoms, or illnesses.

[1043] Prevention of Na v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or ailments refer to the administration of the compounds of the present invention to a subject at risk of such disease, condition, or ailment. One result of prevention may be the reduction of Na+ receptor-mediated diseases, conditions, or ailments in subjects at risk of such disease, condition, or ailment. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or patients. Another consequence of prevention may be the suppression of Na+ receptor-mediated diseases, conditions, or patients at risk. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or morbidities. Another outcome of prevention may be improved levels of Na+ in subjects at risk of developing such diseases, conditions, or morbidities. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or ailments. Another outcome of prevention may be the reduction of Na+ receptor-mediated lesions in subjects at risk of developing such a disease, condition, or ailment. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, conditions, or patients. Another outcome of prevention may be the management of subjects at risk of developing this disease, condition, or patient by Na+. v 1.8 Sodium ion channel activity or Na v 1.8 Receptor-mediated diseases, symptoms, or illnesses.

[1044] One outcome of the treatment may be a reduction in the amount of pain experienced by the subject relative to the pain experienced before the administration of the compound of the present invention. Another outcome of the treatment may be an alleviation of the amount of pain experienced by the subject relative to the pain experienced before the administration of the compound of the present invention. Another outcome of the treatment may be an improvement in the amount of pain experienced by the subject relative to the pain experienced before the administration of the compound of the present invention. Another outcome of the treatment may be a suppression of the amount of pain experienced by the subject relative to the pain experienced before the administration of the compound of the present invention. Another outcome of the treatment may be the management of the amount of pain experienced by the subject relative to the pain experienced before the administration of the compound of the present invention. Another outcome of the treatment may be an improvement in the amount of pain experienced by the subject relative to the pain experienced before the administration of the compound of the present invention.

[1045] Another outcome of the treatment could be preventing subjects from experiencing further pain after administration of the compounds of the present invention.

[1046] Pain prevention refers to the administration of the compounds of this invention to alleviate pain in subjects at risk of pain. Prevention includes, but is not limited to, administration to subjects prior to surgery or other anticipated painful events. One consequence of prevention may be the reduction of pain in subjects at risk of pain. One consequence of prevention may be the suppression of pain in subjects at risk of pain. One consequence of prevention may be the improvement of pain in subjects at risk of pain. One consequence of prevention may be the relief of pain in subjects at risk of pain. One consequence of prevention may be the management of pain in subjects at risk of pain.

[1047] The terms “application of compound” and / or “administration of compound” should be understood as referring to the provision of 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.

[1048] To implement the treatment method of the present invention, the application of the compound of formula I is carried out by administering an effective amount of the compound of formula I to a mammal requiring such treatment or prevention. The need for prophylactic administration according to the method of the invention is determined by using known risk factors. Ultimately, the effective amount of a single compound is determined by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or ailments suffered by the patient, the chosen route of administration, other drugs and treatments the patient may require concurrently, and other factors in the physician's judgment.

[1049] The usefulness of the compounds of the present invention in these diseases or conditions can be confirmed in animal disease models reported in the literature.

[1050] Administration and dosage range

[1051] The compounds of this invention can be administered to mammals, particularly humans, using any suitable route of administration. For example, they can be administered orally, intravenously, by infusion, subcutaneously, transdermally, intramuscularly, intradermally, transmucosally, intramucosally, rectally, topically, parenterally, ocularly, pulmonaryly, or nasally. Dosage forms include tablets, lozenges, dispersants, suspensions, solutions, capsules, creams, ointments, and aerosols. Preferably, the compounds of this invention are administered orally.

[1052] In the treatment or prevention of Na+ inhibition v In cases of 1.8 sodium ion channel activity, appropriate dose levels are generally from about 0.0001 to 500 mg per kg of patient body weight per day, which may be administered once or multiple times. In one embodiment, an appropriate dose level may be from about 0.001 to 500 mg per kg of patient body weight per day. In another embodiment, an appropriate dose level may be from about 0.001 to about 250 mg / kg per day. In another embodiment, an appropriate dose level may be from about 0.01 to about 250 mg / kg per day. In another embodiment, an appropriate dose level may be from about 0.1 to about 100 mg / kg per day. In another embodiment, an appropriate dose level may be from about 0.05 to 100 mg / kg per day. In another embodiment, an appropriate dose level may be from about 0.1 to 50 mg / kg per day. In another embodiment, an appropriate dose level may be from about 0.05 to 0.5 mg / kg per day. In another embodiment, an appropriate dose level may be from about 0.5 to 5 mg / kg per day. In another embodiment, an appropriate dose level may be from about 5 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 0.01 to 1000 mg of 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 active ingredient, for symptomatic dosage adjustment in the patients to be treated. The compound can be administered at a frequency of 1 to 8 times daily; preferably 1 to 4 times daily; more preferably once or twice daily. This dosage regimen can be adjusted to provide the best therapeutic response.

[1053] However, it should be understood that specific dose levels and dosing frequencies for any particular patient can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability of the compound and the duration of its action, age, weight, general health condition, sex, diet, route and time of administration, excretion rate, drug combination, severity of the particular patient’s condition, and the host being treated.

[1054] 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 also be used in pharmaceutical compositions in which the compound of the present invention or a pharmaceutically acceptable salt thereof is the sole active ingredient.

[1055] As in pharmaceutical compositions, the term "composition" is intended to cover products comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly resulting from: any combination, complexation, or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or other types of reaction or interaction of one or more ingredients. Therefore, pharmaceutical compositions of the present invention cover any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[1056] The compounds of the present invention can be used in combination with other medicines that can also be used to treat or improve the diseases or conditions for which the compounds of the present invention are applicable. Such other medicines can be administered simultaneously or sequentially with the compounds of the present invention via the usual route and in the usual amounts. In treating patients suffering from pain, itching, and cough, more than one medicine is usually administered. The compounds of the present invention can generally be administered to patients who are already taking one or more other medicines for these conditions. When a patient's pain does not respond adequately to treatment, the compounds are usually administered to patients who have already been treated with one or more analgesic compounds.

[1057] Combination therapies also include those in which the compounds of the present invention and one or more other drugs are administered at different overlapping schedules. It is also anticipated that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients can be administered at lower doses than when used individually. Therefore, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds of the present invention.

[1058] Examples of other active ingredients that can be administered in combination with, separately from, or in the same pharmaceutical composition as the compounds of the present invention include, but are not limited to:

[1059] (i) Opioid agonists;

[1060] (ii) Opioid antagonists;

[1061] (iii) Calcium channel antagonists;

[1062] (iv) NMDA receptor agonists;

[1063] (v) NMDA receptor antagonists;

[1064] (vi) Selective COX-2 inhibitors;

[1065] (vii) NSAIDs (nonsteroidal anti-inflammatory drugs);

[1066] (viii) Analgesics;

[1067] (ix) Sodium channel inhibitors;

[1068] (x) Anti-NGF antibody;

[1069] (xi)Na v 1.7 Inhibitors;

[1070] (xii)HCN inhibitor;

[1071] (xiii) TRPV1 antagonists;

[1072] (xiv)Na v 1.7 Biological agents; and

[1073] (xv)Na v 1.8 Biological agents; and

[1074] Its pharmaceutically acceptable salt.

[1075] In another embodiment of the invention, the pharmaceutical composition comprises:

[1076] (1) The compound of claim 1 or a pharmaceutically acceptable salt thereof;

[1077] (2) One or more compounds or pharmaceutically acceptable salts thereof, selected from:

[1078] (i) Opioid agonists;

[1079] (ii) Opioid antagonists;

[1080] (iii) Calcium channel antagonists;

[1081] (iv) NMDA receptor agonists;

[1082] (v) NMDA receptor antagonists;

[1083] (vi) Selective COX-2 inhibitors;

[1084] (vii) NSAIDs (nonsteroidal anti-inflammatory drugs);

[1085] (viii) Analgesics;

[1086] (ix) Sodium channel inhibitors;

[1087] (x) Anti-NGF antibody;

[1088] (xi)Na v 1.7 Inhibitors;

[1089] (xii)HCN inhibitor;

[1090] (xiii) TRPV1 antagonists;

[1091] (xiv)Na v 1.7 Biological agents; and

[1092] (xv)Na v 1.8 Biological agents; and

[1093] Its pharmaceutically acceptable salts; and

[1094] (3) Pharmaceutically acceptable carrier.

[1095] Nav 1.7 bioactive agents refer to proteins that inhibit the function of Nav 1.7 channels, including but not limited to antibodies, nanobodies, and peptides. Nav 1.8 bioactive agents refer to proteins that inhibit the function of Nav 1.8 channels, including but not limited to antibodies, nanobodies, and peptides.

[1096] Specific compounds that can be used in combination with the compounds of the present invention include: sodium channel inhibitors, including but not limited to lidocaine, including lidocaine patches; tricyclic antidepressants, including but not limited to amitriptyline; and SRI / NRI drugs, including but not limited to duloxetine.

[1097] Suitable opioid agonists include, but are not limited to, codeine, fentanyl, hydrocodone, hydromorphone, levonorgestrel, pethidine, methadone, morphine, oxycodone, oxymorphone, buprenorphine, butorphanol, dezocine, nalbuphine, pentazocine, and tramadol.

[1098] Suitable opioid antagonists include, but are not limited to, naltrexone and naloxone.

[1099] Suitable calcium channel antagonists include, but are not limited to, amlodipine, diltiazem, felodipine, gabapentin, isradipine, nicardipine, nifedipine, nisodipine, pregabalin, verapamil, and ziconopeptide.

[1100] Suitable NMDA receptor antagonists include, but are not limited to, ketamine, methadone, memantine, amantadine, and dextromethorphan.

[1101] Suitable COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, and parecoxib.

[1102] Suitable NSAIDs or nonsteroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodoxacin, fenprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, meloxicam, naproxen, naproxen sodium, oxapzin, piroxicam, sulindac, and tometetin.

[1103] Suitable analgesics include, but are not limited to, acetaminophen and duloxetine.

[1104] The above combinations include combinations of the compounds of the present invention not only with one other active compound but also with two or more other active compounds. Non-limiting examples include combinations of compounds with two or more active compounds selected from: opioid agonists; opioid antagonists; calcium channel antagonists; NMDA receptor agonists; NMDA receptor antagonists; selective COX-2 inhibitors; NSAIDs (nonsteroidal anti-inflammatory drugs); and analgesics.

[1105] The compounds of the present invention or their pharmaceutically acceptable salts may also be used in combination with spinal cord stimulation therapy and skin stimulation therapy.

[1106] The present invention also provides a method for treating or preventing sodium poisoning. v 1.8 Methods for treating diseases, conditions, or ailments mediated by sodium ion channel activity, including administering such treatment to individuals requiring or suffering from sodium ion channel activity. v 1.8 Patients at risk of disease mediated by sodium ion channel activity should be given a therapeutically effective dose of sodium. v 1.8 Sodium ion channel activity inhibitors and a certain amount of one or more active ingredients work together to provide effective relief.

[1107] In another aspect of the invention, a pharmaceutical composition comprising Na is provided. v 1.8 Sodium ion channel activity inhibitors and one or more active ingredients, and at least one pharmaceutically acceptable carrier or excipient.

[1108] Therefore, according to another aspect of the invention, Na is provided. v 1.8 Sodium ion channel activity inhibitors and one or more active ingredients are used to manufacture substances for the treatment or prevention of sodium ion channel blockers. v1.8 Use of a medicament for diseases, conditions, or ailments mediated by sodium ion channel activity. Therefore, in another or alternative aspect of the invention, a product is provided that comprises Na in a combination formulation. v 1.8 A sodium ion channel activity inhibitor and one or more active ingredients, used simultaneously, separately, or sequentially for the treatment or prevention of sodium ion channel activity. v 1.8 Sodium ion channel activity mediates diseases, symptoms, or ailments. Such combination formulations may, for example, be in a dual-packaging form.

[1109] It should be understood that, in order to treat or prevent patients with pain, itching, and cough, the compounds of the present invention may be used in combination with another agent effective in treating the disease, condition, or patient.

[1110] The present invention also provides a method for treating or preventing patients with pain, itching, and cough, the method comprising administering to a patient requiring such treatment a certain amount of the compound of the present invention and a certain amount of another agent effective in treating the condition, disease, or ailment, such that together they provide effective relief.

[1111] The present invention also provides a method for treating or preventing patients with pain, itching, and cough, the method comprising administering to a patient requiring such treatment a certain amount of the compound of the present invention and a certain amount of another agent that can be used to treat the particular patient, condition, or disease, such that together they provide effective relief.

[1112] The term "therapeuticly effective amount" refers to the amount of a compound of formula I that will elicit a biological or medical response in cells, tissues, systems, animals, or humans that is being sought by researchers, veterinarians, doctors, or other clinicians, including the relief of symptoms of the condition being treated. The novel treatment methods of this invention target conditions known to those skilled in the art. The term "mammal" includes humans and companion animals such as dogs and cats.

[1113] The weight ratio of the compound of Formula I to the second active ingredient can vary and will depend on the effective dose of each ingredient. Typically, the effective dose of each will be used. Therefore, for example, when a compound of Formula I is combined with a COX-2 inhibitor, the weight ratio of the compound of Formula I to the COX-2 inhibitor will typically be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of compounds of Formula I with other active ingredients will also typically be within the aforementioned range, but in each case, the effective dose of each active ingredient should be used.

[1114] Synthetic methods

[1115] The following reaction schemes and examples illustrate methods for synthesizing compounds of structural formula I as described in this invention. These reaction schemes and examples are provided for illustrative purposes and should not be construed as limiting the invention in any way. Unless otherwise stated, all substituents are as defined above. Compounds of structural formula I can be prepared using several strategies based on synthetic transformations known in the organic synthesis literature. The scope of this invention is defined by the appended claims.

[1116] Instruments

[1117] Reversed-phase chromatography was performed using a Gilson GX-281 equipped with columns selected from the following: Phenomenex Synergi C18 (150 mm x 30 mm x 4 microns), YMC-Actus Pro C18 (150 mm x 30 mm x 5 microns), Xtimate C18 (150 mm x 25 mm x 5 microns), Boston Green ODS (150 mm x 30 mm x 5 microns), XSELECT C18 (150 mm x 30 mm x 5 microns), and Waters XSELECT C18 (150 mm x 30 mm x 5 microns). Conditions include 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) and some examples are noted.

[1118] Chiral separation of SFCs was performed using the following conditions on Sepitat Prep SFC 100, Multigram II (MG II), THAR80 prepSFC, or Waters SFC (80, 200, or 350): Chiral Method A: AD-H column, 30% EtOH (0.1% NH3·H2O) / CO2; Chiral Method B: IC column, 45% EtOH (0.1% NH3·H2O) / CO2; Chiral Method C: AD-H column, 30% EtOH / CO2; Chiral Method D: AD-H column, 25% EtOH (0.1% NH3·H2O) / CO2; Chiral Method E: AD-H column, 5-40% EtOH (0.05% DEA) / CO2; Chiral Method F: WHELK-01 column, 30% EtOH (0.1% DEA) / CO2. Chiral Method G: AD-H column, 20% MeOH / CO2; Chiral Method H: OJ-H column, 25% EtOH (0.1% NH3·H2O) / CO2; Chiral Method I: AD-H column, 40% EtOH / CO2; Chiral Method J: OJ-H column, 15% EtOH (0.1% NH3·H2O) / CO2; Chiral Method K: IG-3 column, 40% EtOH / CO2; Chiral Method L: AD-H column, 30% MeOH / CO2; Chiral Method M: AD-H column, 30% MeOH (0.05% DEA) / CO2; Chiral Method N: OJ-H column, 20% EtOH (0.1% NH3·H2O) / CO2; Chiral Method O: AD-H column, 15% MeOH (0.1% DEA) / CO2. Chiral Method P: AD-H column, 30% MeOH (0.1% NH3·H2O) / CO2; Chiral Method Q: AD-H column, 25% MeOH (0.1% NH3·H2O) / CO2; Chiral Method R: OD-H column, 25% EtOH (0.1% NH3·H2O) / CO2; Chiral Method S: WHELK-01 column, 50% EtOH (0.1% NH3·H2O) / CO2; Chiral Method T: AD-H column, 20% EtOH / CO2; Chiral Method U: AS-H column, 25% MeOH / CO2; Chiral Method V: AD-H column, 40% MeOH / CO2; Chiral Method W: OJ-H column, 15% EtOH / CO2. MeOH / CO2; Chiral method X: IA column, 40% MeOH / CO2; Chiral method Y: AD-H column, 40% MeOH (0.05% DEA) / CO2; Chiral method Z: AS-H column, 20% MeOH / CO2; Chiral method AA: AD-H column, 35% EtOH (0.05%) / CO2.Chiral methods AB: AD-H column, 35% MeOH (0.1% NH3·H2O) / CO2; Chiral method AC: IC column, 30% EtOH (0.1% NH3·H2O) / CO2; Chiral method AD: OD-H column, 40% EtOH (0.1% NH3·H2O) / CO2; Chiral method AE: OD-H column, 30% EtOH / CO2; Chiral method AF: AD-H column, 35% EtOH / CO2; Chiral method AG: AD-H column, 13% MeOH / CO2; Chiral method AH: AD-H column, 15-25% MeOH / CO2; Chiral method AI: OJ-H column, 15-25% MeOH / CO2; Chiral method AJ: IC column, 20% MeOH / CO2; Chiral method AK: Chiral Technologies SFC-B (P4VP), 10% MeOH / CO2; Chiral method AL: OJ-H column, 10% MeOH / CO2; Chiral method AM: AD-H column, 10% MeOH / CO2; Chiral method AN: AD-H column, 35% MeOH / CO2; Chiral method AO: AD-H column, 5% MeOH / CO2; Chiral method AP: AD-H column, 25% EtOH / CO2; Chiral method AQ: WHELK-01 column, 20% EtOH / CO2; Chiral method AR: OD-H column, 15% EtOH / CO2.

[1119] LC / MS determinations were performed on a Waters Classing Aquity system equipped with TUV and MS detectors and a Waters SQD mass spectrometer, a Shimadzu 20UV 254 and 220 nM mass spectrometer equipped with a Shimadzu 2010 or 2020 mass spectrometer, or an Agilent 1200 HPLC equipped with DAD / ELSD and G6110 MSD, using one of the following conditions: 1) Ascentis Express C18 (3 x 50 mm) 2.7 μm column, using a mobile phase containing A: 0.05% TFA / water and B: 0.05% TFA / acetonitrile, with the gradient changing from 90:10 (A:B) to 5:95 (A:B) over 6 minutes, a flow rate of 1.8 mL / min, and UV detection at 210 nm; 2) Aquity BEH C18 (1.0 x 1) Agilent YMC J'Sphere H-80 (3 x 50 mm) 5 μm column, using a mobile phase containing A: 0.05% TFA / water and B: 0.05% TFA / acetonitrile, with the gradient changing from 90:10 (A:B) to 5:95 (A:B) within 2 min, at a flow rate of 0.3 mL / min, detected by UV at 215 nm; 2) Agilent YMC J'Sphere H-80 (3 x 50 mm) 5 μm column, using a mobile phase containing A: 0.1% TFA / water and B: acetonitrile, with the gradient changing from 95:5 (A:B) to 0:100 (A:B) within 3.6 min and held at 0:100 (A:B) for 0.4 min, at a flow rate of 1.4 mL / min, detected by UV at 254 and 220 nm and used with an Agilent 1100 quadrupole mass spectrometer; 3) Agilent TC-C18 (2.1 x 50 mm) 5 μm column, using a mobile phase containing A: 0.1% TFA / water and B: acetonitrile, with the gradient changing from 90:10 (A:B) to 5:95 (A:B) within 2 min, at a flow rate of 1.4 mL / min, detected by UV at 254 and 220 nm and used with an Agilent 1100 quadrupole mass spectrometer; 4) Agilent TC-C18 (2.1 x 50 mm) 5 μm column, using a mobile phase containing A: 0.05% TFA / water and B: 0.05% TFA / acetonitrile, with the gradient changing from 90:10 (A:B) to 5:95 (A:B) within 2 min, at a flow rate of 0. A 50 mm 5 μm column was used with a mobile phase containing A: 0.0375% TFA / water and B: 0.01875% TFA / acetonitrile. The gradient was 90:10 (A:B) held for 0.4 min, then changed from 90:10 to 0:100 (A:B) over 3 min and held at 10:90 (A:B) for 0.6 min. The flow rate was 0.8 mL / min. The mass spectrometer was used for UV detection at 254 and 220 nm and an Agilent 6110 quadrupole mass spectrometer.

[1120] proton or 1¹H NMR was performed using a Varian Unity-Inova 400MHz NMR spectrometer equipped with a Varian 400ATB PFG 5mm probe, a Nalorac DBG 400-5 or Nalorac IDG 400-5 probe, a Varian 400MHz MR spectrometer equipped with an Auto X IDPFG Probe 5mm probe, a Varian 400MHz VNMR spectrometer equipped with a PFG 4Nuc Probe 5mm probe, or a Bruker AvanceIII 500MHz spectrometer equipped with a PABBO Probe 5mm probe, according to standard analytical techniques, unless otherwise specified. The results of the spectroscopic analysis were reported. Chemical shift (δ) values ​​were reported in increments (δ), i.e., parts per million (ppm). 1 Chemical shifts in the 1H NMR spectra are given relative to the signals of the residual non-deuterated solvent (CDCl3 reference δ 7.26 ppm; DMSO d⁻⁶ reference δ 2.50 ppm; CD₃OD reference δ 3.31 ppm). Multiplicity is reported by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet, m = multiplet or overlap of non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz).

[1121] Abbreviations

[1122] AcOH is acetic acid; aq. is aqueous; OAc is acetate; BH3 DMS is dimethylborane sulfide; Boc is tert-butoxycarbonyl; Calc'd is calculated; CDI is 1,1′-carbonyl-diimidazole; DAST is diethylaminosulfur trifluoride; DCE is dichloroethane; DCM is dichloromethane; DEA is diethanolamine; Deoxoflour is bis(2-methoxyethyl)aminosulfur trifluoride; DIEA is N,N-diisopropylethylamine; DMA is dimethylacetamide; DME is dimethoxyethane; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1′-bis(diphenylphosphine) )-Ferrocene; EDC is 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; g is grams; h or hr is hours; HATU is 1-[bis(dimethyl-amino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; Hex is hexane; HOAt is 1-hydroxy-7-azabenzotriazole; HPLC is high performance liquid chromatography; IPA is isopropanol; iPrMgCl is isopropyl magnesium chloride; iPrMgC l-LiCl is a lithium chloride-isopropyltrimonium 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 milligram; mL is milliliter; mmol is millimole; NaHMDS is sodium bis(trimethylsilyl)amide; NH4OAc is ammonium acetate; NMO is 4-methylmorpholine N-oxide; NMP is N-methylpyrrolidone; PCC is pyridine chlorochromate; Pd / C is carbon-supported palladium; Pd(dppf)C l2 is [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II); Pd(PPh3)4 is tetra(triphenylphosphine)palladium(O); Pd(tBu3P)2 is bis(tri-tert-butylphosphine)palladium(O); PE is petroleum ether; PG is a protecting group; prep is preparative; rt or RT is room temperature; sat is saturated; SFC is supercritical fluid chromatography; T3P is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide; TBAF is tetrabutylammonium fluoride; tBuXPhos Pd G3 is [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate (II); TEA is triethylamine; THF is tetrahydrofuran; Ti(OEt)4 is titanium ethoxide (IV); Ti(OiPr)4 is titanium isopropoxide (IV); TLC is thin-layer chromatography; TMS-diazomethane is trimethylsilyl-diazomethane; UV is ultraviolet light.

[1123] As illustrated in Scheme A, the compounds of the present invention are typically prepared by condensation between a suitably functionalized aldehyde A-1 and a tert-butylsulfinamide using a dehydrating agent such as Ti(OEt)4 or Ti(OiPr)4 to give intermediate A-2. Intermediate A-2 can then be reacted with a variety of organometallic nucleophiles A-3 to give intermediate A-4, which can be deprotected under acidic conditions to give an amine of formula A-5. Amine A-5 can then be combined with imidazolinone A-6 using amide coupling conditions (Z=OH) or nucleophilic substitution reaction (Z=Cl) to provide a compound of formula A-7. In some embodiments, it may be necessary to remove protecting groups, such as Boc, throughout the synthesis. Aldehydes of type A-1 and organometallic compounds of type A-3 are commercially available or can be synthesized from suitable intermediates.

[1124] Option A

[1125]

[1126] As illustrated in Scheme B, the compounds of the present invention are typically prepared by activating a suitably functionalized carboxylic acid B-1 with (COCl)₂ or an amide B-2 coupled with an amine to give intermediate B-3. These intermediates are then suitable for reaction with various organometallic nucleophiles A-3 to give intermediate B-4. Intermediate B-4 can then be reductively amination in the presence of an amine source and a reducing agent to produce intermediate A-5. In some cases, tert-butylsulfinamide is used as the amine source and deprotection (in an acidic environment) is required after reductive amination. Amine A-5 can then be combined with imidazolinone A-6 using amide coupling conditions (Z=OH) or a nucleophilic substitution reaction (Z=Cl) to provide a compound of formula A-7. In some embodiments, it may be necessary to remove protecting groups, such as Boc, throughout the synthesis. Carboxylic acids of type B-1 and organometallic compounds of type A-3 are commercially available or can be synthesized from suitable intermediates.

[1127] Option B

[1128]

[1129] intermediate

[1130] Intermediate 1

[1131] (3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazol-4-yl)methanamine hydrochloride

[1132]

[1133] Step 1: (R)-N-((2-chlorothiazol-4-yl)methyl)-2-methylpropane-2-sulfmamide.2-Chlorothiazol-4-carboxaldehyde (2.00 g, 13.6 mmol) and (R)-2-methylpropane-2-sulfinamide (1.64 g, 13.6 mmol) were dissolved in THF (68 mL), and then Ti(OEt)4 (5.68 mL, 27.1 mmol) was added. The mixture was stirred for 2 hours, then diluted with brine, filtered through sand, and extracted with EtOAc. The combined organic layers were washed with saturated NH4Cl and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1134] Step 2: (R)-N-((3-chloro-4-fluorophenyl)(2-chlorothiazol-4-yl)methyl)-2-methylpropane-2- sulfonamide. Step 3: (R)-N-((3-chloro-4-fluorophenyl)(2-(3,3,3-trifluoroprop-1-en-2-yl)thiazol-4-yl)methyl)- 2-methylpropane-2-sulfonamide. 2-Chloro-1-fluoro-4-iodobenzene (3.1 mL, 24 mmol) was dissolved in THF (20 mL) and cooled to 0 °C. Then, iPrMgCl (8.0 mL, 16 mmol, 2 M, in THF) was slowly added over 5 minutes. The mixture was stirred for 15 minutes, and then a solution of (R)-N-((2-chlorothiazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (2.0 g, 8.0 mmol) in toluene (100 mL) was slowly added at -25 °C. The mixture was then warmed to room temperature and stirred at room temperature for 1 hour. The mixture was quenched with 1 N HCl and stirred for 10 minutes. The mixture was then extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc:hex) to give the title compound.

[1135] Step 4: (R)-N-((3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazol-4-yl)methyl)- 2-methylpropane-2-sulfonamide. Step 5: (3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazol-4-yl)methanamine hydrochloride. (R)-N-((3-chloro-4-fluorophenyl)(2-chlorothiazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (1.1 g, 3.0 mmol), Na₂CO₃ (0.95 g, 9.0 mmol), Pd(dppf)Cl₂ (1.1 mg, 1.5 mmol), and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxoborhexane (1.3 mL, 6.0 mmol) were dissolved in THF (12 mL) and water (3 mL) and degassed by bubbling N₂ through the solution for 10 minutes. The mixture was then heated to 110 °C and held for 1 hour by microwave irradiation. The mixture was then diluted with saturated Na₂CO₃ and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0-75% EtOAc:hex) to obtain the title compound.

[1136] (R or S)-6-(amino(3-chloro-4-fluorophenyl)methyl)picolinonitrile hydrochloride Step 1: (R)-N-((6-bromopyridin-2-yl)methyl)-2-methylpropane-2-sulfonamide.A solution of (R)-N-((3-chloro-4-fluorophenyl)(2-(3,3,3-trifluoroprop-1-en-2-yl)thiazolyl-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.50 g, 1.1 mmol) and diphenyl-(methyl)sulfonium tetrafluoroborate (0.42 g, 1.5 mmol) in THF (12 mL) was cooled to 0 °C. Then, NaHMDS (0.91 mL, 1.8 mmol) was added at 0 °C over 5 minutes, and the reaction was allowed to warm to room temperature. The mixture was quenched by adding MeOH and concentrated under vacuum. The residue was subjected to silica gel chromatography (0-80% EtOAc:hex) to give the title compound.

[1137] Step 2: (R)-N-((6-bromopyridin-2-yl)(3-chloro-4-fluorophenyl)methyl)-2-methylpropane-2- sulfonamide. A solution of (R)-N-((3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclo-propyl)thiazolyl-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.52 g, 0.85 mmol) in EtOAc (12 mL) was cooled to 0 °C. HCl gas was then bubbled through the mixture for 15 seconds until saturation. The mixture was then concentrated under vacuum to give the title compound.

[1138] Intermediate 2A Step 3: (R)-N-((3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl)-2-methylpropane-2- sulfonamide.

[1139]

[1140] Step 4: (R or S)-6-(amino(3-chloro-4-fluorophenyl)methyl)picolinonitrile. Ti(OEt)4 (2.2 mL, 11 mmol) was added to a mixture of 6-bromopicolinaldehyde (1.0 g, 5.4 mmol) and (R)-2-methylpropane-2-sulfinamide (0.78 g, 6.4 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 hours, then diluted with EtOAc, washed with brine, and filtered. The filtrate was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1141] (R or S)-6-(amino(3-chloro-4-fluorophenyl)methyl)picolinonitrile hydrochloride Step 1: (R)-N-((R or S)-(3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl)-2-methylpropane- 2-sulfonamide. (3-chloro-4-fluorophenyl)-magnesium bromide (7.8 mL, 7.8 mmol, 1 M) was added to a solution of (R)-N-((6-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.75 g, 2.6 mmol) in toluene (20 mL) at -45 °C. The mixture was stirred at -45 °C for 2 h and then quenched with saturated NH4Cl. The mixture was then extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative silica gel TLC (2:1 EtOAc:PE) to give the title compound.

[1142] Step 2: (R or S)-6-(amino(3-chloro-4-fluorophenyl)methyl)picolinonitrile. 6-(difluoromethyl)-5-fluoropicolin-aldehyde Pd(tBu3P)2 (45 mg, 0.089 mmol) was added to a mixture of (R)-N-((6-bromopyridin-2-yl)(3-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (0.13 g, 0.32 mmol) and Zn(CN)2 (0.19 g, 1.6 mmol) in NMP (6 mL). The mixture was heated to 130 °C by microwave and held for 10 minutes. The reaction was then filtered. Water was added to the filtrate, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by reversed-phase HPLC (55:45 to 35:65; water (0.1% TFA): MeCN (0.1% TFA)), followed by lyophilization to give the title compound: the first eluted diastereomer 2A1(R)-N-((R or S)-(3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

[1143] Step 1: 6-chloro-2-(difluoromethyl)-3-fluoropyridine. A solution of 2A1(R)-N-(-(3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.22 g, 0.60 mmol) in HCl (0.50 mL, 2.0 mmol, 4 N, in MeOH) and THF (3 mL) was stirred at 15 °C for 1 hour. The reaction mixture was then concentrated under vacuum to give the title compound as a hydrochloride salt.

[1144] Intermediate 2B

[1145] Step 2: 2-(difluoromethyl)-3-fluoro-6-vinylpyridine.

[1146]

[1147] Step 3: 6-(difluoromethyl)-5-fluoropicolin-aldehyde. (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanaminePd(tBu3P)2 (45 mg, 0.089 mmol) was added to a mixture of (R)-N-((6-bromopyridin-2-yl)(3-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide (0.13 g, 0.32 mmol, as prepared in intermediate 2A) and Zn(CN)2 (0.19 g, 1.6 mmol) in NMP (6 mL). The mixture was heated to 130 °C by microwave and held for 10 min. The reaction was filtered and water was added to the filtrate, followed by extraction with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by reversed-phase HPLC (55:45 to 35:65; water (0.1% TFA): MeCN (0.1% TFA)), followed by lyophilization to give the title compound: the second eluted diastereomer 2B1(R)-N-((R or S)-(3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.

[1148] Step 1: 6-chloro-5-fluoro-N-methoxy-N-methylpicolinamide. A solution of 2B1(R)-N-((R or S)-(3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.22 g, 0.60 mmol) in HCl (0.50 mL, 2.0 mmol, 4 N, in MeOH) and THF (3 mL) was stirred at 15 °C for 1 hour. The reaction was concentrated under vacuum to give the intermediate 2B(R or S)-6-(amino(3-chloro-4-fluorophenyl)methyl)picolinonitrile as a hydrochloride salt.

[1149] Intermediate 3

[1150] Step 2: 5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)picolinamide.

[1151]

[1152] Step 3: (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanone. DAST (5.0 mL, 7.6 mmol) was added to a solution of 6-chloro-3-fluoro-picolinaldehyde (2.0 g, 12 mmol) in CHCl3 (35 mL) at 0 °C. The mixture was degassed and backfilled with N2 (three times). The mixture was then stirred at room temperature for 12 hours, quenched with water, and extracted with DCM. The organic phases were combined and concentrated under vacuum to give the title compound.

[1153] Step 4: (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine.Pd(dppf)Cl2 (0.89 g, 1.21 mmol) was added to a mixture of 6-chloro-2-(difluoro-methyl)-3-fluoropyridine (2.2 g, 12 mmol), potassium trifluoro(vinyl)borate (3.2 g, 24 mmol), and K2CO3 (3.4 g, 24 mmol) in THF (25 mL) and water (0.1 mL). The mixture was stirred at 80 °C for 12 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1154] 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid A mixture of 2-(difluoromethyl)-3-fluoro-6-vinylpyridine (1.8 g crude), NMO (2.4 g, 21 mmol), and OsO4 (0.033 mL, 0.10 mmol) in THF (25 mL) and water (5 mL) was stirred at room temperature for 2 hours. Then, NaIO4 (11 g, 52 mmol) was added to the mixture, and the reaction was stirred at room temperature for 2 hours. The mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1155] Intermediate 4

[1156] ​

[1157]

[1158] ​ CDI (5.5 g, 34 mmol) was added to a mixture of 6-chloro-5-fluoropicolinic acid (5.0 g, 28 mmol) in DCM (20 mL). The mixture was stirred for 1 hour. Then, N,O-dimethylhydroxylamine hydrochloride (3.3 g, 34 mmol) and TEA (12 mL, 85 mmol) were added. The mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–30% EtOAc:PE) to give the title compound.

[1159] ​ 2,2,2-trifluoro (1.1 g, 11 mmol) was added to a mixture of 6-chloro-5-fluoro-N-methoxy-N-methylpicolinamide (3.0 g, 14 mmol), tBuXPhos Pd G3 (1.0 g, 1.4 mmol), and Cs₂CO₃ (9.4 g, 29 mmol) in toluene (20 mL). The mixture was stirred at 80 °C for 16 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0–30% EtOAc:PE) to give the title compound.

[1160] ​ To a solution of 4-bromo-2-chloro-1-fluorobenzene (2.4 g, 12 mmol) in THF (5 mL), iPrMgCl (6.5 mL, 8.5 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. Then, a solution of 5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)picolinamide (1.5 g, 5.3 mmol) in THF (5 mL) was added, and the resulting mixture was stirred at room temperature for 16 hours. Saturated NH4Cl was then added, and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–30% EtOAc:PE) to give the title compound.

[1161] ​ In a 30 mL microwave-safe vial, NH4OAc (0.99 g, 13 mmol) and NaBH3CN (80 mg, 1.3 mmol) were added to a solution of (3-chloro-4-fluorophenyl)(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-2-yl) ketone (0.30 g, 0.85 mmol) in EtOH (5 mL). The mixture was stirred and heated in a microwave reactor at 130 °C for 10 min. The reaction mixture was then concentrated under vacuum and subsequently treated with 2N NaOH until pH > 10. The solution was then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0–30% EtOAc:PE) to give the title compound.

[1162] Intermediate 5

[1163] ​

[1164]

[1165] Step 1: 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid ethyl ester. To a mixture of methyl 1H-pyrazole-3-carboxylate (1.0 g, 7.1 mmol) and K₂CO₃ (2.0 g, 14 mmol) in MeCN (10 mL), trifluoroethyl 2,2,2-trifluoromethanesulfonate (2.5 g, 11 mmol) was added. The resulting mixture was stirred at 80 °C for 18 hours. The reaction was then quenched with water, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (31% EtOAc:PE) to give the title compound.

[1166] Step 2: 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid.To a mixture of ethyl 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylate (1.0 g, 4.5 mmol) in a solution of EtOH (5 mL) and water (5 mL), NaOH (0.36 g, 9.0 mmol) was added. The resulting mixture was stirred at 80 °C for 30 minutes. The mixture was then concentrated under vacuum. The resulting residue was dissolved in EtOAc and washed with hydrochloric acid (0.5 M). The organic layer was separated, dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1167] Intermediate 6

[1168] 5-Fluoro-4-(trifluoromethyl)picolinaldehyde

[1169]

[1170] Step 1: 5-Fluoro-4-(trifluoromethyl)-2-vinylpyridine. Pd(dppf)Cl2 (0.37 g, 0.50 mmol) was added to a mixture of 2-chloro-5-fluoro-4-(trifluoromethyl)pyridine (1.0 g, 5.0 mmol), potassium trifluoro(vinyl)borate (1.0 g, 7.5 mmol), and K2CO3 (1.4 g, 10 mmol) in dioxane (15 mL) and water (1.5 mL). The mixture was stirred at 100 °C for 12 hours. Water was then added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1171] Step 2: 5-Fluoro-4-(trifluoromethyl)picolinaldehyde. A mixture of 0.96 g crude 5-fluoro-4-(trifluoromethyl)-2-vinylpyridine, 1.2 g (10 mmol), and 2.5 mL (0.25 mmol) in THF (20 mL) and water (10 mL) was stirred at room temperature for 12 hours. Then, 3.2 g (15 mmol) of NaIO4 was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture, followed by extraction with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1172] Intermediate 7

[1173] (3-Chloro-2,4-Difluorophenyl)(5-Chloro-6-cyclopropylpyridin-3-yl)methylamine hydrochloride

[1174]

[1175] Step 1: 5-Bromo-3-chloro-2-cyclopropylpyridine.Zinc chloride (0.55 g, 4.0 mmol) in THF (15 mL) was added to a solution of cyclopropylmagnesium bromide (8.1 mL, 4.0 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature for 1 hour, and then 2,5-dibromo-3-chloropyridine (1.0 g, 3.7 mmol) and Pd(PPh3)4 (0.43 g, 0.37 mmol) were added in a single batch. The mixture was stirred at room temperature for 10 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–10% EtOAc:PE) to give the title compound.

[1176] Step 2: (R)-N-((3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclopropylpyridin-3-yl)methyl)-2-methyl Propane-2-sulfinamide. iPrMgCl-LiCl (1.2 mL, 1.5 mmol, 1.3 M, in THF) was added to a solution of 5-bromo-3-chloro-2-cyclopropylpyridine (0.38 g, 1.7 mmol) in 3 mL of THF at 0 °C. The mixture was stirred for 2 hours, and then a mixture of (R)-N-(3-chloro-2,4-difluorobenzyl)-2-methylpropane-2-sulfinamide (0.42 g, 1.5 mmol, from step 1 of Examples 52A and 52B) in 3 mL of THF was added. The reaction mixture was stirred at 0 °C for 2 hours, then diluted with NH4Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-15% EtOAc:PE) to give the title compound.

[1177] Step 3: (3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclopropylpyridin-3-yl)methylamine hydrochloride. HCl (2.0 mL, 8.0 mmol, 4 N, in MeOH) was added to a solution of (R)-N-((3-chloro-2,4-difluorophenyl)(5-chloro-6-cyclo-propylpyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.20 g, 0.46 mmol) in MeOH (2 mL). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to give the title compound.

[1178] Intermediate 8

[1179] 5-Chloro-6-(trifluoromethyl)picolinal

[1180]

[1181] Intermediate 8 was prepared from 3,6-dichloro-2-(trifluoromethyl)pyridine according to a similar procedure to that of intermediate 6.

[1182] Intermediate 9

[1183] (5-chloro-6-(trifluoromethyl)pyridin-3-yl)(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)methylamine hydrochloride

[1184]

[1185] Step 1: 3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(trifluoromethyl) Pyridine. To a solution of 3-chloro-2-(trifluoromethyl)pyridine (2.0 g, 11 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxacyclopentaborane) (4.2 g, 17 mmol) in hexane (30 mL), 4,4'-di-tert-butyl-2,2'-bipyridine (0.30 g, 1.1 mmol) and rhodium(I) bis(1,5-cyclooctadiene)tetrafluoroborate (0.37 g, 0.55 mmol) were added. The mixture was stirred at 65 °C for 18 hours, then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–8% EtOAc:PE) to give the title compound.

[1186] Step 2: 3-Chloro-5-iodo-2-(trifluoromethyl)pyridine. To a solution of compound 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(trifluoromethyl)pyridine (1.0 g, 3.2 mmol) in DME (15 mL), 1-iodopyrrolidine-2,5-dione (2.2 g, 9.8 mmol), CuI (0.062 g, 0.32 mmol), 1,10-phenanthroline (0.059 g, 0.32 mmol), and K₂CO₃ (0.90 g, 6.5 mmol) were added. The mixture was stirred at 50 °C for 12 hours, then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative silica gel TLC (0–1% EtOAc:PE) to give the title compound.

[1187] Step 3: (R)-N-((5-chloro-6-(trifluoromethyl)pyridin-3-yl)(5-fluoro-6-(trifluoromethyl)pyridin-2-yl) 2-Methylpropane-2-sulfinamide.At -40°C, an iPrMgCl-LiCl complex (0.65 mL, 0.85 mmol, 1.3 M, in THF) was added to a solution of 3-chloro-5-iodo-2-(trifluoro-methyl)pyridine (0.28 g, 0.91 mmol) in toluene (3 mL). The mixture was stirred at -40°C for 1 hour. Then, (R)-N-((5-fluoro-6-(trifluoromethyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.18 g, 0.61 mmol, from step 3 of Examples 7A and 7B) was added to toluene (2 mL). The mixture was stirred at -40°C, then slowly heated to 29°C and stirred at 29°C for 4 hours. The mixture was then quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative silica TLC (33% EtOAc:PE) to obtain the title compound.

[1188] Step 4: (5-chloro-6-(trifluoromethyl)pyridin-3-yl)(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)methylamine salt Salt. HCl (2.0 mL, 8.0 mmol, 4 N, in MeOH) was added to a solution of (R)-N-((5-chloro-6-(trifluoromethyl)pyridin-3-yl)(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.24 g, 0.50 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 11 hours and then concentrated under vacuum to give the title compound.

[1189] Intermediate 10

[1190] (3-Chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methylamine

[1191]

[1192] Step 1: Methyl cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate. Methyl 2,2,2-trifluoromethanesulfonate (0.41 g, 1.7 mmol) was added to a mixture of methyl cis-2,6-dimethylpiperidin-4-carboxylate (0.20 g, 1.2 mmol) and K₂CO₃ (0.32 g, 2.3 mmol) in MeCN (10 mL). The resulting mixture was stirred at 100 °C for 12 hours. Water was then added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0–10% EtOAc:PE) to give the title compound.

[1193] Step 2: cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylic acid.At 25 °C, methyl cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxylate (0.31 g, 1.2 mmol) was added to a mixture of MeOH (2.5 mL) and THF (2.5 mL) in an aqueous solution of NaOH (0.61 mL, 3.7 mmol, 6 M). The reaction was stirred at 25 °C for 12 hours, concentrated under vacuum, and dissolved in water. The mixture was extracted with DCM. Then, HCl (1 M) was added to the aqueous mixture until pH ~3, and the mixture was extracted with EtOAc. The combined EtOAc layers were separated and concentrated under vacuum to give the title compound.

[1194] Step 3: cis-N-methoxy-N,2,6-trimethyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide. Di(1H-imidazol-1-yl) ketone (0.24 g, 1.5 mmol) was added to a mixture of cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-carboxylic acid (0.29 g, 1.2 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 1 hour, and then N,O-dimethylhydroxylamine hydrochloride (0.14 g, 1.4 mmol) and TEA (0.32 mL, 2.3 mmol) were added. The resulting mixture was stirred for 12 hours and then concentrated under vacuum. The residue was purified by silica gel chromatography (0–30% EtOAc:PE) to give the title compound.

[1195] Step 4: (3-Chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl ketone. Magnesium (3-chloro-4-fluorophenyl) bromide (0.71 g, 3.0 mmol) was added to a mixture of cis-N-methoxy-N,2,6-trimethyl-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide (0.30 g, 1.0 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1.5 h, then quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-20% EtOAc:PE) to give the title compound.

[1196] Step 5: (3-Chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl amine. NaCNBH3 (73 mg, 1.2 mmol) was added to a mixture of (3-chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl) methyl ketone (0.28 g, 0.77 mmol) and NH4OAc (0.89 g, 12 mmol) in EtOH (8 mL) at 25 °C. The mixture was stirred in a microwave oven at 130 °C for 15 min. The mixture was then concentrated under vacuum, and the resulting residue was purified by preparative silica gel TLC (10% DCM:MeOH) to give the title compound.

[1197] Intermediate 11

[1198] 1-(3-chloro-4-fluorophenyl)-2-((4,4-difluorocyclohexyl)oxy)ethane-1-one

[1199]

[1200] Step 1: 1-(3-chloro-4-fluorophenyl)-2-diazoethane-1-one. A mixture of 3-chloro-4-fluorobenzoic acid (1.0 g, 5.7 mmol) in SOCl2 (10 mL) was stirred at 90 °C for 2 hours. The solvent was then evaporated under reduced pressure. The resulting crude residue was dissolved in THF (10 mL) and MeCN (10 mL) and cooled to 0 °C. TMS-diazomethane (5.7 mL, 11 mmol) was then added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1201] Step 2: 1-(3-chloro-4-fluorophenyl)-2-((4,4-difluorocyclohexyl)oxy)ethane-1-one. Indium trifluoromethanesulfonate (iii) (28 mg, 0.050 mmol) was added to a mixture of 0.10 g crude 1-(3-chloro-4-fluorophenyl)-2-diazoethane-1-one and 0.10 g, 0.76 mmol of 4,4-difluorocyclohexanol in toluene (2 mL). The resulting mixture was stirred at 20 °C for 18 hours. The mixture was concentrated under vacuum and then purified by preparative silica gel TLC (1:5 EtOAc:PE) to give the title compound.

[1202] Intermediate 12

[1203] 2-(tetrahydro-2H-pyran-3-yl)acetic acid

[1204]

[1205] Step 1: 2-(tetrahydro-2H-pyran-3-yl)acetic acid. Methyl 2-(tetrahydro-2H-pyran-3-yl)acetate (0.60 g, 3.8 mmol) was dissolved in MeOH (10 mL), and then LiOH·H₂O (0.32 g, 7.6 mmol) was added to water (2 mL). The reaction was stirred at room temperature for 10 hours, then acidified with 3 M HCl until pH = 2, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound.

[1206] Intermediate 13

[1207] 1-(2,2,2-trifluoroethyl)piperidine-2-carboxaldehyde

[1208]

[1209] Step 1: 2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester.1-(boc)piperidin-2-carboxylic acid (1.0 g, 4.4 mmol) was added to a solution of CDI (1.4 g, 8.7 mmol) in DCM (10 mL) at room temperature for 1 hour. Then, DIEA (2.3 mL, 13 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.64 g, 6.5 mmol) were added, and the resulting mixture was stirred at room temperature for 2 hours. Water was then added, and the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (26% EtOAc:PE) to give the title compound.

[1210] Step 2: N-methoxy-N-methylpiperidine-2-carboxamide. TFA (3.0 mL, 39 mmol) was added to a mixture of tert-butyl 2-(methoxy-(methyl)carbamoyl)piperidine-1-carboxylate (0.40 g, 1.5 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 90 minutes and then concentrated under vacuum to give the title compound.

[1211] Step 3: N-methoxy-N-methyl-1-(2,2,2-trifluoroethyl)piperidine-2-carboxamide. To a mixture of N-methoxy-N-methylpiperidin-2-carboxamide (0.22 g crude) and K₂CO₃ (0.35 g, 2.6 mmol) in MeCN (6 mL), trifluoroethyl 2,2,2-trifluoromethanesulfonate (0.89 g, 3.8 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. Water was then added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (15% EtOAc:PE) to give the title compound.

[1212] Step 4: 1-(2,2,2-trifluoroethyl)piperidine-2-carboxaldehyde. LAH (0.27 g, 7.1 mmol) was added to a mixture of N-methoxy-N-methyl-1-(2,2,2-trifluoroethyl)piperidine-2-carboxamide (1.2 g, 4.7 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then filtered and concentrated to dryness. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1213] Intermediate 14

[1214] 7,7-Difluorobicyclo[4.2.0]oct-1(6),2,4-triene-3-carboxaldehyde

[1215]

[1216] Step 1: 7,7-difluoro-3-iodobicyclo[4.2.0]oct-1(6),2,4-triene.The title compound was prepared from 4-iodo-2-methylbenzoic acid according to a procedure similar to that used in Example 30.

[1217] Step 2: 7,7-Difluorobicyclo[4.2.0]oct-1(6),2,4-triene-3-carboxaldehyde. iPrMgCl (3.0 mL, 6.0 mmol, 2.0 M, in THF) was added to a stirred solution of 7,7-difluoro-3-iodobicyclo[4.2.0]oct-1(6),2,4-triene (1.0 g, 4.0 mmol) and THF (20 mL) at 0 °C. The solution was stirred at 0 °C for 20 min, and then DMF (0.92 mL, 12 mmol) was added. The reaction was stirred at 0 °C for 30 min, quenched with aqueous HCl (1 N), and extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to give the title compound.

[1218] Intermediate 15

[1219] 4-(amino(3-chloro-4-fluorophenyl)methyl)benzonitrile hydrochloride

[1220]

[1221] Step 1: (S)-N-(4-cyanobenzylidene)-2-methylpropane-2-sulfinamide. 4-Formylbenzonitrile (1.3 g, 10 mmol) and (S)-2-methylpropane-2-sulfinamide (1.2 g, 10 mmol) were dissolved in THF (50 mL), and then Ti(OiPr)4 (5.9 mL, 20 mmol) was added. The mixture was stirred for 2 hours, then diluted with brine, filtered through sand, and extracted with EtOAc. The combined organic layers were washed with saturated NH4Cl and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1222] Step 2: 4-(amino(3-chloro-4-fluorophenyl)methyl)benzonitrile hydrochloride. The title compound was prepared from (S)-N-(4-cyanobenzylidene)-2-methylpropane-2-sulfinamide according to a procedure similar to that used in Example 29.

[1223] Intermediate 16

[1224] N-Methoxy-N,1-Dimethyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[1225]

[1226] The title compound was prepared from 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid according to a procedure similar to that in Examples 66A and 66B.

[1227] Intermediate 17

[1228] N-Methoxy-N,1-Dimethyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide

[1229]

[1230] Add to a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (1.0 g, 5.2 mmol) and N,O-dimethylhydroxylamine HCl (0.50 g, 5.2 mmol) in EtOAc (26 mL) (6.1 mL, 10 mmol). Then DIEA (2.7 mL, 15 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was then diluted with saturated potassium dihydrogen phosphate and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1231] Intermediate 18

[1232] N-Methoxy-N,4-Dimethyl-2-(trifluoromethyl)thiazole-5-carboxamide

[1233]

[1234] N-methoxy-N,4-dimethyl-2-(trifluoromethyl)thiazole-5-carboxylic acid was prepared using a procedure similar to that used for the synthesis of intermediate 17.

[1235] Intermediate 19

[1236] 1-Methyl-2-(trifluoromethyl)piperidine-4-carboxylic acid

[1237]

[1238] Acetic acid (0.36 mL, 6.3 mmol, glacial acetic acid) and formaldehyde (0.38 g, 13 mmol) were added to a solution of 2-(trifluoromethyl)piperidin-4-carboxylic acid (0.25 g, 1.3 mmol) in EtOH (15 mL) at room temperature. The reaction mixture was heated at 70 °C for 2 hours. The mixture was then cooled to room temperature and NaBH3CN (0.24 g, 3.8 mmol) was added. The reaction was stirred at room temperature for 15 hours, then quenched by adding water. The mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1239] Intermediate 20

[1240] 6-(difluoromethoxy)-5-fluoronicotinaldehyde

[1241]

[1242] Step 1: 5-Bromo-2-(difluoromethoxy)-3-fluoropyridine.To a solution of 5-bromo-3-fluoropyridin-2-ol (2.0 g, 10 mmol) in MeCN (20 mL), NaH (0.54 g, 14 mmol, 60%, in mineral oil) was added. The mixture was stirred at room temperature for 20 min, then CsF (0.16 g, 1.0 mmol) was added, followed dropwise by trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.3 mL, 11 mmol). The reaction was stirred at room temperature for 2 h, then quenched with H₂O and extracted with Et₂O. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–20% EtOAc:hex) to give the title compound.

[1243] Step 2: 6-(difluoromethoxy)-5-fluoronicotinaldehyde. The title compound was prepared from 5-bromo-2-(difluoromethoxy)-3-fluoropyridine according to a procedure similar to that used in the synthesis of intermediate 6.

[1244] Intermediate 21

[1245] (R)-N-((6-(difluoromethyl)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide

[1246]

[1247] A microwave tube was loaded with 6-(difluoromethyl)nicotinaldehyde (1.0 g, 6.4 mmol), (R)-2-methylpropane-2-sulfinamide (0.93 g, 7.6 mmol), and Ti(OEt)4 (4.0 mL, 19 mmol). The mixture was heated at 90 °C for 25 minutes by microwave irradiation. Water was then added, and the mixture was stirred for 30 minutes, followed by... The mixture was filtered through a filter pad. The filtrate was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0-50% EtOAc:hex) to give the title compound.

[1248] Intermediate 22

[1249] (R)-N-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide

[1250]

[1251] The title compound was prepared from 5-fluoro-6-(trifluoromethyl)nicotinaldehyde according to a procedure similar to that used in the synthesis of intermediate 21.

[1252] Intermediate 23

[1253] (R)-2-Methyl-N-((2-(trifluoromethyl)pyrimidin-5-yl)methylene)propane-2-sulfinamide

[1254]

[1255] The title compound was prepared from 2-(trifluoromethyl)pyrimidine-5-carboxaldehyde according to a procedure similar to that used in the synthesis of intermediate 21.

[1256] Intermediate 24

[1257] 3-Fluoro-5-iodo-2-(2,2,2-trifluoroethoxy)pyridine

[1258]

[1259] To a solution of 2,3-difluoro-5-iodopyridine (3.1 g, 13 mmol) and 2,2,2-trifluoroethane-1-ol (1.1 mL, 14 mmol) in THF (20 mL) at 0 °C, NaH (0.62 g, 16 mmol, 60%, in mineral oil) was added. The mixture was stirred at 0 °C for 30 min, then warmed to room temperature and stirred for 3 h. The mixture was then allowed to partition between EtOAc and brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0–20% EtOAc:hex) to give the title compound.

[1260] Intermediate 25

[1261] 5-Chloro-6-cyclopropylpicolinic acid

[1262]

[1263] Step 1: Methyl 5-chloro-6-cyclopropylpicoline To a solution of methyl 6-bromo-5-chloropyridine-2-carboxylate (0.60 g, 2.4 mmol) in 1,4-dioxane (8 mL), cyclopropylboronic acid (0.23 g, 2.6 mmol), Cs₂CO₃ (1.6 g, 4.8 mmol), and water (0.2 mL) were added. The mixture was purged with N₂ for 5 min. Then, Pd(dppf)Cl₂ (0.16 g, 0.24 mmol) was added, and the mixture was heated to 80 °C and stirred for 5 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–10% EtOAc:hex) to give the title compound.

[1264] Step 2: 5-Chloro-6-cyclopropylpicolinic acid.Water (0.5 mL) and NaOH (0.12 g, 2.9 mmol) were added to a solution of methyl 5-chloro-6-cyclopropyl-picolinate (0.30 g, 1.4 mmol) in THF (3 mL). The mixture was stirred at room temperature for 2 hours, then heated to 40 °C and stirred for 30 minutes. The mixture was then cooled to room temperature and 1 M HCl (2.9 mL, 2.9 mmol) in H₂O was added. The reaction mixture was then extracted with Et₂O, dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound.

[1265] Intermediate 26

[1266] 2-(difluoromethoxy)pyrimidine-5-carboxaldehyde

[1267]

[1268] Step 1: 5-Bromo-2-(difluoromethoxy)pyrimidine. To a solution of 5-bromopyrimidine-2-ol (2.0 g, 11 mmol) in MeCN (50 mL), K₂CO₃ (6.4 g, 46 mmol) and ethyl 2-bromo-2,2-difluoroacetate (4.6 g, 23 mmol) were added. The reaction mixture was stirred at 80 °C for 13 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–10% EtOAc:PE) to give the title compound.

[1269] Step 2: 2-(difluoromethoxy)pyrimidine-5-carboxaldehyde The title compound was prepared from 5-bromo-2-(difluoromethoxy)pyrimidine in a manner similar to that used for intermediate 6.

[1270] Example

[1271] Examples 1A and 1B

[1272] (S)-N-((R)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide

[1273]

[1274] Step 1: 2-bromo-1-(3-chloro-4-fluorophenyl)ethane-1-one.A mixture of 3-chloro-4-fluorobenzoic acid (5.0 g, 29 mmol) in SOCl2 (30 mL) was stirred at 90 °C for 2 hours. The solvent was then evaporated under vacuum. The resulting residue was dissolved in DCM (50 mL) and cooled to 0 °C, and then TMS-diazomethane (43 mL, 86 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours, then cooled to 0 °C. HBr (20 mL, 120 mmol) was then carefully added, accompanied by the escape of gas (N2). After stirring for 30 minutes, the excess acid was neutralized by adding solid Na2CO3. Then an aqueous solution of NaHCO3 was added, and the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting crude product was purified by silica gel chromatography (0-100% EtOAc:PE) to give the title compound.

[1275] Step 2: 2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethane-1-one. K₂CO₃ (19 g, 1.4 mmol) was added to a mixture of 2-bromo-1-(3-chloro-4-fluorophenyl)ethane-1-one (0.21 g, 0.82 mmol) and 3-chloro-4-fluorophenol (0.10 g, 0.68 mmol) in MeCN (3 mL). The resulting mixture was stirred at 15 °C for 8 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and the solvent was concentrated under vacuum. The resulting residue was purified by preparative silica gel TLC (10% EtOAc:PE) to give the title compound.

[1276] Step 3: 2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethane-1-amine. In a 40 mL microwave-safe vial, NH4OAc (0.44 g, 5.7 mmol) and NaBH3CN (0.036 g, 0.57 mmol) were added to a solution of 2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethane-1-one (0.12 g, 0.38 mmol) in EtOH (3 mL). The mixture was stirred in a microwave reactor at 130 °C for 10 min. The reaction mixture was then concentrated to remove most of the EtOH, treated with 2N NaOH until pH > 10, and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1277] Step 4: (S)-N-((R and S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxo Imidazolidine-4-carboxamide. Add 0.12 g crude 2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethane-1-amide, (S)-2-oxoimidazolidine-4-carboxylic acid (59 mg, 0.45 mmol), and DIEA (0.20 mL, 1.1 mmol) to a mixture of 2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethane-1-amide (0.12 g crude), (S)-2-oxoimidazolidine-4-carboxylic acid (59 mg, 0.45 mmol), and DIEA (0.20 mL, 1.1 mmol) in 4 mL of DMF at 0 °C. (0.48 g, 0.75 mmol). The resulting mixture was stirred at 15 °C for 1 hour. The resulting residue was purified by reversed-phase HPLC (40:60 to 30:70; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1278] Step 5: (S)-N-((R or S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxo Imidazolidine-4-carboxamide. (S)-N-((R and S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide was separated by chiral-SFC (Method A) to yield the title compound: the first eluted diastereomer 1A (S)-N-((R or S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted diastereomer 1B (S)-N-((R or S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 1A: LRMS m / z (M+H): calculated 430.1, found 430.0. 1 H NMR (500MHz, CD3OD) δ7.61(dd,J=2.0,7.0Hz,1H),7.39-7.46(m,1H),7.26(t,J=9.0Hz,1H),7.16(t,J=9.0Hz,1H),7.09(dd,J=3.0,6.0Hz,1H),6.91( td,J=3.5,9.0Hz,1H),5.36(t,J=6.0Hz,1H),4.37(dd,J=6.5,10.0Hz,1H) ,4.27(d,J=6.0Hz,2H), 3.83(t,J=9.5Hz,1H), 3.45(dd,J=6.5,9.0Hz,1H). Diastereomer 1B: LRMS m / z(M+H): calculated value 430.1, measured value 430.0. 1 H NMR(500MHz,CD3OD)δ7.46(d,J=7.0Hz,1H),7.27-7.31(m,1H),7.14(t,J=9.0Hz,1H),7.04(t,J=9.0Hz,1H),6.97(dd,J=3.0,6.0Hz,1H),6.7 7-7.81(m,1H),5.21(t,J=6.0Hz,1H),4.25(dd,J=6.0,10.0Hz,1H),4.13(d,J=6.0Hz,2H),3.68(t,J=9.5Hz,1H),3.32(dd,J=6.0,9.0Hz,1H).

[1279] Examples 2A and 2B

[1280] (R)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide and (S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide

[1281]

[1282] Step 1: (R and S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide. Add 0.15 g (1.0 mmol) of 3-methyl-2-oxoimidazolidine-4-carboxylic acid, 0.30 g (1.2 mmol) of bis(4-chlorophenyl)methylamine, and DIEA (0.57 mL, 3.2 mmol) to a solution of 3-methyl-2-oxoimidazolidine-4-carboxylic acid, bis(4-chlorophenyl)methylamine, 0.30 g (1.2 mmol) and DIEA (0.57 mL, 3.2 mmol) in DMF (4 mL) at 0 °C. (1.3 g, 2.1 mmol, 50%, in DMF). The mixture was stirred at room temperature for 12 hours, then water was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (5:95 to 95:5; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1283] Step 2: (R or S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide. Resolution of (R and S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Method B) yielded the title compound: the first eluted enantiomer 2A (R or S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide, and the second eluted enantiomer 2B (R or S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide. Enantiomer 2A: LRMS m / z (M+H): calculated 378.1, observed 378.1. 1 H NMR (500MHz, CD3CN) δ 7.47–7.53 (m, 1H), 7.34–7.40 (m, 4H), 7.23–7.28 (m, 4H), 6.13–6.19 (m, 1H), 4.83 (s, 1H), 4.04–4.10 (m, 1H), 3.54–3.59 (m, 1H), 3.14–3.22 (m, 1H), 2.62–2.66 (m, 3H). Enantiomer 2B: LRMS m / z (M+H): calculated 378.1, measured 378.1. 1H NMR(500MHz,CD3CN)δ7.47-7.53(m,1H),7.34-7.40,(m,4H)7.23-7.27(m,4H),6.13-6.19(m,1H ), 4.83 (s, 1H), 4.03-4.10 (m, 1H), 3.57 (t, J = 9.5Hz, 1H), 3.16-3.20 (m, 1H), 2.61-2.65 (m, 3H).

[1284] Examples 3A and 3B

[1285] (S)-N-((R)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide

[1286]

[1287] Step 1: 3,6-Dichloro-2-(difluoromethyl)pyridine. DAST (3.4 mL, 26 mmol) was slowly added to a mixture of 3,6-dichloropicolinaldehyde (1.5 g, 8.5 mmol) in CHCl3 (35 mL) at 0 °C. The mixture was degassed and backfilled with N2 (X3). The mixture was stirred at room temperature for 12 hours, then quenched with NaHCO3 and water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1288] Step 2: 3-Chloro-2-(difluoromethyl)-6-vinylpyridine. Pd(dppf)Cl2 (0.44 g, 0.61 mmol) was added to a mixture of 2.0 g crude 3,6-dichloro-2-(difluoromethyl)pyridine and 1.7 g, 12 mmol K2CO3 in dioxane (21 mL) and water (4.2 mL). The mixture was stirred at 100 °C for 2 hours, then filtered and concentrated to give the title compound.

[1289] Step 3: 5-Chloro-6-(difluoromethyl)picolinaldehyde.A solution of 3-chloro-2-(difluoromethyl)-6-vinylpyridine (1.5 g crude), NMO (1.9 g, 16 mmol), and OsO4 (0.025 mL, 0.079 mmol) in THF (25 mL) and water (5 mL) was stirred at room temperature for 2 hours. Then, NaIO4 (8.5 g, 40 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was concentrated under vacuum to give the title compound.

[1290] Step 4: (R)-N-((5-chloro-6-(difluoromethyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinyl amine. Ti(OEt)4 (2.8 mL, 14 mmol) was added to a mixture of 5-chloro-6-(difluoromethyl)picolinaldehyde (1.1 g crude) and (R)-2-methylpropane-2-sulfinamide (1.0 g, 8.6 mmol) in THF (25 mL) at 0 °C. The resulting mixture was stirred at room temperature for 18 hours, then diluted with EtOAc and washed with brine. The mixture was filtered, and the filtrate was concentrated to dryness. The crude product was purified by silica gel chromatography (23% EtOAc:PE) to give the title compound.

[1291] Step 5: (R)-N-((5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl) 2-Methylpropane-2-sulfinamide. iPrMgCl-LiCl (3.1 mL, 4.1 mmol, 1.3 M, in THF) was added to a solution of 3-chloro-5-iodo-2-(trifluoro-methyl)pyridine (1.4 g, 4.5 mmol) in toluene (3 mL) at 0 °C. The reaction mixture was stirred for 2 h, and then a mixture of (R)-N-((5-chloro-6-(difluoromethyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.60 g, 2.0 mmol) in toluene (3 mL) was added at -40 °C. The reaction mixture was stirred at -40 °C for 2 h, and then concentrated. The concentrate was purified by silica gel chromatography (25% EtOAc:PE) to give the title compound.

[1292] Step 6: (5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methylamine salt Salt. (R)-N-((5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (1.0 g, 2.1 mmol) was dissolved in HCl (5 mL, 20 mmol, 4 N, in MeOH) and stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum to give the title compound.

[1293] Step 7: (S)-N-((R and S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)-pyridin-2-yl) (Pyridine-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide.Add at 0°C to a mixture of (5-chloro-6-(difluoro-methyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methylamine hydrochloride (0.10 g crude), (S)-2-oxoimidazolidine-4-carboxylic acid (0.038 g, 0.29 mmol), and DIEA (0.13 mL, 0.73 mmol) in 2 mL of DMF. (0.31 g, 0.49 mmol, 50%, in EtOAc). The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reversed-phase HPLC (35:65 to 65:35; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1294] Step 8: (S)-N-((R or S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-2-yl) (Pyridine-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Separation of (S)-N-((R and S)-(5-chloro-6-(di-fluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Method C) yielded the title compound: the first eluted diastereomer 3A, (S)-N-((R or S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted diastereomer 3B, (S)-N-((R or S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 3A: LRMS m / z(M+H): calculated value 484.0, measured value 484.0. 1 ¹H NMR (400MHz, CD₃OD) δ 9.10–9.14 (m, ¹H), 8.66 (d, J = 1.6 Hz, ¹H), 8.14 (s, ¹H), 8.03 (d, J = 8.4 Hz, ¹H), 7.66 (d, J = 8.4 Hz, ¹H), 6.81–7.14 (m, ¹H), 6.42–6.48 (m, ¹H), 4.40 (m, ¹H), 3.80 (t, J = 9.6 Hz, ¹H), 3.47 (m, ¹H). Diastereomer 3B: LRMS m / z (M+H): calculated 484.0, measured 483.9. 1H NMR (400MHz, CD3OD) δ8.65(d,J=1.6Hz,1H),8.13(s,1H),8.03(d,J=8.4Hz,1H),7.66(d,J=8.4Hz, 1H), 6.82-7.15 (m, 1H), 6.44 (s, 1H), 4.38-4.42 (m, 1H), 3.79 (t, J = 9.6Hz, 1H), 3.43-3.47 (m, 1H).

[1295] Examples 4A and 4B

[1296] (S)-N-((R)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide

[1297]

[1298] Step 1: N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide. DIEA (4.4 mL, 25 mmol) and HATU (6.3 g, 17 mmol) were added to a solution of 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (1.5 g, 8.3 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred for 0.5 h, then N,O-dimethylhydroxylamine hydrochloride (1.2 g, 12 mmol) was added, and the resulting mixture was stirred at room temperature for another 2 h. Water was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography (10–100% EtOAc:PE) to give the title compound.

[1299] Step 2: (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl) methyl ketone. Magnesium (3-chloro-4-fluorophenyl) bromide (13 mL, 13 mmol, in THF, 1 M) was added to a mixture of N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide (0.60 g, 2.7 mmol) in THF (3 mL). The mixture was stirred at 0 °C for 2 hours. Then, an aqueous solution of NH4Cl was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under vacuum to give the title compound.

[1300] Step 3: (R)-N-((3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-methylpropane Alkyl-2-sulfinamide.Ti(OEt)4 (0.56 mL, 2.7 mmol) was added to a microwave tube containing (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl) methyl ketone (0.40 g, 1.4 mmol) and (R)-2-methylpropane-2-sulfinamide (0.25 g, 2.0 mmol) in toluene (3 mL). The mixture was microwaved at 105 °C for 30 min and then cooled to room temperature. The mixture was dissolved in THF (5 mL) and water (0.01 mL) and cooled to -78 °C, followed by the addition of NaBH4 (57 mg, 1.5 mmol). The mixture was stirred at -78 °C for 1 h, then gradually warmed to 0 °C over 1 h and stirred at 0 °C for 1 h. The mixture was then warmed to room temperature, and an aqueous solution of NaHCO3 was added, followed by extraction with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was purified by preparative silica TLC (50% EtOAc:PE) to obtain the title compound.

[1301] Step 4: (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methylamine hydrochloride. HCl (3.0 mL, 12 mmol, 4 M, in MeOH) was added to a mixture of (R)-N-((3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.30 g, 0.75 mmol) in MeOH (1 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum to give the title compound.

[1302] Step 5: (S)-N-((R and S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)- 2-Oxoimidazolidine-4-carboxamide. Add (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methylamine hydrochloride (0.15 g crude), (S)-2-oxoimidazolidine-4-carboxylic acid (89 mg, 0.68 mmol), and DIEA (0.24 mL, 1.4 mmol) to a mixture of (3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methylamine hydrochloride (0.15 g crude), (S)-2-oxoimidazolidine-4-carboxylic acid (89 mg, 0.68 mmol), and DIEA (0.24 mL, 1.4 mmol) in DMF (3 mL) at 0 °C. (0.58 g, 0.91 mmol, 50%, in EtOAc). The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reversed-phase HPLC (35:65 to 55:45; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1303] Step 6: (S)-N-((R or S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)- 2-Oxoimidazolidine-4-carboxamide.Separation of (S)-N-((R and S)-(3-chloro-4-fluorophenyl)(5-(trifluoro-methyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Method A) yielded the title compound: the first eluted diastereomer 4A (S)-N-((R or S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted diastereomer 4B (S)-N-((R or S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 4A: LRMS m / z(M+H): calculated value 406.1, measured value 406.0. 1 ¹H NMR (400MHz, CD₃OD) δ 7.49 (dd, J = 2.0, 6.8Hz, 1H), 7.21–7.37 (m, 2H), 6.44–6.46 (m, 1H), 6.35 (s, 1H), 4.36 (dd, J = 6.0, 10.0Hz, 1H), 3.78 (t, J = 9.6Hz, 1H), 3.45 (dd, J = 6.4, 9.2Hz, 1H). Diastereomer 4B: LRMS m / z (M+H): calculated 406.1, measured 406.0. 1 H NMR (400MHz, CD3OD) δ7.42-7.51(m,1H),7.22-7.34(m,2H),6.45(s,1H),6. 37 (s, 1H), 4.37 (dd, J = 6.0, 10.0 Hz, 1H), 3.79 (t, J = 9.6 Hz, 1H), 3.47 (m, 1H).

[1304] Examples 5A and 5B

[1305] (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide

[1306]

[1307] Step 1: cyclopent-3-ene-1-carboxylic acid benzyl ester.(Bromomethyl)benzene (1.6 g, 9.4 mmol) was added to a stirred solution of cyclopent-3-en-1-carboxylic acid (1.0 g, 8.9 mmol) and K₂CO₃ (2.5 g, 18 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 3 hours, then diluted with EtOAc and washed with water and brine. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound.

[1308] Step 2: 3,4-Dihydroxycyclopentane-1-carboxylic acid benzyl ester. OsO4 (0.28 mL, 0.89 mmol) was added to a stirred solution of cyclopentyl-3-ene-1-carboxylic acid benzyl ester (1.8 g, 8.9 mmol) and NMO (1.3 g, 11 mmol) in THF (24 mL) and water (6 mL). The reaction was stirred at room temperature for 12 hours, then quenched with saturated Na2SO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the residue, which was purified by silica gel chromatography (50% EtOAc:PE) to give the title compound.

[1309] Step 3: 4-oxo-2-(2-oxoethyl)butyrate benzyl ester. NaIO4 (0.38 g, 1.8 mmol) was added to a stirred solution of 0.28 g (1.2 mmol) of 3,4-dihydroxy-cyclopentane-1-carboxylic acid benzyl ester in THF (6 mL) and water (2 mL). The reaction was stirred at room temperature for 3 hours, then diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1310] Step 4: 1-(1-(trifluoromethyl)cyclopropyl)piperidine-4-carboxylic acid benzyl ester. NaHCO3 (0.22 g, 2.6 mmol) was added to a stirred solution of 4-oxo-2-(2-oxoethyl)butyrate (0.30 g, 1.3 mmol) and 1-(trifluoromethyl)cyclopropylamine hydrochloride (0.21 g, 1.3 mmol) in EtOH (15 mL). The reaction was stirred at room temperature for 15 min, and then NaCNBH3 (80 mg, 1.3 mmol) was added to the mixture at room temperature. The reaction was then stirred at 50 °C for 48 h, quenched with water, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the residue, which was purified by preparative silica gel TLC (15% EtOAc:PE) to give the title compound.

[1311] Step 5: 1-(1-(trifluoromethyl)cyclopropyl)piperidine-4-carboxylic acid.NaOH (0.13 g, 3.2 mmol) was added to a stirred solution of 1-(1-(trifluoromethyl)cyclopropyl)piperidine-4-carboxylate (0.21 g, 0.64 mmol) in MeOH (3 mL) and water (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to pH 3 with 1 M HCl, and the solvent was removed by freeze-drying to give the title compound.

[1312] Step 6: N-methoxy-N-methyl-1-(1-(trifluoromethyl)cyclopropyl)piperidine-4-carboxamide. HATU (0.36 g, 0.95 mmol) was added to a stirred solution of 1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-carboxylic acid (0.15 g, crude), N,O-dimethylhydroxylamine hydrochloride (0.12 g, 1.3 mmol), and DIPEA (0.44 mL, 2.5 mmol) in DMF (3.0 mL) at room temperature. The reaction was stirred at room temperature for 12 hours, then diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1313] Step 7: (3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)-methyl ketone. Magnesium (3-chloro-2,4-difluorophenyl)bromide (1.0 mL, 1.0 mmol) was added to a stirred solution of N-methoxy-N-methyl-1-(1-(trifluoromethyl)cyclopropyl)-piperidine-4-carboxamide (0.14 g crude) in 6.0 mL of THF at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 2 h. The reaction mixture was then quenched with saturated NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum to give the residue, which was purified by preparative silica gel TLC (15% EtOAc:PE) to give the title compound.

[1314] Step 8: (R)-N-((3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methylene 2-methylpropane-2-sulfinamide. (R)-2-methylpropane-2-sulfinamide (57 mg, 0.47 mmol) and Ti(OEt)4 (0.43 g, 1.9 mmol) were added to a stirred solution of (3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl) methyl ketone (0.12 g, 0.31 mmol) in toluene (1.0 mL) at room temperature. The reaction mixture was stirred at 100 °C for 1 hour, then cooled to room temperature and quenched with brine (2.0 mL). The mixture was then diluted with EtOAc and passed through... Filtration. Wash the filtrate with brine. Separate the organic layer, dry with Na2SO4, filter, and concentrate under vacuum to obtain the title compound.

[1315] Step 9. (R)-N-((3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl 2-methylpropane-2-sulfinamide.NaBH4 (10 mg, 0.26 mmol) was added to a stirred solution of (R)-N-((3-chloro-2,4-difluorophenyl)(1-(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methylene)-2-methylpropane-2-sulfinamide (0.12 g crude) in 3.0 mL of THF at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours. The reaction mixture was then diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1316] Step 10: (3-Chloro-2,4-Difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methylamine hydrochloride Salt. A mixture of (R)-N-((3-chloro-2,4-difluorophenyl)(1-(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide (0.12 g crude) and HCl (1.0 mL, 2.0 mmol, 2 N, in MeOH) was stirred at room temperature for 2 hours. The mixture was then concentrated under vacuum to give the title compound.

[1317] Step 11: (S)-N-((R and S)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)-piperidine- 4-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Add (3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methylamine hydrochloride (70 mg crude), DIPEA (89 mg, 0.69 mmol), and ((S)-2-oxoimidazolidine-4-carboxylic acid (28 mg, 0.22 mmol)) to a stirred solution of (3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methylamine hydrochloride (70 mg crude), DIPEA (89 mg, 0.69 mmol), and ((S)-2-oxoimidazolidine-4-carboxylic acid (28 mg, 0.22 mmol)) in DMF (2.0 mL) at room temperature. (0.22 g, 0.34 mmol, 50 wt%, in EtOAc). The reaction was stirred at room temperature for 6 hours. The residue was purified by reversed-phase HPLC (42:58 to 72:28; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1318] Step 12: (S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)-piperidine- 4-yl)methyl)-2-oxoimidazolidine-4-carboxamide.Separation of (S)-N-((R and S)-(3-chloro-2,4-difluorophenyl)(1-(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Method D) yielded the title compound: the first eluted diastereomer 5A (S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(1-(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted diastereomer 5B (S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)(1-(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 5A: LRMS m / z(M+H): calculated value 481.1, measured value 481.0. 1 H NMR (400MHz, CD3OD) δ7.29-7.43(m,1H),7.01-7.09(m,1H),4.89(d,J=9.6Hz,1H),4.26(dd,J=10.0,6.4Hz,1H),3.74(t,J=9.6Hz,1H),3.29-3.38(m ,1H),3.07(d,J=11.2Hz,1H),2.97(d,J=10.8Hz,1H),2.55-2.77(m,2H),1 .72-1.92(m,2H),1.03-1.30(m,3H),0.92-1.03(m,2H),0.74-0.83(m,2H). Diastereomer 5B: LRMS m / z(M+H): calculated value 481.1, measured value 481.0. 1 H NMR(400MHz,CD3OD)δ8.43(d,J=8.0Hz,1H)7.25-7.33(m,1H),7.06-7.15(m,1H),4.89(d,J=9 .6Hz,1H),4.28(dd,J=10.0,6.4Hz,1H),3.74(t,J=9.6Hz,1H),3.29-3.37(m,1H),3.08(d,J=1 2.4Hz,1H),2.97(d,J=11.6Hz,1H),2.73(t,J=11.2Hz,1H),2.62(t,J=11.2Hz,1H),1.88(d,J= 12.4Hz, 1H), 1.79 (d, J = 11.6Hz, 1H), 1.06-1.28 (m, 3H), 0.92-1.03 (m, 2H), 0.74-0.83 (m, 2H).

[1319] Example 6

[1320] (S)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide

[1321]

[1322] Step 1: 5-Chloro-4-(trifluoromethyl)-2-vinylpyrimidine. PdCl₂(PPh₃)₂ (32 mg, 0.046 mmol) was added to a mixture of 2,5-dichloro-4-(trifluoromethyl)pyrimidine (0.20 g, 0.92 mmol), potassium trifluoro(vinyl)borate (0.12 g, 0.92 mmol), and cesium carbonate (0.90 g, 2.8 mmol) in THF (5 mL) and water (0.5 mL). The mixture was stirred at 85 °C for 12 hours, then water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give the title compound.

[1323] Step 2: 5-Chloro-4-(trifluoromethyl)pyrimidine-2-carboxaldehyde. A mixture of 5-chloro-4-(trifluoromethyl)-2-vinylpyrimidine (0.16 g, 0.77 mmol), NMO (0.18 g, 1.5 mmol), and OsO4 (2.3 mL, 0.23 mmol) in THF (3 mL) and water (1.5 mL) was stirred at room temperature for 12 hours. Then, NaIO4 (0.49 mg, 2.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was then added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to give the title compound.

[1324] Step 3: (R)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)methylene)-2-methylpropane-2-sulfinyl amine. Ti(OEt)4 (0.36 g, 1.6 mmol) was added to a mixture of 5-chloro-4-(trifluoromethyl)pyrimidin-2-carboxaldehyde (0.11 g, 0.52 mmol) and (R)-2-methylpropane-2-sulfinamide (95 mg, 0.78 mmol) in THF (5 mL). The mixture was stirred at 80 °C for 2 hours, followed by the addition of water and filtration. The filtrate was extracted with EtOAc, the EtOAc layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (20% EtOAc:PE) to give the title compound.

[1325] Step 4: (R)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methyl)-2-methylpropane- 2-Sulfanamide.A solution of (R)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)methylene)-2-methylpropane-2-sulfinamide (60 mg, 0.17 mmol) in THF (5 mL) was cooled to -40 °C, and then (4-chlorophenyl)magnesium bromide (0.41 mL, 0.41 mmol) was slowly added. The reaction was stirred at -40 °C for 5 hours and then quenched with saturated NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative silica gel TLC (33% EtOAc:PE) to give the title compound.

[1326] Step 5: (5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methylamine. Hydrogen chloride (2.0 mL, 8.0 mmol, in MeOH) was added to a mixture of (R)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methyl)-2-methyl-propane-2-sulfinamide (35 mg, 0.073 mmol) in MeOH (2 mL) at room temperature. The reaction was stirred at room temperature for 3 hours, and then concentrated to give the title compound, which was used in the next step without further purification.

[1327] Step 6: (S)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methyl)-2-oxoimidazole Alkyl-4-carboxamide. Add at room temperature to a solution of (S)-2-oxoimidazolidine-4-carboxylic acid (5.8 mg, 0.045 mmol), (5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methylamine (20 mg, 0.045 mmol), and TEA (0.019 mL, 0.13 mmol) in 5 mL of DMF. (57 mg, 0.089 mmol). The resulting mixture was stirred at 40 °C for 1.5 h, and then concentrated to obtain the residue. The residue was purified by reversed-phase HPLC (30:70 to 60:40; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound. LRMS m / z (M+H): calculated 434.0, found 434.1. 1 H NMR(CD3OD,500MHz)δ9.18-9.01(m,1H),7.45-7.35(m,4H),6.48-6.14(m,1H),4.48-4.31(m,1H),3.82(dt,J=9.7,4.1Hz,1H),3.60-3.43(m,1H)

[1328] Examples 7A and 7B

[1329] (S)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide

[1330]

[1331] Step 1: 3-Fluoro-2-(trifluoromethyl)-6-vinylpyridine. PdCl₂(PPh₃)₂ (35 mg, 0.050 mmol) was added to a mixture of 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine (0.20 g, 1.0 mmol), potassium trifluoro(vinyl)borate (0.13 g, 1.0 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in THF (3 mL) and water (0.3 mL). The mixture was stirred at 70 °C for 12 hours. Water was then added, and the mixture was extracted with DCM. The organic layers were combined, dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to give the title compound.

[1332] Step 2: 5-Fluoro-6-(trifluoromethyl)picolinaldehyde. A mixture of 3-fluoro-2-(trifluoromethyl)-6-vinylpyridine (0.16 g, 0.75 mmol), NMO (0.18 g, 1.5 mmol), and OsO4 (0.075 mL, 0.075 mmol) in THF (5 mL) and water (2.5 mL) was stirred at room temperature for 12 hours. Then, NaIO4 (0.48 g, 2.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was then added, and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1333] Step 3: (R)-N-((5-fluoro-6-(trifluoromethyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinyl amine. Ti(OEt)4 (0.41 mL, 2.0 mmol) was added to a mixture of 5-fluoro-6-(trifluoromethyl)picolinaldehyde (0.15 g, 0.66 mmol) and (R)-2-methylpropane-2-sulfinamide (0.12 g, 0.99 mmol) in THF (10 mL) at 15 °C. The resulting mixture was stirred at 80 °C for 2 hours, then diluted with EtOAc and brine, and filtered. The filtrate was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (20% EtOAc:PE) to give the title compound.

[1334] Step 4: (R)-N-((5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2- Methylpropane-2-sulfinamide.(4-(trifluoro-6-(trifluoromethyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (0.14 g, 0.42 mmol) in THF (5 mL) was added to magnesium bromide (1.3 mL, 1.3 mmol) at -78 °C. The mixture was stirred at -78 °C for 1.5 h, then quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (25% EtOAc:PE) to give the title compound.

[1335] Step 5: (5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methylamine hydrochloride. HCl (3.0 mL, 6.0 mmol, 2 M, in MeOH) was added to a solution of (R)-N-((5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoro-methoxy)phenyl)methyl)-2-methylpropane-2-sulfinamide (0.18 g, 0.37 mmol) in MeOH (1 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated directly to give the title compound.

[1336] Step 6: (S)-N-((R and S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)-phenyl) Methyl)-2-oxoimidazolidine-4-carboxamide. Add (0.12 g crude) of (5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methylamine hydrochloride, (S)-2-oxoimidazolidine-4-carboxylic acid (34 mg, 0.26 mmol), and DIEA (0.14 mL, 0.80 mmol) to a solution of (5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methylamine hydrochloride, (S)-2-oxoimidazolidine-4-carboxylic acid (34 mg, 0.26 mmol), and DIEA (0.14 mL, 0.80 mmol) in DMF (8 mL) at 0 °C. (0.25 g, 0.40 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated directly under vacuum. The resulting residue was purified by reversed-phase HPLC (30:70 to 60:40; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1337] Step 7: (S)-N-((R or S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)-phenyl) Methyl)-2-oxoimidazolidine-4-carboxamide.Separation of (S)-N-((R and S)-(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Method E) yielded the title compound: the first eluted diastereomer 7A (S)-N-((R or S)-(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide and the second eluted diastereomer 7B (S)-N-((R or S)-(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 7A: LRMS m / z(M+H): calculated value 467.1, measured value 467.2. 1 H NMR (500MHz, CD3OD) δ 8.98 (d, J = 7.5Hz, 1H), 7.91–7.82 (m, 1H), 7.75 (dd, J = 3.5, 9.0Hz, 1H), 7.48 (d, J = 8.5Hz, 2H), 7.29 (d, J = 8.0Hz, 2H), 6.38–6.29 (m, 1H), 4.42 (dd, J = 6.0, 10.0Hz, 1H), 3.82 (t, J = 9.5Hz, 1H), 3.50 (dd, J = 6.0, 9.5Hz, 1H). Diastereomer 7B: LRMS m / z (M+H): calculated 467.1, measured 466.5. 1 H NMR(500MHz,CD3OD)δ8.93(d,J=7.5Hz,1H),7.92-7.83(m,1H),7.76(dd,J=3.5,9.0Hz,1H),7.50(d,J=8.5Hz,2H),7.2 9(d,J=8.1Hz,2H),6.39-6.32(m,1H),4.41(dd,J=6.5,10.1Hz,1H),3.82(t,J=9.5Hz,1H),3.49(dd,J=6.5,9.0Hz,1H).

[1338] Examples 8A, 8B and 8C

[1339] (S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide

[1340]

[1341] Step 1: 6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol.BH3·DMS (5.1 mL, 54 mmol) was added to a solution of 2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran (6.0 g, 38 mmol) in THF (80 mL) at 0 °C. The mixture was stirred at 18 °C for 2 h, then cooled to 0 °C. NaOAc (3.2 g, 38 mmol) was then added, followed by hydrogen peroxide (13 g, 0.12 mol). The mixture was stirred at 18 °C for 12 h, diluted with water, and extracted with EtOAc. The combined organic layers were washed with saturated Na2SO3, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1342] Step 2: 6-((benzyloxy)methyl)dihydro-2H-pyran-3(4H)-one. PCC (9.7 g, 45 mmol) was added to a solution of 5.0 g crude 6-(benzyloxy)-methyl)tetrahydro-2H-pyran-3-ol in 100 mL DCM at 0 °C. The mixture was stirred at 18 °C for 10 h. The reaction mixture was then filtered. The filtrate was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-20% EtOAc:PE) to give the title compound.

[1343] Step 3: 6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol. TBAF (29 mL, 29 mmol) was added dropwise to a solution of 6-((benzyloxy)methyl)dihydro-2H-pyran-3(4H)-one (3.0 g, 14 mmol) and trimethyl(trifluoro-methyl)silane (4.8 g, 34 mmol) in THF (80 mL) at 0 °C. The mixture was stirred at 18 °C for 18 h. Then, HCl solution (34 mL, 0.20 mol, 6 M) was added. The mixture was stirred at 18 °C for 2 h, filtered, the filtrate was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-30% EtOAc:PE) to give the title compound.

[1344] Step 4: 2-((benzyloxy)methyl)-5-(trifluoromethyl)-3,4-dihydro-2H-pyran.A solution of 6-((benzyloxy)methyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol (1.2 g, 4.1 mmol), N,N-dimethylpyridin-4-amine (0.20 g, 1.7 mmol), and pyridine (11 g, 0.14 mol) in THF (50 mL) was added to a solution of thionyl chloride (4.9 g, 41 mmol). The reaction mixture was heated to reflux at 80 °C. After 24 hours, the reaction mixture was cooled to 0 °C in an ice bath, and TEA (10 g, 0.10 mmol) was added dropwise over 5 minutes. Water was added dropwise over 2 minutes, and then water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layers were combined, concentrated under vacuum, and washed with brine. The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0–5% EtOAc:PE) to give the title compound.

[1345] Step 5: (trans)-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran. Pd / C (0.70 g) was added to a solution of 2-((benzyloxy)methyl)-5-(trifluoromethyl)-3,4-dihydro-2H-pyran (1.8 g, 6.6 mmol) in MeOH (20 mL). The mixture was stirred at 18 °C for 16 hours under a H2 atmosphere (30 psi). The mixture was then filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0–5% EtOAc:PE) to give the title compound.

[1346] Step 6: ((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol. Pd / C (0.19 g) was added to a solution of (trans)-2-((benzyloxy)methyl)-5-(trifluoromethyl)tetrahydro-2H-pyran (0.50 g, 1.8 mmol) in MeOH (12 mL). The mixture was stirred at room temperature for 16 hours under a H2 atmosphere (30 psi). The mixture was then filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1347] Step 7: (trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxaldehyde. (Methylsulfinyl)methane (0.21 g, 2.7 mmol) was added to a solution of oxaloyl chloride (1.0 g, 8.2 mmol) in DCM (10 mL) at -70 °C. The mixture was stirred at -70 °C for 30 min, and ((trans)-5-(trifluoromethyl)-tetrahydro-2H-pyran-2-yl)methanol (0.50 g crude) was added dropwise to DCM (20 mL). The mixture was stirred at -70 °C for 2 h, and then TEA (2.8 g, 27 mmol) was added. The reaction mixture was stirred at -70 °C for 30 min, then warmed to room temperature and stirred at room temperature for 1 h. The mixture was then diluted with water and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1348] Step 8: (R)-2-methyl-N-((E)-((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methylene 2-propane-2-sulfinamide. To a solution of (trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxaldehyde (0.40 g crude) in THF (15 mL), (R)-2-methylpropane-2-sulfinamide (0.53 g, 4.4 mmol) and Ti(OEt)4 (1.0 g, 4.4 mmol) were added. The mixture was stirred at 55 °C for 2 hours. Brine was then added, and the mixture was filtered. The filtrate was diluted with water, extracted with EtOAc, and washed with brine. The organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The resulting residue was purified by preparative silica gel TLC (20%, EtOAc:PE) to give the title compound.

[1349] Step 9: (R)-N-((3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2- 2-Methylpropane-2-sulfinamide. Isopropyl magnesium chloride (72 mg, 0.70 mmol) was added to a solution of 1-bromo-3-chloro-2,4-difluorobenzene (0.16 g, 0.70 mmol) in 5 mL of THF at 0 °C. The mixture was stirred at room temperature for 6 hours. Then, (R)-2-methyl-N-((E)-((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methylene)propane-2-sulfinamide (0.20 g, 0.70 mmol) in 5 mL of THF was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. Saturated NH4Cl was added to the reaction solution, followed by dilution with water and extraction with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative silica gel TLC (25% EtOAc:PE) to give the title compound.

[1350] Step 10: (3-Chloro-2,4-Difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methylamine Hydrochloride. HCl (2.0 mL, 8.0 mmol, 4 N, in MeOH) was added to a solution of (R)-N-((3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.16 g, 0.37 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 11 hours. The mixture was then concentrated to give the title compound.

[1351] Step 11: (S)-N-((R and S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H- pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Add (S)-2-oxoimidazolidine-4-carboxylic acid (40 mg, 0.30 mmol) and TEA (31 mg, 0.30 mmol) to a solution of (3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methylamine hydrochloride (50 mg crude) in DMF (1.5 mL). (0.19 g, 0.30 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then purified by reversed-phase HPLC (34:66 to 64:36; water (0.1% TFA): MeCN (0.1% TFA)) and subsequently lyophilized to give the title compound.

[1352] Step 12: (S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H- pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Purification of a mixture of (4S)-N-((3-chloro-2,4-difluorophenyl)(5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Method F) yielded the title compound: the first eluted peak (shown as a mixture of the two compounds) 8A(S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide The second eluting peak of imidazolidin-4-carboxamide is 8B(S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidin-4-carboxamide, and the third eluting peak is 8C(S)-N-((R or S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidin-4-carboxamide. Isomer 8A: LRMS m / z (M+H): calculated value 442.1, measured value 442.0. 1 ¹H NMR (400MHz, CD₃OD): δ 7.46–7.31 (m, 1H), 7.16–6.96 (m, 1H), 5.23–5.09 (m, 1H), 4.42–4.30 (m, 1H), 4.22–4.08 (m, 1H), 3.83–3.61 (m, 2H), 3.46–3.33 (m, 2H), 2.56–2.32 (m, 2H), 2.13–1.93 (m, 1H), 1.68–1.49 (m, 2H). Isomer 8B: LRMS m / z (M+H): calculated 442.1, measured 442.0. 1¹H NMR (400MHz, CD₃OD) δ 7.45–7.36 (m, 1H), 7.17–7.03 (m, 1H), 5.17 (d, J = 5.2 Hz, 1H), 4.33–4.35 (m, 1H), 4.13–4.17 (m, 1H), 3.74–3.79 (m, 1H), 3.63–3.67 (m, 1H), 3.47–3.36 (m, 2H), 2.42–2.52 (m, 1H), 2.03–2.10 (m, 1H), 1.71–1.49 (m, 3H). Isomer 8C: LRMS m / z (M+H): calculated 442.1, measured 442.0. 1 H NMR (400MHz, CD3OD) δ7.48-7.34(m,1H),7.07-7.12(m,1H),5.23(d,J=6.0Hz,1H),4.27-4.31(m,1H),4.08-4.12(m,1H),3.79-3.65(m,2 H),3.47-3.33(m,2H),2.45-2.30(m,1H),2.45-2.30(m,1H),2.03-2.08(m,1H),1.87-1.92(m,1H),1.73-1.59(m,1H),1.40-1.12(m,1H).

[1353] Examples 9A and 9B

[1354] (S)-N-((R)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide

[1355]

[1356] Step 1: (4S)-N-((R and S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazole Alkyl-4-carboxamide. Add to a solution of (S)-2-oxoimidazolidine-4-carboxylic acid (0.13 g, 1.0 mmol) and (R and S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methylamine (0.30 g, 1.0 mmol) in EtOAc (5 mL) (1.2 mL, 2.0 mmol). Then DIEA (0.35 mL, 2.0 mmol) was added, and the reaction was stirred for 2 hours. The mixture was then concentrated under vacuum and purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH):hex) to give the title compound.

[1357] Step 2: (S)-N-((R or S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine- 4-Formamide(4S)-N-((R and S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide was separated by chiral-SFC (Method G) to yield the title compound: the first eluted diastereomer 9A (4S)-N-((R or S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted diastereomer 9B (4S)-N-((R or S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 9A: LRMS m / z (M+H): calculated 414.1, found 414.3. 1 H NMR (500MHz, DMSO-d6) δ 8.86 (d, J = 8.3Hz, 1H), 7.45–7.26 (m, 8H), 6.57 (s, 1H), 6.29 (s, 1H), 6.20 (d, J = 8.2Hz, 1H), 4.22 (dd, J = 9.0, 6.1Hz, 1H), 3.56 (t, J = 9.2Hz, 1H), 3.29–3.17 (m, 1H). Diastereomer 9B: LRMS m / z (M+H): calculated 414.1, measured 414.3. 1 HNMR(500MHz,DMSO-d6)δ8.85(d,J=8.3Hz,1H),7.44–7.33(m,7H),7.29(d,J=7.5Hz,1H),6.57(s,1H),6 .29(s,1H),6.20(d,J=8.3Hz,1H),4.21(dd,J=9.1,6.3Hz,1H),3.55(t,J=9.3Hz,1H),3.27–3.17(m,1H).

[1358] Table 1. The compounds of Examples 10A-18B were prepared according to a synthetic procedure similar to that of Examples 9A and 9B.

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365] Example 19

[1366] (S)-2-oxo-N-((R and S)-(6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methyl)imidazolidine-4-carboxamide

[1367]

[1368] Step 1: (S)-2-methyl-N-((2-(trifluoromethyl)thiazolyl-4-yl)methylene)propane-2-sulfinamide. 2-(trifluoromethyl)thiazol-4-carboxaldehyde (3.0 g, 17 mmol) and (S)-2-methylpropane-2-sulfinamide (2.0 g, 17 mmol) were dissolved in THF (83 mL), and then Ti(OEt)4 (9.8 mL, 33 mmol) was added. The mixture was stirred for 2 hours, then diluted with brine, filtered through sand, and extracted with EtOAc. The combined organic layers were washed with saturated NH4Cl and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1369] Step 2: (S)-2-methyl-N-((6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methyl 2-propane-2-sulfinamide. 5-Bromo-2-(trifluoromethyl)pyridine (0.45 g, 2.0 mmol) was dissolved in THF (10 mL) and cooled to -78 °C. n-Butyllithium (0.88 mL, 2.1 mmol) was slowly added to this solution over 5 minutes. The mixture was stirred for 15 minutes, and then slowly added at -78 °C to a solution of (S)-2-methyl-N-((2-(trifluoromethyl)thiazolyl-4-yl)methylene)propane-2-sulfinamide (0.28 g, 1.0 mmol) in THF (10 mL). After stirring for 1 hour, the reaction was quenched with saturated NH4Cl and stirred for 10 minutes, then passed through… The mixture was filtered through a pad and concentrated under vacuum. The resulting residue was purified by reversed-phase HPLC (75:25 to 5:95; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1370] Step 3: (6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methylamine hydrochloride. (S)-2-methyl-N-((S and R)-(6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoro-methyl)thiazolyl-4-yl)methyl)propane-2-sulfinamide (0.43 g, 1.0 mmol) was dissolved in EtOAc (20 mL) and bubbled with HCl gas until saturated (~15 seconds). The mixture was then concentrated under vacuum to give the title compound.

[1371] Step 4: (S)-2-oxo-N-((R and S)-(6-( Trifluoromethyl )pyridin-3-yl)(2-(trifluoromethyl)thiazole- 4-yl)methyl)imidazolidine-4-carboxamide.4-Methylmorpholine (18 μl, 0.16 mmol) was added to a solution of (S)-2-oxoimidazolidine-4-carboxylic acid (10 mg, 0.08 mmol), (6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methylamine hydrochloride (26 mg, 0.080 mmol), and HATU (30 mg, 0.080 mmol) in DMSO (0.53 mL). The reaction was stirred at 23 °C for 2 h. The mixture was then filtered and purified by mass-directed reversed-phase HPLC to give the title compound. LRMS m / z (M+H): calculated 440.1, found 440.1. 1 H NMR (500MHz, DMSO-d6) δ9.17(d,J=8.0Hz,1H),8.79(s,1H),8.08(s,1H),8.05(d,J=8.1Hz,1H),7.94(d,J=8.2Hz,1H),6.57( s,0.7H)6.32(s,0.3H),6.52(d,J=8.0Hz,1H),4.24(dd,J=9.3,5.8Hz,1H),3.55(t,0.3H),3.46(t,0.7H),3.27–3.21(m,1H).

[1372] Examples 20A and 20B

[1373] (R)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide and (S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide

[1374]

[1375] Step 1: Ethyl 3-((bis(4-chlorophenyl)methyl)amino)-2-((boc)amino)-3-oxopropionic acid. Add 2-((boc)amino)-3-ethoxy-3-oxopropionic acid (0.80 g, 3.2 mmol), bis(4-chlorophenyl)methylamine (0.98 g, 3.9 mmol), and TEA (1.4 mL, 9.7 mmol) to a solution of 2-((boc)amino)-3-ethoxy-3-oxopropionic acid (0.80 g, 3.2 mmol), bis(4-chlorophenyl)methylamine (0.98 g, 3.9 mmol), and TEA (1.4 mL, 9.7 mmol) in DMF (10 mL) at 0 °C. (3.1 g, 4.9 mmol, 50%, in DMF). The mixture was stirred at room temperature for 1 hour. The mixture was then washed with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (25% EtOAc:PE) to give the title compound.

[1376] Step 2: 3-((bis(4-chlorophenyl)methyl)amino)-2-(( boc Ethyl amino-2-methyl-3-oxopropionic acid.MeI (0.16 mL, 2.5 mmol) was added to a mixture of ethyl 3-((bis(4-chlorophenyl)methyl)amino)-2-((boc)amino)-3-oxopropionate (1.0 g, 2.0 mmol) and K₂CO₃ (0.86 g, 6.2 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 12 hours, then water was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (20–46% EtOAc:PE) to give the title compound.

[1377] Step 3: Ethyl 2-amino-3-((bis(4-chlorophenyl)methyl)amino)-2-methyl-3-oxopropionate. HCl (8.0 mL, 32 mmol, 4 N, in EtOAc) was added to a mixture of ethyl 3-((bis(4-chlorophenyl)methyl)amino)-2-((boc)amino)-2-methyl-3-oxopropionic acid (0.79 g, 1.6 mmol) in EtOAc (10 mL). The mixture was stirred at room temperature for 1 hour and concentrated under vacuum to give the title compound.

[1378] Step 4: Ethyl 3-((bis(4-chlorophenyl)methyl)amino)-2-methyl-3-oxo-2-ureopropionic acid. A solution of ethyl 2-amino-3-((bis(4-chlorophenyl)methyl)amino)-2-methyl-3-oxopropionate (0.85 g, 2.2 mmol) and potassium cyanate (0.23 g, 2.8 mmol) in THF (7 mL) and water (3.5 mL) was stirred at 50 °C for 12 hours. The mixture was then concentrated under vacuum. The resulting residue was purified by reversed-phase HPLC (55:45 to 31:69; water (0.1% TFA): MeCN (0.1% TFA)) and subsequently lyophilized to give the title compound.

[1379] Step 5: (R and S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide. Sodium glycolate (0.76 mL, 0.38 mmol) was added to a stirred reflux solution of ethyl 3-((bis(4-chlorophenyl)methyl)amino)-2-methyl-3-oxo-2-ureopropionic acid (0.16 g, 0.36 mmol) in EtOH (3 mL). The mixture was stirred at 90 °C for 12 h, and then concentrated under vacuum. The solid was filtered off, and the filtrate was purified by reversed-phase HPLC (51:49 to 31:69; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1380] Step 6: (R or S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide.Resolution of (R and S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide by chiral-SFC (Method N) yielded the title compound: the first eluted enantiomer 20A (R or S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide, and the second eluted enantiomer 20B (R or S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide. Enantiomer 20A: LRMS m / z (M+H): calculated 392.1, found 392.2. 1 ¹H NMR (500MHz, CD₃CN) δ 7.55–7.61 (m, ¹H), 7.29–7.42 (m, 4H), 7.13–7.26 (m, 4H), 6.54 (s, ¹H), 6.06–6.12 (m, ¹H), 1.57–1.65 (m, 3H). Enantiomer 20B: LRMS m / z (M+H): calculated 392.1, measured 392.2. 1 H NMR (500MHz, CD3CN) δ7.55-7.63(m,1H),7.33-7.39(m,4H),7.20-7.26(m,4H),6.54(s,1H),6.06-6.12(m,1H),1.61(s,3H).

[1381] Examples 21A and 21B

[1382] (R)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide

[1383]

[1384] Step 1: 3-(((benzyloxy)carbonyl)amino)-2-((boc)amino)propionic acid. A solution of 3-amino-2-((boc)amino)propionic acid (4.0 g, 20 mmol) and Na₂CO₃ (4.6 g, 43 mmol) in water (30 mL) was stirred for 3 minutes, followed by the addition of 1,4-dioxane (30 mL). After 5 minutes, benzyl chloroformate (3.1 mL, 22 mmol) was added dropwise at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours, poured into water, and washed with EtOAc. 2N HCl was then added until pH ~2, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to give the title compound.

[1385] Step 2. (3-((bis(4-chlorophenyl)methyl)amino)-3-oxopropane-1,2-diyl)dicarbamate benzyl ester tert-butyl ester. Add 3-(((benzyloxy)carbonyl)amino)-2-((boc)amino)propionic acid (2.0 g, 5.9 mmol), bis(4-chlorophenyl)methylamine (1.6 g, 6.2 mmol) and DIEA (3.1 mL, 18 mmol) to a mixture of 3-(((benzyloxy)carbonyl)amino)-2-((boc)amino)propionic acid (2.0 g, 5.9 mmol), bis(4-chlorophenyl)methylamine (1.6 g, 6.2 mmol), and DIEA (3.1 mL, 18 mmol) in DMF (25 mL) at 0 °C. (5.6 g, 8.9 mmol, 50%, in DMF). The mixture was stirred at room temperature for 2 hours. Water was then added, and the mixture was extracted with EtOAc. The organic layers were combined, filtered, the resulting solid was washed with PE, and the filtrate was dried under vacuum to give the title compound.

[1386] Step 3. (2-Amino-3-((bis(4-chlorophenyl)methyl)amino)-3-oxopropyl)carbamate benzyl ester hydrochloride Salt. HCl (8.0 mL, 32 mmol, 4 N, in EtOAc) was added to a mixture of (2.0 g, 3.5 mmol) of tert-butyl (3-((bis(4-chlorophenyl)methyl)amino)-3-oxopropane-1,2-diyl)dicarbamate benzyl tert-butyl ester (EtOAc) in 10 mL. The mixture was stirred at room temperature for 5 hours and then concentrated under vacuum to give the title compound.

[1387] Step 4: (3-((bis(4-chlorophenyl)methyl)amino)-2-((2-hydroxyethyl)amino)-3-oxopropyl)amino Benzyl carbamate. A mixture of (2-amino-3-((bis(4-chlorophenyl)methyl)amino)-3-oxopropyl)carbamate hydrochloride (0.50 g, 1.1 mmol), 2-bromoethanol (0.19 mL, 2.6 mmol), and K₂CO₃ (0.29 g, 2.1 mmol) in MeCN (6 mL) was stirred at 80 °C for 24 h. The mixture was then filtered and purified by reversed-phase HPLC (66:34 to 46:54; water (0.1% TFA): MeCN (0.1% TFA)), followed by lyophilization to give the title compound.

[1388] Step 5: (R and S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxyl amine. Potassium 2-methylpropane-2-olate (1.2 mL, 1.2 mmol) was added to a solution of (3-((bis(4-chlorophenyl)methyl)amino)-2-((2-hydroxy-ethyl)amino)-3-oxopropyl)carbamate (0.30 g, 0.58 mmol) in MeCN (4 mL). The reaction was stirred at 80 °C for 2 h, and the mixture was then filtered and purified by reversed-phase HPLC (61:39 to 46:54; water (0.1% TFA): MeCN (0.1% TFA)), followed by lyophilization to give the title compound.

[1389] Step 6: (R or S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxyl amine.Resolution of (R and S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide by chiral-SFC (Phenomenex-Amylose-1, co-solvent: 45% EtOH (0.1% NH3·H2O)) yielded the title compound: the first eluted enantiomer 21A (R or S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted enantiomer 21B (R or S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide. Enantiomer 21A: LRMS m / z (M+H): calculated 408.1, found 408.0. 1 ¹H NMR (500MHz, CD₃CN) δ 7.90–7.98 (m, 1H), 7.34–7.39 (m, 4H), 7.23–7.28 (m, 4H), 6.11–6.17 (m, 1H), 4.90 (br s, 1H), 4.23–4.29 (m, 1H), 3.60–3.69 (m, 2H), 3.46–3.52 (m, 1H), 3.36 (t, J = 5.5Hz, 1H), 3.18–3.26 (m, 1H), 3.16–3.19 (m, 2H). Enantiomer 21B: LRMS m / z (M+H): calculated 408.1, measured 408.0. 1 H NMR(500MHz,CD3CN)δ7.91-7.99(m,1H),7.34-7.38(m,4H),7.23-7.29(m,4H),6.11-6.17(m,1H),4.91(br s,1H),4.24-4.30(m,1H),3.59-3.69(m,2H),3.43-3.53(m,1H),3.37(br s,1H),3.18-3.26(m,1H),3.16-3.19(m,2H).

[1390] Examples 22A and 22B

[1391] (S)-N-((R)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide and (S)-N-((S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide

[1392]

[1393] Step 1: 2-(4-chlorophenyl)-2-(1,3-dioxoisoindoline-2-yl)acetic acid.A solution of 2-amino-2-(4-chlorophenyl)acetic acid (3.0 g, 16 mmol), AcOH (42 mL), and pyridine (28 mL) was stirred at 120 °C for 10 hours. The reaction mixture was then filtered, the filtrate was diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–15% DCM:MeOH) to give the title compound.

[1394] Step 2: 2-(3-bromo-1-(4-chlorophenyl)-2-oxopropyl)isoindoline-1,3-dione. Oxaloyl chloride (0.80 g, 6.3 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(1,3-dioxoisoindoline-2-yl)acetic acid (1.0 g, 3.2 mmol) in DCM (15 mL). The mixture was stirred at 16 °C for 11 hours, then concentrated under vacuum. The resulting residue was suspended in DCM (15 mL), and (diazomethyl)trimethylsilane (6.3 mL, 13 mmol) was added at -20 °C. The mixture was stirred at 16 °C for 2 hours, then cooled to -20 °C, followed by dropwise addition of hydrogen bromide (3.0 mL, 3.2 mmol). The reaction was stirred at 16 °C for 2 hours, then quenched at 0 °C with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the title compound.

[1395] Step 3: 2-((4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)isoindoline-1,3-dione. 2,2,2-trifluoroacetamidine (0.27 g, 2.4 mmol) was added to a solution of 2-(3-bromo-1-(4-chlorophenyl)-2-oxopropyl)isoindoline-1,3-dione (1.0 g crude) and NaHCO3 (0.40 g, 4.8 mmol) in THF (10 mL). The mixture was stirred at 60 °C for 11 h, then diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative silica gel TLC (25% EtOAc:PE) to give the title compound.

[1396] Step 4: (4-Chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-5-yl)methylamine 2,2,2-trifluoro-acetate. N₂H₄·H₂O (74 mg, 1.5 mmol) was added to a solution of 2-((4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-isoindoline-1,3-dione (0.20 g, 0.49 mmol) in EtOH (3 mL). The mixture was stirred at 16 °C for 11 h and then diluted with water and MeCN. The residue was purified by reversed-phase HPLC (80:20 to 50:50; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1397] Step 5: (S)-N-((R and S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxo Imidazolidine-4-carboxamide. Add (S)-2-oxoimidazolidine-4-carboxylic acid (27 mg, 0.21 mmol) and TEA (43 mg, 0.42 mmol) to a solution of (4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-5-yl)methylamine 2,2,2-trifluoroacetate (58 mg, 0.21 mmol) in DMF (2 mL). Then add (0.13 g, 0.42 mmol) was used, and the mixture was stirred at 16 °C for 11 hours. The mixture was then diluted with MeCN and purified by reversed-phase HPLC (83:17 to 53:47; water (0.1% TFA): MeCN (0.1% TFA)), followed by lyophilization to give the title compound.

[1398] Step 6: (S)-N-((R or S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxo Imidazolidine-4-carboxamide. (S)-N-((R and S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide was subjected to chiral-SFC (method H) to give the title compound: the first eluted diastereomer 22A (S)-N-((R or S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted diastereomer 22B (S)-N-((R or S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide. Diastereomer 22A: LRMS m / z (M+H): calculated 388.1, found 388.0. 1 ¹H NMR (400MHz, CD₃OD) δ 7.33–7.39 (m, 4H), 6.98 (s, 1H), 6.10–6.28 (m, 1H), 4.33–4.38 (m, 1H), 3.75–3.80 (m, 1H), 3.45–3.49 (m, 1H). Diastereomer 22B: LRMS m / z (M+H): calculated 388.1, measured 388.0. 1 H NMR (400MHz, CD3OD) δ7.29-7.45(m,4H),6.99(s,1H),6.18(s,1H),4.33-4.38(m,1H),3.75-3.80(m,1H),3.45-3.49(m,1H).

[1399] Examples 23A, 23B, 23C and 23D

[1400] (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((cis)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide, (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((trans)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide, (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((trans)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide, and (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((cis)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-

[1401] Oxoimidazolidine-4-carboxamide

[1402]

[1403] Step 1: 2-(4-(trifluoromethyl) ring-shaped ring 2-(diethoxyphosphoryl)tert-butyl acetate. 2-(diethoxyphosphoryl)tert-butyl acetate (3.0 g, 12 mmol) was added dropwise to a mixture of NaH (0.52 g, 13 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at room temperature for 0.5 h, and then 4-(trifluoromethyl)-cyclohexane-1-one (1.5 g, 9.0 mmol) was slowly added at 0 °C. The reaction was slowly heated to room temperature and stirred at room temperature for 8 h. The mixture was then concentrated under vacuum. The resulting residue was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (15% EtOAc:PE) to give the title compound.

[1404] Step 2: 2-(4-(trifluoromethyl)cyclohexyl)tert-butyl acetate. Pd / C (1.0 g, 10% in activated carbon) was added to a solution of 2-(4-(trifluoromethyl)cyclohexyl)acetate tert-butyl (2.3 g, 8.7 mmol) in MeOH (30 mL) under a nitrogen atmosphere. The mixture was degassed and backfilled with H2 (3 times). The resulting mixture was stirred at room temperature under H2 (pressure: 50 psi) for 12 hours. The catalyst was then filtered off, and the filtrate was concentrated under vacuum to give the title compound.

[1405] Step 3: 2-(4-(trifluoromethyl)cyclohexyl)acetic acid. TFA (4.0 mL, 52 mmol) was added to a solution of tert-butyl 2-(4-(trifluoromethyl)cyclohexyl)acetate (1.9 g crude) in DCM (15 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was then concentrated directly under vacuum to give the title compound.

[1406] Step 4: N-methoxy-N-methyl-2-(4-(trifluoromethyl)cyclohexyl)acetamide.CDI (1.2 g, 7.1 mmol) was added to a solution of 1.5 g crude 2-(4-(trifluoromethyl)cyclohexyl)acetic acid in DCM (20 mL), and the mixture was stirred at room temperature for 1 hour. Then, TEA (2.0 mL, 14 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.70 g, 7.1 mmol) were added, and the resulting mixture was stirred at room temperature for 1 hour. Water was then added, and the mixture was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (25% EtOAc:PE) to give the title compound.

[1407] Step 5: 1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethane-1-one. iPrMgCl (1.7 mL, 3.4 mmol, 2 M, in THF) was added to a solution of 1-bromo-3-chloro-2,4-difluorobenzene (0.90 g, 4.0 mmol) in THF (1 mL) at 0 °C. The mixture was stirred for 2 h, and then added to a solution of N-methoxy-N-methyl-2-(4-(trifluoromethyl)cyclohexyl)acetamide (0.30 g, 1.2 mmol) in THF (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 12 h, then quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (10% EtOAc:PE) to give the title compound.

[1408] Step 6: (R,Z)-N-(1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethylene)-2- Methylpropane-2-sulfinamide. 1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethane-1-one (0.31 g, 0.91 mmol), (R)-2-methylpropane-2-sulfinamide (0.16 mg, 1.4 mmol), Ti(OEt)4 (0.37 mL, 1.8 mmol), and toluene (3 mL) were loaded into a microwave tube. The mixture was microwaved at 105 °C for 30 min and then cooled to room temperature. The reaction mixture was diluted with water and EtOAc. The mixture was filtered and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound.

[1409] Step 7: (R)-N-(1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethyl)-2-methyl Propane-2-sulfinamide.A solution of (R,Z)-N-(1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethylene)-2-methylpropane-2-sulfinamide (0.30 g crude) in THF (3 mL) and water (0.01 mL) was cooled to -78 °C. NaBH4 (38 mg, 1.0 mmol) was then added, and the mixture was stirred at -78 °C for 20 min. The reaction was then quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (35% EtOAc:PE) to give the title compound.

[1410] Step 8: 1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethane-1-amine hydrochloride HCl (0.5 mL, 2 mmol, 4 N, in MeOH) was added to a solution of (R)-N-(1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)-cyclohexyl)ethyl)-2-methylpropane-2-sulfinamide (0.25 g, 0.56 mmol) in THF (3 mL). The reaction was stirred at room temperature for 1 hour, and then directly concentrated to give the title compound.

[1411] Step 9: (S)-N-(-1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxo Imidazolidin-4-carboxamide. Add 1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethane-1-amine hydrochloride (0.20 g crude), (S)-2-oxoimidazolidine-4-carboxylic acid (70 mg, 0.54 mmol), and DIPEA (0.28 mL, 1.6 mmol) to a solution of 1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethane-1-amine hydrochloride (0.20 g crude), (S)-2-oxoimidazolidine-4-carboxylic acid (70 mg, 0.54 mmol), and DIPEA (0.28 mL, 1.6 mmol) in MeCN (2 mL) at 0 °C. (0.51 g, 0.81 mmol, 50%, in EtOAc). The reaction was stirred at room temperature for 1 hour and then filtered. The filtrate was purified by reversed-phase HPLC (44:56 to 24:76; water (0.1% TFA): MeCN (0.1% TFA)) and then lyophilized to give the title compound.

[1412] Step 10: (S)-N-((R or S)-1-(3-chloro-2,4-difluorophenyl)-2-((cis or trans)-4-(trifluoromethyl) (-cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide.The title compound was obtained by chiral-SFC (Method O), then chiral-SFC (Method P), and then (Method Q) resolution of (S)-N-(-1-(3-chloro-2,4-difluorophenyl)-2-(4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide: the first eluted isomer 23A (S)-N-((R or S)-1-(3-chloro-2,4-difluorophenyl)-2-((cis or trans)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide, and the second eluted isomer 23B (S)-N-((R or S)-1-(3-chloro- The eluted isomers were 2,4-difluorophenyl)-2-((cis or trans)-4-(trifluoro-methyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide, the third eluted isomer being 23C(S)-N-((R or S)-1-(3-chloro-2,4-difluorophenyl)-2-((cis or trans)-4-(trifluoro-methyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-...

Claims

1. A compound with structural formula I: Or its pharmaceutically acceptable salt, wherein A is selected from: 1) Phenyl, and 2) Pyridine, In which phenyl and pyridine are either unsubstituted or selected from one to five R groups. a The substituents are replaced; B is selected independently from: 1) Phenyl, 2) Pyridine, 3) Thiazole, 4) Pyrimidine, 5) Pyrazine, 6) Pyridazine, 7) Imidazole, 8) Pyrazole, 9) Oxazole, 10) Benzofurans, 11) Benzo[d]oxazole, 12) Benzo[d]thiazole, 13) Indazole, 14) Thiazolo[5,4-b]pyridine, 15) Pyrazolo[1,5-a]pyridine, 16) -(CH2)2-phenyl, 17) -CH2-O-phenyl, 18) -CH2-O-pyridine, 19) Cyclobutane, 20) Cyclohexane, 21) Bicyclo[1.1.1]pentane, 22) Spiro[3.3]heptane, 23) Azacyclic butane, 24) Piperidine, 25) Tetrahydropyran, 26) Tetrahydrofuran, 27) Azabicyclo[3.1.0]hexane, 28) -CH2-cyclohexane, 29) -CH2-tetrahydropyran, 30) -CH2-O-cyclohexane, and 31) Bicyclo[4.2.0]octtriene, B was not replaced or was selected from one to five of R. b The substituents are replaced; R 1 R 2 R 3 R 4 R 5 and R 7 Each is hydrogen; R 6 It is hydrogen; Each Ra is selected independently from: 1) -CF3, 2) -OCF3, 3) -CHF2, 4) -OCH2CF3, 5) CN, 6) Halogens, and 7) -C 2-6 alkynyl group, Each R a Unsubstituted or selected from one to six halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted; and Each R b Selected independently from: 1) -CF3, 2) -OCF3, 3) -CHF2, 4) -OCHF2, 5) –CH2CF3, 6) –CH(CF3)CH3, 7) –OCH2CF3, 8) CN 9) Halogens, 10) –S(O)2C 1-6 alkyl, 11) -C 1-6 Alkyl groups, and 12) -C 3-6 cycloalkyl, Each R b Unsubstituted or selected from one to six halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and OC 1-6 Substituents of alkyl groups; The condition is to exclude the following compounds: 。 2. The compound according to claim 1, wherein A is phenyl, wherein the phenyl group is unsubstituted or substituted with one to five derivatives selected from R. a It is replaced by a substituent; or by a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein B is independently selected from: 1) Phenyl, 2) Pyridine, 3) Thiazoles, and 4) Cyclobutane, B was not replaced or was selected from one to five of R. b It is replaced by a substituent; or by a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein... A is a phenyl group, wherein the phenyl group is unsubstituted or is selected from one to five groups chosen from R. a The substituents are replaced; B is selected independently from: 1) Phenyl, 2) Pyridine, 3) Thiazoles, and 4) Cyclobutane, B was not replaced or was selected from one to five of R. b The substituents are replaced; R 1 R 2 R 3 R 4 R 5 R 6 and R 7 It is hydrogen; Each R a Selected independently from: 1) -CF3, 2) -OCF3, and 3) Halogens; Each R b Selected independently from: 1) -CF3, 2) -OCF3, 3) –OCH2CF3, and 4) Halogens, Each R b Unsubstituted or selected from one to six halogens, CF3, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and OC 1-6 Substituents of alkyl groups; Or its pharmaceutically acceptable salt.

5. A compound, said compound being selected from: 1) (S)-N-((R)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide; 2) (S)-N-((S)-2-(3-chloro-4-fluorophenoxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-oxoimidazolidine-4-carboxamide; 3) (R)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide and (S)-N-(bis(4-chlorophenyl)methyl)-3-methyl-2-oxoimidazolidine-4-carboxamide; 4) (S)-N-((R)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 5) (S)-N-((S)-(5-chloro-6-(difluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 6) (S)-N-((R)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 7) (S)-N-((S)-(3-chloro-4-fluorophenyl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 8) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 9) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(1-(1-(trifluoromethyl)cyclopropyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 10) (S)-N-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)(4-chlorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 11) (S)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 12) (S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 13) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 14) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 15) (S)-N-((R)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 16) (S)-N-((S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 17) (R)-N-[bis(4-chlorophenyl)methyl]-1-methyl-2-oxoimidazolidine-4-carboxamide; 18) (S)-N-[bis(4-chlorophenyl)methyl]-1-methyl-2-oxoimidazolidine-4-carboxamide; 19) (4S)-N-{((R)-3-chloro-4-fluorophenyl)[5-fluoro-6-(2,2,2-trifluoro-ethoxy)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 20) (4S)-N-{((S)-3-chloro-4-fluorophenyl)[5-fluoro-6-(2,2,2-trifluoro-ethoxy)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 21) (4S)-N-[((R)-3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl]-2-oxoimidazolidine-4-carboxamide; 22) (4S)-N-[((S)-3-chloro-4-fluorophenyl)(6-cyanopyridin-2-yl)methyl]-2-oxoimidazolidine-4-carboxamide; 23) (4S)-N-[((R)-5-chloro-6-cyclopropylpyridin-3-yl)(3-chloro-2,4-difluoro-phenyl)methyl]-2-oxoimidazolidine-4-carboxamide; 24) (4S)-N-[((S)-5-chloro-6-cyclo-propylpyridin-3-yl)(3-chloro-2,4-difluoro-phenyl)methyl]-2-oxoimidazolidine-4-carboxamide; 25) (4S)-N-{[(R)-5-chloro-6-(trifluoromethyl)pyridin-3-yl][5-fluoro-6-(trifluoro-methyl)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 26) (4S)-N-{[(S)-5-chloro-6-(trifluoromethyl)pyridin-3-yl][5-fluoro-6-(trifluoro-methyl)pyridin-2-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 27) (S)-N-((R)-(3-chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 28) (S)-N-((S)-(3-chloro-4-fluorophenyl)(cis-2,6-dimethyl-1-(2,2,2-trifluoroethyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 29) (S)-N-((R)-(3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazolyl-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 30) (S)-N-((S)-(3-chloro-4-fluorophenyl)(2-(1-(trifluoromethyl)cyclopropyl)thiazolyl-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 31) (S)-N-((R)-(4-chlorophenyl)(4-fluoro-3-(trifluoro-methyl)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 32) (S)-N-((S)-(4-chlorophenyl)(4-fluoro-3-(trifluoro-methyl)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 33) (S)-N-((R)-(3-chloro-4-fluoro-phenyl)(4-cyano-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 34) (S)-N-((S)-(3-chloro-4-fluoro-phenyl)(4-cyano-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 35) (S)-2-oxo-N-((R)-(6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methyl)imidazolidine-4-carboxamide; 36) (S)-2-oxo-N-((S)-(6-(trifluoromethyl)pyridin-3-yl)(2-(trifluoromethyl)thiazolyl-4-yl)methyl)imidazolidine-4-carboxamide; 37) (R)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide; 38) (S)-N-(bis(4-chlorophenyl)methyl)-4-methyl-2,5-dioxoimidazolidine-4-carboxamide; 39) (R)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide; 40) (S)-N-(bis(4-chlorophenyl)methyl)-3-(2-hydroxyethyl)-2-oxoimidazolidine-4-carboxamide; 41) (S)-N-((R)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 42) (S)-N-((S)-(4-chlorophenyl)(2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 43) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((cis)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide; 44) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((trans)-4-(trifluoromethyl)cyclohexyl)-ethyl)-2-oxoimidazolidine-4-carboxamide; 45) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((trans)-4-(trifluoromethyl)cyclohexyl)-ethyl)-2-oxoimidazolidine-4-carboxamide; 46) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((cis)-4-(trifluoromethyl)cyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide; 47) (4S)-N-{(R)-(3-chloro-2,4-difluorophenyl)[6-(trifluoromethoxy)pyridin-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 48) (4S)-N-{(S)-(3-chloro-2,4-difluorophenyl)[6-(trifluoromethoxy)pyridin-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 49) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-(4,4-difluorocyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide; 50) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-(4,4-difluorocyclohexyl)ethyl)-2-oxoimidazolidine-4-carboxamide; 51) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide; 52) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide; 53) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide; 54) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-2-oxoimidazolidine-4-carboxamide; 55) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 56) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 57) ((4S)-N-{(R)-(3-chloro-4-fluorophenyl)[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 58) (4S)-N-{(S)-(3-chloro-4-fluorophenyl)[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl}-2-oxoimidazolidine-4-carboxamide; 59) (4S)-N-{1-((R)-3-chloro-4-fluorophenyl)-2-[(4,4-difluoro-cyclohexyl)oxy]ethyl}-2-oxoimidazolidine-4-carboxamide; 60) (4S)-N-{1-((S)-3-chloro-4-fluorophenyl)-2-[(4,4-difluoro-cyclohexyl)oxy]ethyl}-2-oxoimidazolidine-4-carboxamide; 61) (4S)-N-[(R)-(3-chloro-2,4-di-fluorophenyl)(3,3-dimethylcyclobutyl)methyl]-2-oxoimidazolidine-4-carboxamide; 62) (4S)-N-[(S)-(3-chloro-2,4-di-fluorophenyl)(3,3-dimethylcyclobutyl)methyl]-2-oxoimidazolidine-4-carboxamide; 63) (S)-N-((R)-(3-chloro-4-fluorophenyl)(1-methyl-3-(tri-fluoromethyl)-1H-pyrazol-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 64) (S)-N-((S)-(3-chloro-4-fluorophenyl)(1-methyl-3-(tri-fluoromethyl)-1H-pyrazol-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 65) (S)-N-((R)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-oxoimidazolidine-4-carboxamide; 66) (S)-N-((S)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-oxoimidazolidine-4-carboxamide; 67) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 68) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 69) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 70) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 71) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazolyl-5-yl)-methyl)-2-oxoimidazolidine-4-carboxamide; 72) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(2,2,2-trifluoroethoxy)thiazolyl-5-yl)-methyl)-2-oxoimidazolidine-4-carboxamide; 73) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 74) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 75) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptane-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 76) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptane-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 77) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 78) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 79) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 80) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 81) (S)-N-((R)-3-chloro-4-(trifluoromethoxy)phenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 82) (S)-N-((S)-3-chloro-4-(trifluoromethoxy)phenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 83) (S)-N-((R)-(5-chloro-6-cyclopropylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 84) (S)-N-((S)-(5-chloro-6-cyclopropylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide; 85) (S)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazol-4-yl)-13-methyl)-2-oxoimidazolidine-4-carboxamide; 86) (S)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(1-(trifluoromethyl)-1H-pyrazol-4-yl)-13-methyl)-2-oxoimidazolidine-4-carboxamide; 87) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 88) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethoxy)-5-fluoropyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 89) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 90) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 91) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 92) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 93) (S)-N-((R)-(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)(6-(trifluoromethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 94) (S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(6-(trifluoromethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 95) (S)-N-((R)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)(5-fluoro-6-(trifluoro-methyl)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 96) (S)-N-((S)-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)(5-fluoro-6-(trifluoro-methyl)-pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 97) (S)-N-((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide 98) (S)-N-((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)oxazol-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 99) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 100) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(trifluoromethyl)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 101) (S)-N-((R)-3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)pyrimidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 102) (S)-N-((S)-3-chloro-4-(trifluoromethoxy)phenyl)(2-(trifluoromethyl)pyrimidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 103) (4S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)-methyl)-2-oxoimidazolidine-4-carboxamide; 104) (4S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)-methyl)-2-oxoimidazolidine-4-carboxamide; 105) (4S)-N-((R)-(3-chloro-2,4-difluorophenyl)(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 106) (4S)-N-((S)-(3-chloro-2,4-difluorophenyl)(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 107) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-3-(4-chlorophenyl)propyl)-2-oxo-imidazolidine-4-carboxamide; 108) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-3-(4-chlorophenyl)propyl)-2-oxo-imidazolidine-4-carboxamide; 109) (4S)-N-(1-(3-chloro-4-fluorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)ethyl)-2-oxoimidazolidine-4-carboxamide; 110) (S)-N-((R)-1-(3-chloro-2,4-difluorophenyl)-2-cyclohexylethyl)-2-oxoimidazolidine-4-carboxamide; 111) (S)-N-((S)-1-(3-chloro-2,4-difluorophenyl)-2-cyclohexylethyl)-2-oxoimidazolidine-4-carboxamide; 112) (4S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 113) (4S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 114) (S)-N-((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 115) (S)-N-((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(5-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 116) (S)-N-((R)-(4-chloro-3-cyanophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 117) (S)-N-((S)-(4-chloro-3-cyanophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 118) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)((R)-1-(2,2,2-trifluoroethyl)piperidin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 119) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)((S)-1-(2,2,2-trifluoroethyl)piperidin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 120) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((S)-1-(2,2,2-trifluoroethyl)piperidin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 121) (S)-N-((S)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 122) (S)-N-((R)-(4-chlorophenyl)(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 123) (S)-N-((S)-(4-chlorophenyl)(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 124) (S)-N-((R)-(4-chloro-3-(trifluoromethyl)-phenyl)(4-cyanophenyl)-methyl)-2-oxo-imidazolidine-4-carboxamide; 125) (S)-N-((S)-(4-chloro-3-(trifluoromethyl)-phenyl)(4-cyanophenyl)-methyl)-2-oxo-imidazolidine-4-carboxamide; 126) (S)-N-(bis(3-chloro-4-fluorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 127) (S)-N-((R)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 128) (S)-N-((S)-(3-chloro-4-fluorophenyl)(5-chloro-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 129) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)-5-fluoropyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 130) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(difluoromethyl)-5-fluoropyridin-2-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 131) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 132) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(2-(difluoromethoxy)pyrimidin-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 133) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((S)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 134) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((R)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 135) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((S)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 136) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(3-methyl-1-((R)-1,1,1-trifluoropropane-2-yl)azacyclobutane-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 137) (S)-N-((R)-(3-chloro-4-fluorophenyl)(2-methylbenzo[d]thiazolyl)methyl)-2-oxoimidazolidine-4-carboxamide; 138) (S)-N-((S)-(3-chloro-4-fluorophenyl)(2-methylbenzo[d]thiazolyl)methyl)-2-oxoimidazolidine-4-carboxamide; 139) (S)-N-((R)-(3-chloro-4-fluorophenyl)(trans-2-(trifluoromethyl)cyclobutyl)methyl)-2-oxoimidazolidine-4-carboxamide; 140) (S)-N-((S)-(3-chloro-4-fluorophenyl)(trans-2-(trifluoromethyl)cyclobutyl)methyl)-2-oxoimidazolidine-4-carboxamide; 141) (4S)-N-((3-chloro-4-fluorophenyl)(3,3-dimethyl-2-(trifluoromethyl)cyclobutyl)methyl)-2-oxoimidazolidine-4-carboxamide; 142) (4S)-N-((3-chloro-4-fluorophenyl)(4-fluorobicyclo[4.2.0]oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 143) (S)-N-((R)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 144) (S)-N-((R)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 145) (S)-N-((S)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 146) (S)-N-((S)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 147) (S)-N-((R)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 148) (S)-N-((R)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 149) (S)-N-((S)-(3-chloro-4-fluoro-phenyl)((R)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 150) (S)-N-((S)-(3-chloro-4-fluoro-phenyl)((S)-2-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 151) (4S)-N-((3-chloro-4-fluorophenyl)(4-chlorobicyclo[4.2.0]-oct-1(6),2,4-trien-7-yl)-methyl)-2-oxoimidazolidine-4-carboxamide; 152) (4S)-N-((3-chloro-4-fluorophenyl)(thiazo[5,4-b]pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 153) (S)-N-((R)-(3-chloro-4-fluorophenyl)(5-chlorobenzofuran-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 154) (S)-N-((S)-(3-chloro-4-fluorophenyl)(5-chlorobenzofuran-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 155) (S)-N-((R)-(4-chlorophenyl)(6-(difluoromethoxy)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 156) (S)-N-((S)-(4-chlorophenyl)(6-(difluoromethoxy)pyridin-2-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 157) (S)-N-((R)-(4-chlorophenyl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 158) (S)-N-((S)-(4-chlorophenyl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 159) (4S)-N-((4-chlorophenyl)(4-methyl-2-(trifluoro-methyl)thiazolyl-5-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 160) (4S)-N-((1(R))-(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethyl)-3-azabicyclo-[3.1.0]hexane-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 161) (4S)-N-((1(S))-(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethyl)-3-azabicyclo-[3.1.0]-hexane-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 162) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)((cis)-1-methyl-2-(trifluoro-methyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 163) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)((trans)-1-methyl-2-(trifluoro-methyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 164) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((cis)-1-methyl-2-(trifluoro-methyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 165) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((trans)-1-methyl-2-(trifluoro-methyl)-piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 166) (S)-N-((R)-(3-chloro-2,4-difluorophenyl)((cis)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 167) S)-N-((R)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 168) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((cis)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 169) (S)-N-((S)-(3-chloro-2,4-difluorophenyl)((trans)-5-(trifluoromethyl)-tetrahydrofuran-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 170) (S)-N-((R)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 171) (S)-N-((S)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 172) (4S)-N-(benzo[d]thiazolyl-6-yl(4-chlorophenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 173) (S)-N-((R)-(4-chlorophenyl)(1H-indazol-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 174) (S)-N-((S)-(4-chlorophenyl)(1H-indazol-6-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 175) (S)-N-((R)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 176) (S)-N-((S)-(4-chlorophenyl)(pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 177) (S)-N-((R)-(4-chlorophenyl)(2-methylbenzo[d]oxazol-6-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 178) (S)-N-((S)-(4-chlorophenyl)(2-methylbenzo[d]oxazol-6-yl)methyl)-2-oxo-imidazolidine-4-carboxamide; 179) (S)-N-((R)-(4-chlorophenyl)(2-methylbenzo[d]thiazolyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 180) (S)-N-((S)-(4-chlorophenyl)(2-methylbenzo[d]thiazolyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 181) (S)-N-((R)-(3-chloro-4-fluorophenyl)(4-(methylsulfonyl)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 182) (S)-N-((S)-(3-chloro-4-fluorophenyl)(4-(methylsulfonyl)phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 183) (4S)-N-[(3-chloro-4-fluorophenyl)(5-cyanopyridin-2-yl)methyl]-2-oxoimidazolidine-4-carboxamide; 184) (S)-N-((R)-benzo[d]thiazolyl-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 185) (S)-N-((S)-benzo[d]thiazolyl-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 186) (S)-N-((R)-benzo[d]oxazol-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 187) (S)-N-((S)-benzo[d]oxazol-2-yl(3-chloro-4-fluoro-phenyl)methyl)-2-oxo-imidazolidine-4-carboxamide; 188) (S)-N-((R)-(8,8-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 189) (S)-N-((S)-(8,8-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; 190) (S)-N-((R)-(4-chlorophenyl)(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 191) (S)-N-((S)-(4-chlorophenyl)(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 192) (4S)-N-((R)(4-chlorophenyl)((R)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 193) (4S)-N-((R)(4-chlorophenyl)((S)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; 194) (4S)-N-((S)(4-chlorophenyl)((S)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; and 195) (4S)-N-((S)(4-chlorophenyl)((R)2,2-dimethyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-oxoimidazolidine-4-carboxamide; Or its pharmaceutically acceptable salt.

6. The compound according to claim 5, wherein the compound is: (S)-N-((R)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)-phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, wherein the compound is: (S)-N-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethoxy)-phenyl)-methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 5, wherein the compound is: (S)-N-((R)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 5, wherein the compound is: (S)-N-((S)-(3-chlorophenyl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 5, wherein the compound is: (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 5, wherein the compound is: (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 5, wherein the compound is: (S)-N-((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 5, wherein the compound is: (S)-N-((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-oxoimidazolidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for preparation of a compound that can be used in mammals in need of treating sodium allergy. v 1.8 Drugs that inhibit the activity of the 1.8 channel are effective for symptoms, patients, or diseases.

16. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a treatment, prevention, or control of sodium allergy. v 1.8 Drugs that inhibit the activity of the 1.8 channel in patients with painful conditions, cough symptoms, acute pruritus, or chronic pruritus.

17. The use according to claim 16, wherein the condition is a pain condition.

18. The use of claim 17, wherein the pain condition is selected from: acute pain, inflammatory pain, or neuropathic pain.

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