| Title of Invention | TERAHYDRO-PYRIMIDOAZEPINES AS MODULATORS OF TRPV1 |
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| Abstract | Certain tetrahydro-pyrimidoazepine compounds are described, which are useful as TRPV1 modulators. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by TRPV1. Thus, the compounds may be administered to treat, e.g., pain, itch cough, asthma, or inflammatory bowel disease. |
| Full Text | TETRAHYDRO-PYRIMIDOAZEPINES AS MODULATORS OF TRPV1 Cross-Reference to Related Application This application claims priority to United States Provisional Application No. 60)785.415. filed March. 21. 2006. Field o[ the Invention The present invention relates to certain tetrahydro-pyrimidoazepine compounds. pharmaceutical compositions containing them. and methods o[ using them for the treatment o[ disease states. disorders. and conditions mediated by TRPV1 activity. Background o[ the Invention Transient receptor potential (TRP) channel proteins constitute a large and diverse family o[ proteins that are expressed in many tissues and cell types. One TRP channel protein o[ particular interest is the vanilloid receptor 1 (TRPV1 or VR1). a non- selective Ca+2 channel that is the molecular target o[ vanilloid compounds (e.g.. capsaicin and reslniferatoxin). Such vanilloid compounds are known to selectively depolarize nociceptors. specialized primary afferent neurons involved in the signaling pathway that leads to the sensation o[ pain. TRPV1 is activated by a diverse range o[ stimuli. including vanillolds. membrane depolarization. heat. stretch. low pH. inflammatory mediators (e.g.. llpoxygenase metabolites). and endocannabinoid compounds. Because heightened activity o[ nociceptors contributes to unwanted pain. inflammatory conditions. thermoregulation. and control o[ smooth muscle tone and reflexes in mammals. modulation o[ signaling In this pathway Is Important in treatment and prophylaxis o[ various clinical syl]dromes (Caterina. M.J.. Pain 2003. 105(1-2). 5-9; Caterina. M.J. et. al.. Annu. Rev. Neurosci. 2001. 24. 487-517; Tominaga. M. et.al.. J. Neurobiol. 2004. 61. 3-12; Voets. T. etal.. Nature 2004.430. 748-754). Because o[ TRPV1's connection with the sensory nervous system. TRPV1 agonists and antagonists may be therapeutically useful in the treatment or prophylaxis o[ disease states. disorders. and conditions mediated by TRPV1 activity. such as: I) pain (e.g.. acute. chronic. inflammatory. or neuropathic pain); ii) itch (Kim et al.. Neurosci. Lett. 2004. 361. 159) and various inflammatory disorders (Stucky. C.L. etal.. Neuroscience 1998. 84. 1257; Moore. BA. etal.. Am. J. Physiol. Gastrointest. Liver Physlol. 2002. 282. G1045; Kwak. J.Y. et.al.. Neurosclence 1998. 86. 619; Morris. V.H. et.al.. Pain 1997. 71. 179; Greiff. L. et.al.. Thorax 1995. 50. 225); lii) inner ear disorders (Balaban. CD. et al.. Hear. Res. 2003. 175.165-70; Zheng. J. et al.. J. Neurophys. 2003. 90.444-55); iv) fever and other disorders or symptoms affected by thermoregulation (Jancso-Gabor et al.. J. Physiol. 1970. 206.495; Swanson et al.. J. Med. Chem. 48.1857; lida et al.. Neurosci. Lett. 2005. 378. 28); v) tracheobronchlal and diaphragmatic dysfunction; and vi) gastrointestinal and urinary tract disorders (Lazzeri. M. et al.. Eur. Urology 200. 792-798; Apostolidis. A. et.al.. Urology 2005. 65. 400-405). Additionally. TRPV1 modulators may be therapeutically useful in the treatment or prophylaxis o[ anxiety (Marsch. R. et al.. J. Neuroscl. 2007. 27(4). 832- 839); eye-related disorders (such as glaucoma. vision loss. and increased intraocular pressure) (Calkins. D.J. et al.. Abstract from ARVO 2006 Annual Meeting. Program #1557. Poster #B93); baldness (e.g.. by stimulating hair growth) (Bodo. E. et al.. Am. J. Pathol. 2005. 166(4). 985-998); diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion) (Razavi. R. et al.. Cell 2006. 127(6). 1097-1099; Akiba. Y. et al.. Biochem. Biophy. Res. Commun. 2004. 321(1). 219-225). Addosis is a well-established feature o[ cerebral ischaemia. Tissue pH may fall to 6 or lower. sufficient to activate TRPV1 channels expressed in the CNS. TRPV1 antagonists therefore may be useful in the treatment o[ disorders associated with reduced blood flow to the CNS or CNS hypoxia. such as head trauma. spinal injury. thromboembolic or hemorrhagic stroke. transient ischaemic attacks. cerebral vasospasm. hypoglycaemia. cardiac arrest. status epilepticus. perinatal asphyxia. Alzheimer's disease. and Huntington's Disease. International Publication No. WO05)014558 (Feb. 17. 2005) describes certain aminopyrimidine inhibitors o[ voltage-gated sodium and potassium channel. Various bicydic pyrimidines are disclosed as serotonin receptor modulators in U.S. Patent Appl. No. 11)460.294. filed July 27. 2006 (Attorney Docket No. PRD2511). Condensed pyl]midine compounds are disclosed as inhibitors o[ voltage-gated Ion channels in Intl. Publication No. WO 05)014558. Various bicydic pyrimidines are also disclosed In Intl. Publication No. WO 05)066171 and U.S. Patent Appl. Publ. 2005)0166032 as Inhibitors o[ the TRPV1 channel. However. there remains a need for potent TRPV1 modulators with desirable pharmaceutical properties. Summary o[ the Invention Certain tetrahydro-pyrimidoazepine derivatives have now been found to have TRPV1-modulating activity. Thus. the invention is directed to the general and preferred embodiments defined. respectively. by the independent and dependent claims appended hereto. which are incorporated by reference herein. Thus. In one general aspect the invention relates to compounds o[ the following Formula (I): wherein: R1 is -H; -NRaRb; -OH; a -C1-6alkyl. -OC1-6alkyl. -O-(saturated monocycBc cycloalkyl). -OC1alkyl-(saturated monocyclic cycloalkyl). -O-(saturated monocyclic heterocycloalkyl). -O-phenyl. -O-benzyl. -S-C1-6alkyl. -S-(saturated monocyclic cycloalkyl). -SC1alkyl-(saturated monocyclic cycloalkyl). -S- (saturated monocyclic heterocycloalkyl). -S-phenyl. -S-benzyl. or -SO2-C1-6alkyl group unsubstituted or substituted with one or two moieties independently selected from the group consisting o[ -C1-6alkyl. -OH. -OC1-4alkyl. -NRaRb. and halo substituents; or a phenyl. monocyclic cycloalkyl. or monocyclic heteroaryl group unsubstituted or substituted with a -C1-6alkyl. -OH. -OC1-4alkyl. -NReRf. or halo substituent; where Ra and Rb are each independently-H; -Chalky); a -C2-3alkyl group substituted with a -OH. -OC1-4alkyl. -NRcRd. or halo substituent; or a saturated monocyclic cycloalkyl. -C1alkyl-(saturated monocyclic cycloalkyl). saturated monocyclic heterocycloalkyl. -C1alkyl-(saturated monocyclic heterocycloalkyl). phenyl. benzyl. or -C1alkyl-(monocyclic heteroaryl) group unsubstituted or substituted with one. two. or three moieties independently selected from the group consisting o[ -C1-6alkyl. -OH. -OC1-4alkyl. -NRpRq. and halo substituents; or Ra and Rb taken together with their nitrogen o[ attachment form a saturated monocyclic heterocycloalkyl or bridged bicyclic heteacycloalkyl group unsubstituted or substituted with one. two. or three moieties independently selected from the group consisting o[ -C1-6alkyl. -C1-4alkyl-OH. -C1-2alkyl- OC1-2alkyl. -OH. -OC1-4alkyl. -NRpRq. halo. -CO2H. and benzyl substituents; where Rc and Rd are each independently -H or -C1-6alkyl; or Rc and Rd taken together with their nitrogen o[ attachment form a saturated monocyclic heterocydoalkyl; where Rp and Rq are each Independently -H or -C1-6alkyl; or Rp and Rq taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl; where Re and Rf are each Independently -H or -C1-6alkyl; or Re and Rf taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl; R2 is-H or-C1-6alkyl; R3 is a monocydic cycloalkyl. phenyl. benzyl. phenethyl. indanyl. thlazolyl. thiophenyl. pyridyl. pyridylmethyl. pyrlmdinyl. pyrazlnyl. pyridazinyl. benzothiadiazolyl. quinolinyl. isoquinolinyl. tetrahydroquinoilnyl. or tetrahydroisoquinolinyl group unsubstituted or substituted with one. two. or three Rg substltuents; where each Ra substituent is -C1-6alkyl; -C1-4alkyl-OH unsubstituted or substituted with -CF3; saturated monocydic cydoalkyl; -OH; -OC1-6alkyl; phenoxy; -CN; -NO2; -N(Rh)Rl; -C1-4.alkyl-N(Rh)R1; -C(O)N(Rh)R1; -N(Rh)C(O)R1; -N(Rh)SO2C1-6alkyl; -C(O)C1-6lkyl; -S(O)o-2-C1-6alkyl; -SO2CF3; -SO2N(R)1; -SCF3; halo; -CF3; -OCF3; -CO2H; -CO2C1-6alkyl: -C(R1)(Rx)CN; -C(R1)(Rx)-OH; -C(R1)(Rx)-CO2C1-6alkyl; -C(RIXRX)-CO2H; -C(R1)(Rx)-C(O)N(Rh)Rl; phenyl; or monocydic heteroaryl; or two adjacent R° substituents taken together form -OC1-2alkylO-; where Rh and R1 are each Independently -H or -C1-6alkyl; or Rh and R1 (when both are present) taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl group; R1 is independently -H. -C1-6alkyl. or -CF3; Rx is -H or -Chalky!; or R1 and Rx taken together with the carbon to which they are attached form a monocydic cydoalkyl ring;and Ar is a phenyl. pyridyl. imldazolyl. pyrimidinyl. pyridazinyl. or fused-bicyclic heteroaryl group unsubstituted or substituted with one. two. or three Rk substituents; where each Rk substituent is independently -C1-6alkyl. -C1-2alkyl-OH. -OH. -OC1-6alkyl. phenoxy. -CN. -NO2. -N(R')Rm. -C(O)N(R1)Rm -N(R1)C(O)Rm. -N(R')SO2C1-8alky1. -N(R1)SO2CF3. -C(O)C1-6alkyl. -S(O)o-2-C1-6alkyl. -SO2CF3. -N(R1)SO2CF3. -SCF3. halo. -CF3. -OCF3. -CO2H. or-COzC1-6alkyl: or two adjacent Rk substituents taken together form -OC1-2alkylO-; where R1 and Rm are each independently -H.-C1-6alkyl. saturated monocycllc cydoalkyl. or -CF3. The invention also relates to pharmaceutlcally acceptable salts. phanmaceutically acceptable prodrugs. and pharmaceutically active metabolites o[ compounds o[ Formula (I). In certain preferred embodiments. the compound o[ Formula (I) is a compound selected from those species described or exemplified in the detailed description below. In a further general aspect. the invention relates to pharmaceutical compositions each comprising: (a) an effective amount o[ an agent selected from compounds o[ Formula (I) and pharmaceutically acceptable salts. pharmaceutically acceptable prodrugs. and pharmaceutically active metabolites thereo[. and (b) a pharmaceutically acceptable excipient. In another general aspect. the invention is directed to a method o[ treating a subject suffering from or diagnosed with a disease. disorder. or medical condition mediated by TRPV1 activity. comprising administering to the subject in need o[ such treatment an effective amount o[ a compound o[ Formula (I). or a pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite o[ such compound. In certain preferred embodiments o[ the inventive method. the disease. disorder. or medical condition is selected from: pain (acute. chronic. Inflammatory. or neuropathic pain); itch or various inflammatory disorders; inner ear disorders; fever and other conditions or disorders o[ thermoregulation; tracheobronchial and diaphragmatic dysfunction; gastrointestinal and urinary tract disorders; and disorders associated with reduced blood flow to the CNS or CNS hypoxia. Additional embodiments. features. and advantages o[ the Invention will be apparent from the following detailed description and through practice o[ the invention. Detailed Description o[ Invention and its Preferred Embodiments The Invention may be more fully appreciated by reference to the following description. including the following glossary o[ terms and the concluding examples. For the sake o[ brevity. the disclosures o[ the publications. Including patents. cited in this specification are herein incorporated by reference. As used herein. the termns "including". "containing" and "comprising" are used herein in their open. non-limiting sense. The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Exemplary alkyl groups Include methyl (Me. which also may be structurally depicted by a ) symbol). ethyl (Et). n-propyl. isopropyl. butyl. isobutyl. sec-butyl. tert-butyl (tBu). pentyl. isopentyl. tert-pentyl. hexyl. isohexyl. and the like. The term "alkenyl" refers to a straight- or branched-chain alkenyl group having from 2 to 12 carbon atoms in the chain. (The double bond o[ the alkenyl group is formed by two sp2 hybridized carbon atoms.) Illustrative alkenyl groups include prop-2-enyl. but-2-enyl. but-3-enyl. 2-methylprop-2-enyl. hex-2-enyl. and the like. The term "cycloalkyt" refers to a saturated or partially saturated. monocyclic. fused polycydic. or bridged polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples o[ cycloalkyl groups include the following moieties: A "heterocycloalkyl" refers to a monocyclic. or fused. bridged. or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen. oxygen. and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative examples o[ heterocycloalkyl groups include: The term "heteroaryl" refers to a monocyclic. fused blcyclic. or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen. oxygen. and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples o[ heteroaryl groups include the following moieties: Those skilled in the art will recognize that the species o[ cycloalkyl. heterocycloalkyl. and heteroaryl groups listed or illustrated above are not exhaustive. and that additional species within the scope o[ these defined terms may also be selected. The term "halogen" represents chlorine. fluorine. bromine or iodine. The term "halo" represents chloro. fluoro. bromo or iodo. The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no subst(tuents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" Is used to describe a structural system. the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent. it is understood that such a moiety or group is intended to be unsubstituted. Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular. compounds o[ any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers o[ the compounds o[ the general formula. and mixtures thereo[. are considered within the scope o[ the formula. Thus. any formula given herein is Intended to represent a racemate. one or more enantiomeric forms. one or more diastereomeric forms. one or more atropisomeric forms. and mixtures thereo[. Furthermore. certain structures may exist as geometric isomers (i.e.. cis and trans isomers). as tautomers. or as atropisomers. Additionally. any formula given herein is intended to embrace hydrates. solvates. and porymorphs o[ such compounds. and mixtures thereo[. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms o[ the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples o[ isotopes that can be incorporated into compounds o[ the invention include isotopes o[ hydrogen. carbon. nitrogen. oxygen. phosphorous. fluorine. and chlorine. such as 2H. 3H. 11C. 13C. 14C. 15N. 180.170.31P. 33P. 35S. 16F. 36CI.125l. respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with 14C). reaction kinetic studies (with. for example 2H or 3H). detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays. or in radioactive treatment o[ patients. In particular. an 18F or 11C labeled compound may be particularly preferred for PET or SPECT studies. Further. substitution with heavier isotopes such as deuterium (i.e.. 2H) may afford certain therapeutic advantages resulting from greater metabolic stability. for example increased in vivo half-life or reduced dosage requirements. lsotopically labeled compounds o[ this invention and prodrugs thereo[ can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. When referring to any formula given herein. the selection o[ a particular moiety from a list o[ possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words. where a variable appears more than once. the choice o[ the species from a specified list Is independent o[ the choice o[ the species for the same variable elsewhere In the formula. In preferred embodiments o[ agents o[ Formula (I). R1 is -H or -OH. In further preferred enmbodiments. R1 is isopropyl or cydopropyl. In further preferred embodiments. R1 is a -©-(saturated monocyclic cycloalkyl). -OC1alkyl-(saturated monocyclic cycloalkyl). -O-(saturated monocyclic heterocycloalkyl). -O-phenyl. or -O-benzyl group unsubstituted or substituted with one or two moieties independently selected from the group consisting o[ methyl. ethyl. and isopropyl substituents. In further preferred embodiments. R1 is a -S-C1-6alkyl. -S-{saturated monocydic cycloalkyl). -SC1alkyl-(saturated monocyclic cycloalkyl). -S-(saturated monocyclic heterocycloalkyl). -S-phenyl. or -S-benzyl group unsubstituted or substituted with a methyl. ethyl. or isopropyl substituent. In further preferred embodiments. R1 is methylsulfanyl or methylsulfonyl. In further preferred embodiments. R1 is a monocyclic heteroaryl group unsubstituted or substituted with a methyl substituent. In further preferred embodiments. R1 is a'furanyl. thiophenyl. thiazolyl. or pyridyl group unsubstituted or substituted with a methyl substituent In preferred embodiments. Ra and Rb are each independently -H; methyl. ethyl. propyl. isopropyl. butyl. isobutyl. sec-butyl. tert-butyl. pentyl. isopentyl. or hexyl; an ethyl or propyl group substituted with an -OC1-6alkyl or -NRcRd substituent; or a cyclopropyl. cyclobutyl. cydopentyl. cydohexyl. cydoheptyl. cyclopropytmethyl. cydopentylmethyl. cydohexylmethyl. aziridinyl. pyrrolkJinyi. tetrahydro[uranyl. piperidinyl. tetrahydropyranyl. piperazinyl. morpholinyl. thiomorpholinyl. 1.1-dioxo-1A6-thionrK)rpholin-4-yl. phenyj. or furanylmethyl group unsubstituted or substituted with a methyl or methoxy substituent. In further preferred embodiments. R" and Rb are each independently-H. methyl. isopropyl. methoxyethyl. cydopropyl. cyclohexyl. cyclopropytmethyl. 2-piperidin-1-yl-ethyl. or 2-dimethylamino-ethyl. In further preferred embodiments. Ra and RB taken together with their nitrogen o[ attachment form an aziridinyl. pyrrolidinyl. piperidinyl. 2-oxo-piperidin-1-yi. piperazinyl. oxo-piperazinyl. morpholinyl. thiomorpholinyl. 1.1- dioxo-1A6-thk)morpholin-4-yl. 1.1-dioxo-1A9-[1.2lthiazinan-2-yl. azepanyl. 1.4- oxazepanyl. or 7-azabicyclo[2.2.1]hept-7-yl group unsubstituted or substituted with a -C1-6alkyl. hydroxymethyl. hydroxyethyl. methoxymethyl. methoxyethyl. fluoro. -OH. or-CO2H substituent. In preferred embodiments. Rc and Rd taken together with their nitrogen o[ attachment form piperidinyl. morpholinyl. or pyrrolidinyl. In preferred embodiments. R3 is a monocydic cycloalkyl. pyridylmethyl. benzothiadiazolyl. tetrahydroquinolinyl. ortetrahydroisoquinolinyl group unsubstituted or substituted with one. two. or three Rg substituents. In further preferred embodiments. R3 is a 2-pyridyl group unsubstituted or substituted with one or two R8 substituents. In further preferred embodiments. R3 is a 2-pyridyl group unsubstituted or substituted with one or two R° substituents. In further preferred embodiments. R3 is a 3-pyridyl group unsubstituted or substituted with one R9 substituent In preferred embodiments. each R° substituent is independently methyl. isopropyl. tert-outyl. -CF3. fluoro. chJoro. bromo. -OCF3. -SO2NH2. -OCH3. phenoxy. -C(CH3)2-CN. -C(CH3)z-OH. -NO2. -CN. -NH2. -C(O)CH3. -SO2CF3. -SCF3. - CON(CH3)2. -CO2H. phenyl. cydohexyl. pyrrolidinyl. piperidinyl. morpholinyl. -SCH3. oxazolyl. -SO2-(pyrrolidinyl). -SO2N(CH3)2. -C(CH3)2-CO2CH3. -C(CH3)2-CO2H. 1- hydroxy-ethyl. 2-hydroxy-1.1 -dimethyl-ethyl. 3.3.3-trifluoro-1-hydroxy-propy1.3.3.3- trffluoro-1-hydroxy-1-methyl-propy1. or -SO2CH3; or two adjacent R9 substituents taken together form -OC1-6alkylO-. In further preferred embodiments. each R8 substituent is independently methyl. isopropyl. tert-butyl. fluoro. -CF3. chloro. -C(CH3)2-CN. -C(CH3)2-OH. -C(CH3)2-CH2OH. -C(CH3)2-CO2H. acetyl. -SO2CH3. or -SO2CF3. In preferred embodiments. Rh and R1 taken together with their nitrogen o[ attachment form pyrrolidinyl. piperidinyl. plperazinyl. or morpholinyl. In preferred embodiments. R1 is -H. methyl. or -CF3. In preferred embodiments. Rx is -H or methyl. In further preferred embodiments. R1 and R" taken together with the carbon to which they are attached form a cyclopropyl ring. In preferred embodiments. Ar is 2-pyridyl substituted with -CF3. In further preferred embodiments. Ar is 2-pyridyl substituted with -Cl. -Br. -F. methyl. -SO2CH3. or -SO2CH2CH3. In further preferred embodiments. Ar is 2-pyridyl. substituted with one or two Rk substituents Independently selected from the group consisting o[: -CF3. fluoro. chloro. bromo. -SO2CH3. -NH2. -NO2. -CO2CH3. -NHSO2CH3. -CN. -CONH2. -SO2CH2CH3. -SO2NH2. -SO2NH-cyclopropyl. -SO2NH- Isopropyl. -CO2H. -CH2OH. and methyl. In preferred embodiments. R1 and Rm are each independently-H. methyl. ethyl. isopropyl. -CF3. or cyclopropyl. In preferred embodiments. R1 is -H. In other preferred embodiments. R1 is -NR"Rb. and Ra and Rb are as previously defined. In further preferred embodiments. R1 is a -C1-6alkyl group unsubstituted or substituted with a -OH. - OC1-4alkyl. -NReRf. or halo substituent. and R° and R( are as previously defined. In further preferred embodiments. R1 is methyl or isopropyl. In still further preferred embodiments. R1 is a methyl group substituted with a -OC1-6alkyl or-NR"Rf substituent. and R" and Rf are as previously defined. In further preferred embodiments. R1 is methoxymethyl or piperidinylmethyl. In other preferred embodiments. R1 is methoxy. methylsulfanyl. or methytsulfonyl. In additional preferred embodiments. R1 is cyclopropyl. In preferred embodiments. R" and Rb are each independently-H; methyl. ethyl. propyl. isopropyl. butyl. isobutyl. sec-butyl. tert-butyl. pentyl. isopentyl. or hexyi; an ethyl or propyl group substituted with an -OC-i-«alkyl or -NR°Rd substituent; or a cyclopropyl. cyclobutyl. cydopentyl. cyclohexyl. cydoheptyl. cyclopropylmethyl. cyclopentylmethyl. aziridinyl. pyrrolidinyl. tetrahydro[uranyl. piperidinyl. tetrahydropyl]anyl. piperazinyi. morpholinyl. thlomorpholinyl. 1.1-dk)xo- 1A6-thlomorpholin-4-yl. or phenyl group unsubstituted or substituted with a -Ci. 6alkyl. -OC2alkyt. or halo substrtuent; and R° and Rd are as previously defined. In other preferred embodiments. R" and Rb are each independently -H. methyl. methoxyethyl. cyclopropyl. cyclopropylmethyl. 2-piperidin-1-yl-ethyl. or 2- dimethylamino-ethyl. Alternatively. Ra and Rb taken together with their nitrogen o[ attachment form an aziridinyl. pyrroJIdinyl. piperidinyi. 2-oxo-piperidin-1-y1. piperazlnyl. oxo-piperazinyl. morpholinyl. thiomorpholinyl. 1.1-dioxo-1A8- thiomorpholln-4-yl. 1.1-dioxo-1A9-[1.2]thiazinan-2-yl. orazepanyi group unsubstituted or substituted with a -C1-6alkyl. -OH. or -CO2H substituent. In preferred embodiments. Rc and Rd are each independently -H. methyl. or ethyl. Atternatively. Rc and R" taken together with their nitrogen o[ attachment form piperidinyi. In preferred embodiments. Rp and Rq are each independently -H. methyl. or ethyl. In preferred embodiments. R" and Rf are each independently -H. methyl. or ethyl. Preferably. R2 Is -H or methyl; more preferably. R2 is -H. Preferably. R3 te a phenyl. pyridyl. pyrimWinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two R° substituents. and each R° substituent is as previously deflned. In further preferred embodiments. R3 is a pyridyl. pyrimldinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two Rg substituents. and each R° substituent is as previously defined. In additional preferred embodiments. R3 is a pyridyl. thiazolyl. or pyridazinyl group unsubstituted or substituted with one or two R° substituents. and each R° substituent is as previously defined. In still further preferred embodiments. R3 is a phenyl group substituted with one or two Rg substituents. and each R8 substituent is as previously defined. In still further preferred embodiments. R3 is a benzyl or phenethyl group unsubstituted or substituted with one or two R° substituents. and each Rg substituent is as previously defined. In still further preferred embodiments. R3 is a 2-pyridyl group unsubstituted or substituted with one R° substituent. and R° substituent is as previously defined. Preferably. each Rg substituent is -C1-6alkyl. -OH. -OC1-6alkyl. phenoxy. -CN. -NO?. -N2JR1. -C(O)N(Rh)Rl. -N(Rh)C(O)R\ -N(R")SO2C1-6alkyl; -CfOJd-ealkyl. -SfOJo-j-C1-6alkyl. -SO2CF3. -S02N(Rh)R'. -SCF3. halo. -CO2H. -CO2C..«alkyl. -C(RJ)2-CN. or -C(F2)2-OH. and Rh. R1. and R" are as previously defined. Alternatively. two adjacent RB moieties taken together form -OCi-2alkylO-. In further preferred embodiments. each Rg substltuent is isopropyl. tert-butyl. -CF3. chloro. -OCF3. -SO2NH2. -OCH3. phenoxy. bromo. -C(CH3)2-CN. -C(CH3)2-OH. -NO2. -CN. -NH2. -C(O)CH3. -SO2CF3. or -SCF3; or two adjacent Rg substltuents taken together form -OCi-2alkylO-. In still further preferred embodiments. each Rg substituent Is isopropyl. tert-butyl. -CF3. chloro. -C(CH3)2-CN. -C(CH3)2-OH. or -SO2CF3. In preferred embodiments. Rh and R1 are each independently -H. methyl. or ethyl. In preferred embodiments. R' is —H. methyl. or ethyl. In preferred embodiments. Ar is a phenyl group unsubstituted or substituted with one or two Rk substituents. and each Rk substituent is as previously defined. In further preferred embodiments. Ar is a phenyl group substituted with a -NO2. -N(R")Rm. -CfOMR'jR"". -N(R')C(O)Rm. -N(R')SO2C1-6alkyl. -N(R')SO2CF3. -SO2CH3. or -SO2CF3 substituent. and R1 and Rm are as previously defined. In still further preferred embodiments. Ar is a fused-bicyclic heteroaryl group unsubstituted or substituted with one or two Rk substituents. and each Rk substituent is as previously defined. In still further preferred embodiments. Ar is 2- pyridyl substituted with -CF3. -NO2. or -N(R')Rm. and R1 and R™ are as previously defined. In still further preferred embodiments. Ar Is 2-pyridyl substituted with -Cl. -Br. methyl. or -SO2CH3. In still further preferred embodiments. Ar is quinoxallnyl or phthalizinyl. In still further preferred embodiments. Ar is a phenyl. pyridyi. pyrimidinyl. or fused-bicyclic heteroaryl group substituted on a carbon ring atom at a position ortho to the point o[ attachment with an R" substituent. and the Rk substituent is as previously defined. In preferred embodiments. each Rk substituent is -C22alkyl. -OH. phenoxy. -CN. -NO2) -N(R')Rm. -C(O)N(Rl)Rrn. -N(R')C(O)Rm. -N(Rl)SO2C14)alkyl. -N(R')SO2CF3. -C(O)d-8alkyl. -S(O) -OCF3. -CO2H. or -CCkCi-ealkyl; or two adjacent Rk substituents taken together form -OCi.2alky1O-; and R1 and R"1 are as previously defined. In still further preferred embodiments. each Rk substttuent is -N(R')Rm. -NO2. -N(R')SO2CF3. or -N(R')SO2CH3. and R1 and Rm are as previously defined. In preferred embodiments. R1 and Rm are each Independently-H. methyl. ethyl. or -CF3. Further preferred embodiments o[ the present invention include compounds o[ Formula (I) wherein: a) R1 is -H. -NRaRb. -C1-6alkvl. -O-C1-6alkyl. -S-C1-6alkyl. -SOrC1-6alkyl. -CHr O-C1-6alkyl. or -CH2-NR°Rf; R2 is -H; R3 is a pyridyl. pyrimldinyl. pyrazinyl. quinolinyi. or isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar is a phenyt group substituted with one or two R11 substituents; and R". Rb. R". Rf. R8. and R" are as previously defined; or b) R1 is -H. -NR'Rb. -C2alkyl. -O-C1-6alkyl. -S-C1-6alkyl. -SOa-Cmalkyl. -CH2- O-C.2alkyl. or -CHrNR"Rf; R2 Is -H; R3 Is a benzyl. phenethyl. indanyl. pyridyl. pyrimidinyl. pyrazinyl. quinolinyi. or Isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar is a phenyl group substituted with one or two Rk substituents. where each Rk substituent is -C22alkyl. -OH. phenoxy. -CN. -NO2. -N(R')Rm. -C(O)N(Rl)Rm. -NtR'jCfOJFT. -N(R')SO2C1-6alkyl. -N(R')SO2CF3l -C(O)C1-6alkyl. -S(0)o.2-Ci and RB. R". R#. Rf. Rfl. R1. and Rm are as previously defined; or c) R1 is -H. -NR"Rb. -Chalky!. -O-Ci-«alkyl. -S-C1-6lkyl. -SOrC1-6alkyl. -CH2- O-C1-6alkyl. or -CH;rNR"Rf; R2 is -H; R3 is a benzyl or phenethyl group unsubstituted or substituted with one or two RB substituents; and Ar is 2-pyridyl substituted with -CF3. -NC2. or -N(R')Rm; and R". Rb. R". Rf. R°. R1. and Rm are as previously defined; or d) R1 is -Ci-salkyl; R2 is -H; R3 is a phenyl. pyridyl. pyrimidinyl. pyrazinyl. quinolinyi. or isoquinolinyl group unsubstituted or substituted with one or two R9 aubstituents; and Ar is a phenyl. pyridyl. pyrimidinyl. or fused-bicydic heteroaryl group unsubstituted or substituted with one or two Rk substituents; and R° and F? are as previously defined; or e) R1 is -H. -NR'Rb. -C14alkyl. -O-C1-6alkyl. -S-C1-6alkyl. -SO2-Cmalkyl. -CH2- O-Ctualkyl. or -CHT-NR'R': R2 IS -H; RS is a phenyl. benzyl. phenethyl. indanyl. pyridyl. pyrimidinyl. pyrazinyl. quinolinyi. or isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar Is a fused-blcyclic hateroaryl group unsubstituted or substituted with one or two Rk substituents; and R\ Rb. R-. Rf. R°. and R" are as previously defined; or f) R1 is -NR°Rb; R2 is -H; R3 is a phenyl group substituted with one or two R° substituents. where each R° substituent is -Chalky). -OH. -OC2ealkyl. phenoxy. -CN. -NO2. -N(Rh)R1. -C(O)N(Rh)R'. -N(Rh)C(O)R'. -NCR2SOzCoalkyt. -C(O)C1-6alkyl. -S(0)o.2-C1-6lkyi. -SO2CF3. -SO2N(Rh)Rl. -SCF3. halo. -CO2H. -CCbC1-6alkyl. -C(R')2-CN) or -C(R))2-OH; or two adjacent R° substituents taken together form -OCi.2alky1O-: and Ar is a phenyJ. pyridyi. pyrimidinyl. orfused- bicydic heteroaryl group unsubstituted or substituted with one or two Rk substituents; and R". Rb. Rh. R1. R1. and Rk are as previously defined; or g) R1 Is -NR'Rb; R2 is -H; R3 is a phenyl. benzyl. phenethyl. Indanyl. pyridyl. pyrimidinyl. pyraziny). quinoliny). or isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar is a phenyl group unsubstituted or substituted with one or two Rk substituents; and R8. Rb. R°. and R" are as previously defined. The invention includes also pharmaceutically acceptable salts o[ the compounds represented by Formula (I). preferably o[ those described above. Pharmaceutically acceptable salts o[ the specific compounds exemplified herein are especially preferred. A "pharmaceuticalfy acceptable salt" is intended to mean a salt o[ a free acid or base o[ a compound represented by Formula (I) that is non-toxic. biologically tolerable. or otherwise biologically suitable for administration to the subject See. generally. S.M. Berge et al.. "Pharmaceutical Salts". J. Pharm. Sd.. 1977.66:1-19. and Handbook o[ Pharmaceutical Salts. Properties. Selection. and Use. Stahl and Wermuth. Eds.. Wiley-VCH and VHCA. Zurich. 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues o[ patients without undue toxicity. irritation. or allergic response. A compound o[ Formula (I) may possess a sufficiently acidic group. a sufficiently basic group. or both types o[ functional groups. and accordingly react with a number o[ inorganic or organic bases. and inorganic and organic acids. to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include sulfates. pyrosulfates. bisulfates. sulfrtes. blsulfites. phosphates. monohydrogen-phosphates. dihydrogenphosphates. metaphosphates. pyrophosphates. chlorides. bromides. iodides. acetates. propionates. decanoates. caprylates. acrylates. formates. isobutyrates. caproates. heptanoates. proptolates. oxalates. malonates. succinates. suberates. sebacates. fumarates. maleates. butyl]e-1.4-dioates. hexyl]e-1.6-dioatos. ben2oates. chlorobenzoates. methyibenzoates. dinitrobenzoates. hydroxybenzoates. methoxybenzoates. phttialates. sulfonates. xyleneeuffonatos. phenylacetates. phenyl propionates. phenylbutyrates. citrates. lactates. v-hydroxybutyrates. glycolates. tartrates. methane-sulfonates. propanesulfonates. naphthalene-1-sulfonates. naprtthalene-2- sulfonates. and mandelates. If the compound o[ Formula (I) contains a basic nitrogen. the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art. for example. treatment o[ the free base with an inorganic acid. such as hydrochloric acid. hydrobromic acid. sulfuric acid. sulfamic acid. nitric acid. boric acid. phosphoric acid. and the like. or with an organic acid. such as acetic acid. phenylacetic acid. propionic acid. steartc acid. lactic acid. ascorbic acid. maleic acid. hydroxymaleic acid. isethIonic acid. succinic add. valeric acid. fumaric acid. malonic acid. pyruvic acid. oxalic acid. glycotic acid. salicylic acid. oleic acid. palmitic acid. lauric acid. a pyranoskjyl acid. such as glucuronic acid or galacturonic acid. an alpha-hydroxy acid. 6uch as mandelic acid. citric acid. or tartaric add. an amino acid. such as aspartic acid or glutamic acid. an aromatic acid. such as benzoic add. 2-acetoxybenzoic acid. naphthoic acid. or cinnamlc acid. a sulfdnic acid. such as laurylsuifonic acid. p-toluenesulfonic acid. methanesulfonic add. or ethanesulfonic add. or the like. If the compound o[ Formula (I) is an acid. such as a carboxylic add or sulfonic acid. the desired pharmaceutically acceptable salt may be prepared by any suitable method. for example. treatment o[ the free add with an inorganic or organic base. such a6 an amine (primary. secondary or tertiary). an alkali metal hydroxide. or alkaline earth metal hydroxide. or the like. Illustrative examples o[ suitable salts Indude organic salts derived from amino acids. such as glyclne and arginine. ammonia. carbonates. bicarbonates. primary. secondary. and tertiary amines. and cydic amines. such as benzylamines. pyrrolidines. piperidino. morpholine. and plperazine. and inorganic salts derived from sodium. calcium. potassium. magnesium. manganese. iron. copper. zinc. aluminum. and lithium. In preferred embodiments. the present invention relates to compounds o[ Formula (I) and to sulfate. hydrochloride. fumarate. tartrate. phosphate. metnanesulfonic acid (mesylate). benzenesulfonic acid (besylate). and p- toluansulfonic acid (tosyiate) salts thereo[. The invention also relates to treatment methods employing pharmaceutically acceptable prodrugs o[ the compounds o[ Formula (I). The term "prodrug" means a precursor o[ a designated compound that. following administration to a subject. yields the compound In vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage. or under physiological conditions (e.g.. a prodrug on being brought to physiological pH is converted to the compound o[ Formula (I)). A "pharmaceutically acceptable prodrug" is a prodrug that is not toxic. biologically intolerable. or otherwise biologically unsuitable for administration to the subject Illustrative procedures for the selection and preparation o[ suitable prodrug derivatives are described. for example. in "Design o[ Prodrugs". ed. H. Bundgaard. Elsevier. 1985. Exemplary prodrugs include compounds having an amino acid residue. or a poJypeptide chain o[ two or more (e.g.. two. three or four) amino add residues. covalently joined through an amide or ester bond to a free amino. hydroxy. or carboxylic acid group o[ a compound o[ Formula (I). Examples o[ amino acid residues include the twenty naturally occurring amino acids. commonly designated by three letter symbols. as well as 4-hydroxyproline. hydroxylysine. demosine. isodemosine. 3-methylhistidine. norvalin. beta-alanine. gamma-aminobutyric acid. citrulline homocysteine. homoserine. omithine and methionine sulfone. Additional types o[ prodrugs may be produced. for instance. by derivatizing free carboxyl groups o[ structures o[ Formula (I) as amides or alkyl esters. Exemplary amides include those derived from ammonia. primary C1-6alkyl amines and secondary di(C1-6alkyl) amines. Secondary amines include 5- or 6-membered heterocydoalkyl or heteroaryl ring moieties. Preferred amides are derived from ammonia. C1-3alkyl primary amines. and di(C1-2alkyl)amines. Exemplary esters o[ the invention include d.7alkyl. C5-7cycloalkyl. phenyl. and phenyl(C1-6alkyl) esters. Preferred esters include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy groups using groups Including hemisuccinates. phosphate esters. dimethylaminoacetates. and phosphoryloxymethyioxycarbonyls. following procedures such as those outlined in Adv. Drug Delivery Rev. 1996. 19.115. Carbamate derivatives o[ hydroxy and amino groups may also yield prodrugs. Carbonate derivatives. sulfonate esters. and sulfate esters o[ hydroxy groups may also provide prodrugs. Derivatization o[ hydroxy groups as (acyloxy)methyl and (acykloxy)ethyl ethers. wherein the acyl group may be an alkyl ester. optionally substituted with one or more ether. amine. or carboxytic acid functionalities. or where the acyl group is an amino add ester as described above. is also useful to yield prodrugs. Prodrugs o[ this type may be prepared as described in J. Med. Chem. 1996. 39. 10. Free amines can also be derivatized as amides. sulfonamides or phosphonamides. All o[ these prodrug moieties may incorporate groups including ether. amine. and carboxytic acid functionalities. Pharmaceutically active metabolites may also be used in the methods o[ the invention. A "pharmaceutically active metabolite" means a pharmacologically active product o[ metabolism in the body o[ a compound o[ Formula (I) or salt thereo[. Prodrugs and active metabolites o[ a compound may be determined using routine techniques known or available in the art. See. e.g.. Bertollnl et al.. J. Med. Chem. 1997. 40. 2011-2016; Shan et al.. J. Pharm. Scl. 1997. 86 (7). 765-767; Bagshawe. Drug Dev. Res. 1995. 34. 220-230; Bodor. Adv. Drug Res. 1984. 73. 224-331; Bundgaard. Design o[ Prodrugs (Elsevier Press. 1985); and Larsen. Design and Application o[ Prodrugs. Drug Design and Development (Krogsgaard- Larsen et al.. eds.. Harwood Academic Publishers. 1991). The compounds o[ Formula (I) and their pharmaceutically acceptable salts. pharmaceutically acceptable prodrugs. and pharmaceutically active metabolites (collectively. "agents") o[ the present Invention are useful as TRPV1 modulators in the methods o[ the Invention. The agents may be used in the inventive methods for the treatment or prevention o[ medical conditions. diseases. or disorders mediated through modulation o[ TRPV1. such as those described herein. Symptoms or disease states are intended to be included within the scope o[ "medical conditions. disorders. or diseases." Accordingly. the invention relates to methods o[ using the pharmaceutical agents described herein to treat subjects diagnosed with or suffering from a disease. disorder. or condition mediated through TRPV1 activity. such as: I) pain (acute. chronic. inflammatory. or neuropathic pain); ii) itch or various inflammatory disorders; iii) inner ear disorders; iv) fever and other disorders o[ thermoregulation; v) tracheobronchial and diaphragmatic dysfunction; vi) gastrointestinal and urinary tract disorders; and vii) disorders associated with reduced blood flow to the CNS or CNS hypoxia. In a preferred embodiment. an agent o[ the present invention Is administered to treat pain. Pain may be associated with various diseases. disorders. or conditions. and may include various etiologies. Exemplary types o[ pain treatable with a TRPV1- modulating agent according to the invention include pain arising from or caused by: osteoarthritis. rotator cuff disorders. arthritis (e.g.. rheumatoid arthritis or inflammatory arthritis). fibromyalgia. migraine and headache (e.g. cluster headache. sinus headache. or tension headache; see. Goadsby Curr. Pain Headache Reports 2004. 8. 393). sinusitis. oral mucositis. toothache. dental trauma. dental extractions. dental infections. bum. sunburn. dermatitis. psoriasis. eczema. insect sting or bite. burn pain (Bolkskei et al.. Pain 2005. in press). musculoskeletal disorders. bony fractures. ligamentous sprains. plantar fasciitis. costochondritis. tendonitis. bursitis. tennis elbow. pitcher's elbow. patellar tendonitis. repetitive strain injury. myo[ascial syl]drome. muscle strain. myositis. temporomandlbular joint disorder. amputation. low back pain. spinal cord injury. neck pain. whiplash. bladder spasms. Gl tract disorders. interstitial cystitis. urinary tract infection. urethral colic. renal colic. pharyl]gitis. cold sores. stomatitis. external otitis. otitis media (Chan et al.. Lancet 2003. 361. 385). burning mouth syl]drome. mucositis. esophageal pain. esophageal spasms. abdominal disorders. gastroesophageal reflux disease. pancreatitis. enteritis. irritable bowel i disorder. inflammatory bowel disease. Crohn's disease. ulcerative colitis. colon distension. abdominal constriction. diverticulosis. diverticulitis. intestinal gas. hemorrhoids. anal fissures. anorectal disorders. prostatitis. epididymitis. testicular pain. proctitls. rectal pain. cholecystitis. labor. childbirth. endometriosis. menstrual cramps. pelvic pain. vulvodyl]la. vaglnitis. orolabial and genital infections (e.g. herpes simplex). pleurisy. pericarditis. non-cardiac chest pain. contusions. abrasions. skin incision (Honore. P. et al.. J. Pharmacol. Exp. Ther. 2005. 314.410-21). postoperative pain. peripheral neuropathy. central neuropathy. diabetic neuropathy. acute herpetic neuralgia. post-herpetic neuralgia. trigeminal neuralgia. glossopharyl]geal neuralgia. atypical facial pain. gradiculopathy. HIV associated neuropathy. physical nerve damage. causalgia. reflex sympathetic dystrophy. sciatica. cervical. thoracic or lumbar radiculopathy. brachial plexopathy. lumbar plexopathy. neurodegeneratlve disorders. occipital neuralgia. intercostal neuralgia. supraorbital neuralgia. inguinal neuralgia. meralgia paresthetica. genito[emoral neuralgia. carpal tunnel syl]drome. Morton's neuroma. post-mastectomy syl]drome. post-thoracotomy syl]drome. post-polio syl]drome. Guillain-Barre syl]drome. Rayl]aud's syl]drome. coronary artery spasm (Printzmetal's or variant angina). visceral hyperalgesia (Pomonis. J.D. et al. J. Pharmacol. Exp. Ther. 2003. 306. 387; Walker. K.M. et al.. J. Pharmacol. Exp. Ther. 2003. 304(1). 56-62). thalamic pain. cancer (e.g. pain caused by cancer. by treatment o[ cancer by radiation or chemotherapy. or by nerve or bone lesions associated with cancer (see. Menendez. L. et al.. Neurosci. Lett. 2005. 393 (1). 70-73; Asai. H. et al.. Pain 2005. 117. 19-29). or bone destruction pain (see. Ghilardi. J.R. etal.. J. Neurosci. 2005. 25. 3126-31)). infection. or metabolic disease. Additionally. the compounds may be used to treat pain indications such as visceral pain. ocular pain. thermal pain. dental pain. capsaicin-induced pain (as well as other symptoms Induced by capsaicin such as cough. lachrymation. and bronchospasm). In another preferred embodiment. agents are administered to treat itch. which may arise from various sources. such as dermatological or inflammatory disorders; or inflammatory disorders selected from the group consisting o[: renal or hepatobUiary disorders. immunologfcal disorders. medication reactions and unknown)idiopathic conditions. Inflammatory disorders treatable with an inventive agent include. for example. inflammatory bowel disease (IBD). Crohn's disease. and ulcerative colitis (Geppetti. P. et al.. Br. J. Pharmacol. 2004. 141. 1313-20; Ylangou. Y. et al.. Lancet 2001. 357.1338-39; Kimball. E.S. etal.. Neurogastroenterol. MptiL. 2004.16. 811). ostebarthritis (Szabo. A. et al.. J. Pharmacol. Exp. Ther. 2005. 314.111-119). psoriasis. pson'atic arthritis. rheumatoid arthritis. myasthenia gravis. mu(ti pie sclerosis. scleroderma. glomerulonephritis. pancreatitis. inflammatory hepatitis. asthma. chronic obstructive pulmonary disease. allergic rhinitis. uveitis. and cardiovascular manifestations o[ inflammation including atherosclerosis. myocarditis. pericarditis. and vasculitis. In another preferred embodiment. inner ear disorders are treated with an inventive agent. Such disorders include. for example. hyperacusis. tinnitus. vestibular hypersensitivity. and episodic vertigo. In another preferred embodiment. tracheobronchial and diaphragmatic dysfunctions are treated with an inventive agent. including. for example. asthma and allergy-related immune responses (Agopyan. N. et al.. Am. J. Physiol. Lung Cell Mol. Physlol. 2004. 286. L563-72; Agopyan. N. et al.. Toxlcoi. Appl. Pharmacol. 2003.192. 21-35). cough (e.g.. acute or chronic cough. or cough caused by irritation from gastroesophageal reflux disease; see. Lalloo. U.G. et al.. J. Appl Physlot. 1995. 79(4). 1082-7). bronchospasm. chronic obstructive pulmonary disease. chronic bronchitis. emphysema. and hiccups (hiccoughs. singultus). In yet another preferred embodiment. gastrointestinal and urinary tract disorders are treated with an inventive agent. such as. bladder overactivtty. inflammatory hyperalgesia. visceral hyperreflexia o[ the urinary bladder. homorrhagic cystitis (Dinis. P. et al.. J. Neurosci. 2004. 24. 11253-11263). interstitial cystitis (Sculptoreanu. A. et al.. Neurosci. Lett. 2005. 381. 42-46). inflammatory prostate disease. prostatitis (Sanchez. M. et al.. Eur. J. Pharmacol. 2005. 515. 20-27). nausea. vomiting. intestinal cramping. intestinal bloating. bladder spasms. urinary urgency. defecation urgency and urge incontinence. In another preferred embodiment. disorders associated with reduced blood flow to the CNS or CNS hypoxia are treated with an Inventive agent. Such disorders include. for example. head trauma. spinal injury. thromboembolic or hemontiagic stroke. transient ischaemic attacks. cerebral vasospasm. hypoglycaemia. cardiac arrest. status epilepticus. perinatal asphyxia. Alzheimer's disease. and Huntingdon's Disease. In other embodiments. agents are administered to treat other diseases. disorders. or conditions mediated through TRPV1 activity. such as: anxiety; learning or memory disorders; eye-related disorders (such as glaucoma. vision loss. increased intraocular pressure. and conjunctivitis); baldness (e.g.. by stimulating hair growth); diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion); obesity (e.g.. through appetite suppression); dyspepsia; biliary colic; renal colic; painful bladder syl]drome; Inflamed esophagus; upper airway disease; urinary Incontinence; acute cystitis; and envenomations (such as marine. snake. or insect stings or bites. including Jellyfish. spider. or stingray envenomations). In especially preferred embodiments o[ the therapeutic methods o[ the invention. effective amounts o[ the TRPV1 modulators o[ the present invention are administered to treat pain. itch. cough. asthma. or Inflammatory bowel disease. The term "treat" or "treating" as used herein is intended to refer to administration o[ an agent or composition o[ the invention to a subject for the purpose o[ effecting a therapeutic or prophylactic benefit through modulation o[ TRPV1 activity. Treating includes reversing. ameliorating. alleviating. inhibiting the progress o[. lessening the severity o[. or preventing a disease. disorder. or condition. or one or more symptoms o[ such disease. disorder or condition mediated through modulation o[ TRPV1 activity. The term "subject" refers to a mammalian patient In need o[ such treatment. such as a human. "Modulators" include both inhibitors and activators. where "inhibitors" refer to compounds that decrease. prevent. inactivate. desensitize or down-regulate TRPV1 expression or activity. and "activators" are compounds that increase. activate. facilitate. sensitize. or up-regulate TRPV1 expression or activity. In treatment methods according to the invention. an effective amount o[ a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease. disorder. or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need o[ such treatment for the designated disease. disorder. or condition. Effective amounts or doses o[ the agents o[ the present invention may be ascertained by routine methods such as modeling. dose escalation studies or clinical trials. and by taking into consideration routine factors. e.g.. the mode or route o[ administration or drug delivery. the pharmacoklnetics o[ the agent. the severity and course o[ the disease. disorder. or condition. the subject's previous or ongoing therapy. the subject's health status and response to drugs. and the judgment o[ the treating physician. An exemplary dose is in the range o[ from about 0.001 to about 200 mg o[ agent per kg o[ subject's body weight per day. preferably about 0.05 to 100 mg)kg)day. or about 1 to 35 mg)kg)day. or about 0.1 to 10 mg)kg daily in single or divided dosage units (e.g.. BIO. TID. QID). For a 70-kg human. an illustrative range for a suitable dosage amount Is from about 0.05 to about 7 g)day. or about 0.2 to about 2.5 g)day. Once improvement o[ the patient's disease. disorder. or condition has occurred. the dose may be adjusted for preventative or maintenance treatment. For example. the dosage or the frequency o[ administration. or both. may be reduced as a function o[ the symptoms. to a level at which the desired therapeutic or prophylactic effect is maintained. Of course. if symptoms have been alleviated to an appropriate level. treatment may cease. Patients may. however. require intermittent treatment on a long-term basis upon any recurrence o[ symptoms. In addition. the agents o[ the invention may be used in combination with additional active compounds in the treatment o[ the above conditions. The additional compounds may be coadministered separately with an agent o[ Formula (I) or included with such an agent as an additional active ingredient in a pharmaceutical composition according to the invention. In an exemplary embodiment. additional active compounds are those that are known or discovered to be effective in the treatment o[ conditions. disorders. or diseases mediated by TRPV1 activity. such as another TRPV1 modulator or a compound active against another target associated with the particular condition. disorder. or disease. The combination may serve to increase efficacy (e.g.. by including in the combination a compound potentiating the potency or effectiveness o[ an agent according to the invention). decrease one or more side effects. or decrease the required dose o[ the agent according to the invention. In one illustrative embodiment. a composition according to the invention may contain one or more additional active ingredients selected from opioids. NSAIDs (e.g.. ibupro[en. cyclooxygenase-2 (COX-2) inhibitors. and naproxen). gabapentin. pregabalin. tramadol. acetaminophen. and aspirin. The agents o[ the invention are used. alone or in combination with one or more other active ingredients. to formulate pharmaceutical compositions o[ the Invention. A pharmaceutical composition o[ the Invention comprises: (a) an effective amount o[ a pharmaceutical agent in accordance with the Invention; and (b) A pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a substance that is not toxic. biologically intolerable. or otherwise biologically unsuitable for administration to a subject. such as an inert substance. added to a pharmacological composition or otherwise used as a vehicle. carrier. or diluent to facilitate administration o[ a pharmaceutical agent and that Is compatible therewith. Examples o[ excipients include calcium carbonate. calcium phosphate. various sugars and types o[ starch. cellulose derivatives. gelatin. vegetable oils. and polyethylene glycols. Delivery forms o[ the pharmaceutical compositions containing one or more dosage units o[ the pharmaceutical agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route o[ delivery. e.g.. oral. parenteral. rectal. topical. or ocular routes. or by inhalation. The preparation may be in the form o[ tablets. capsules. sachets. dragees. powders. granules. lozenges. powders for reconstitution. liquid preparations. or suppositories. Preferably. the compositions are formulated for intravenous infusion. topical administration. or oral administration. For oral administration. the compounds o[ the Invention can be provided In the form o[ tablets or capsules. or as a solution. emulsion. or suspension. To prepare the oral compositions. the agents may be formulated to yield a dosage o[. e.g.. from about 0.05 to about 50 mg)kg daily. or from about 0.05 to about 20 mg)kg daily. or from about 0.1 to about 10 mg)kg daily. Oral tablets may include the agent and any other active ingredients mixed with compatible phamnaceutically acceptable excipients such as diluents. disintegrating agents. binding agents. lubricating agents. sweetening agents. flavoring agents. coloring agents and preservative agents. Suitable inert fillers Include sodium and calcium carbonate. sodium and calcium phosphate. lactose. starch. sugar. glucose. methyl cellulose. magnesium stearate. mannKol. sorbitol. and the like. Exemplary liquid oral excipients include ethanol. glycenol. water. and tho like. Starch. poryvinyi-pyrrolkjone (PVP). sodium starch glycolate. microcrystalline cellulose. and alglnlc acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent. if present. may be magnesium stearate. stearic acid or talc. If desired. the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. or may be coated with an enteric coating. Capsules for oral administration include hard and so[t gelatin capsules. To prepare hard gelatin capsules. active ingredient may be mixed with a solid. semi- solid. or liquid diluent. So[t gelatin capsules may be prepared by mixing the active ingredient with water. an oil such as peanut oil. sesame oil. or olive oil. liquid paraffin. a mixture o[ mono and di-glycerides o[ short chain fatty acids. polyethylene glycol 400. or propytene glycol. Liquids for oral administration may bo in the form o[ suspensions. solutions. emulsions or syrups or may be lyophllized or presented as a dry product for reconstltution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable exdpients such as suspending agents (for example. sorbltol. methyl cellulose. sodium alginate. gelatin. hydroxyethylcellulose. carboxymethylcellulose. aluminum stearate gel and the like); non-aqueous vehicles. e.g.. oil (for example. almond oil or fractionated coconut oil). propylene glycol. ethyl alcohol. or water; preservatives (for example. i methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and. if desired. flavoring or coloring agents. The active agents o[ this invention may also be administered by non-oral routes. For example. the compositions may be formulated for rectal administration as a suppository. For parenteral use. including intravenous. intramuscular. intrapentoneal. or subcutaneous routes. the agents o[ the invention may be provided in sterile aqueous solutions or suspensions. buffered to an appropriate pH and isotonictty or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and Isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices. in multi-dose forms such as vials from which the appropriate dose may be withdrawn. or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative Infusion doses range from about 1 to 1000 ng)kg)minute o[ agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical administration. the agents may be mixed with a pharmaceutical carrier at a concentration o[ about 0.1% to about 10% o[ drug to vehicle. Another mode o[ administering the agents o[ the invention may utilize a patch formulation to affect transdermal delivery. Agents may alternatively be administered in methods o[ this invention by inhalation. via the nasal or oral routes. e.g.. In a spray formulation also containing a suitable carrier. Preferred agents useful in methods o[ the invention will now be described by reference to illustrative syl]thetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that. to obtain the various compounds herein. starting materials may be suitably selected so that the ultimately desired substituents wHI be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively. it may be necessary or desirable to employ. in the place o[ the ultimately desired substituent. a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified. the variables are as defined above in reference to Formula (I). Referring to general Scheme A. compounds o[ Formula (I) may be prepared from -ketoesters (VI). where X1 is a suitable ami no protecting group. such as a benzyl or carbamate group. Protected piperidones (V) are commercially available or may be prepared according to known methods. Preferred protecting groups for amines includo tert-butyl carbamate (Boc) or benzyl groups. -Ketoesters (VI) may be prepared according to general techniques known in the art For example. p- ketoesters (VI) may be accessed from piperidones (V) by ring expansion o[ piperidones (V) with ethyl dlazoacetate In the presence o[ a Lewis acid. such as BF3-OEt. in a suitable solvent. such as Et2O or CH2CI2 or a mixture thereo[. at temperatures ranging from about 0 °C to about room temperature (rt). p- Ketoesters (VI) may be reacted with amWines or carboximidamides (VII). or with ureas or thloureas (VIII). for example. in the presence o[ NaOEt or KOtBu. In a solvent such as EtOH or tBuOH or a mixture thereo[. at temperatures between rt and the reflux temperature o[ the solvent. to form hydroxy pyrimkjines (IX). Where the condensation is done with a urea or thiourea. in situ alkytation with an alky) chloride or bromide provides pyrimidines (IX) where R1 is -S-C1-6alkyl or-O-Ci. 6alkyt. The X1 protecting group may be removed using known methods. For example. a Boc group may be removed with an acid such as TFA or HCJ. in a solvent such as Et2O. dioxane. EtOH. or MeOH or a mixture thereo[. to form amines (IX) where X1 + -H. Where an acid salt is obtained. the corresponding free base may be obtained by suitable general methods known in the art Preferably. the free base is obtained by filtration o[ the salt through resin-bound carbonate using an alcoholic solvent. preferably MeOH. Where X1 is a benzyl group. the group may be removed according to standard methods. such as hydrogenation in the presence o[ a palladium catalyst such as Pd)C or Pd(OH)2)C. in a solvent such as EtOH. Hydroxy pyrimidines (IX) where X1 is -H may then be converted to amines (X) using known methods such as SN-aryl substitution. or palladium- mediated cross-couplings. SN-ATVI substitution may be accomplished by treatment o[ hydroxy pyrimidines (XI). where X1 is -H. with Ar-HAL (where HAL Is halo). such as 2-chk)ro-3-trifluorornethyl-pyridine. in the presence o[ a base such K2CO3. In a polar solvent such as DMSO. at temperatures between about rt and the reflux temperature o[ the solvent Palladium-mediated cross-couplings are done by reacting Ar-HAL in the presence o[ a palladium catalyst. Preferably. hydroxy pyrimidines (IX). where X1 is -H. are treated with EtaN or (iPr)2NEt. in suitable solvents. such as n-BuOH. tBuOH. t-amyl alcohol. DMF. DMSO. DME. or NMP. or a mixture thereo[. at temperatures from about 100 to about 200 °C. Pyrimidines (X) can then be activated for use in palladium-mediated cross-coupling reactions or SN2 reactions by general procedures known in the art For example. treatment with POCb. PCI3. PBrj. or POBrs affords the corresponding halopyrimldines (XI) where Z is chloride or bromide. Treatment o[ pyrimidines (X) with trifluoromethane- sulfonic anhydride or N-phenyl-bis(trifluoromethanesulfonimide) In DCE. CH2CI2. or THF. or a mixture thereo[. In the presence o[ a base such as pyridine. EtsN. (IPrJaNEt. or KOtBu. provides triflates (XI) where Z is -OSO2CF3. In a preferred embodiment. pyrimidines (X) are treated with POCI3 in CH3CN at temperatures from about 80 to about 100 °C. Substitution o[ pyrimidines (XI) with amines HN(R2)R3 to produce compounds o[ Formula (I) may be accomplished by various suitable methods within the routine purview o[ artisans. Where Z Is Cl. substitution may involve heating chloro-pyrimidines (XI) with suitable amines (XII) in alcoholic solvents such as MeOH. EtOH. tBuOH. n-BuOH. ort-amyl-OH. or a mixture thereo[. at temperatures from about rt to about the reflux temperature o[ the solvent. Preferably. the solvent Is n-BuOH and the temperature is about 130 °C. Alternatively. chloro-pyrimidines (XI) may be reacted with amines (XII) in the presence o[ an acid catalyst. preferably p-toiuenesulfonic acid or TFA. in toluene or dioxane. at temperatures from about 100 to about 150 °C. to provide compounds o[ Formula (I). Coupling o[ halides or triflates (XI) with amines (XII). in the presence o[ a catalyst such as Pd(OAc)2. Pd(PPh3)<. pdci2pphsfe. or pdcypo-> tobk. in a solvent such as THF. 1.4-dioxane. DMA. DMF. DME. or toluene. or mixtures thereo[. In the presence o[ a base such as NaOtBu. Na2CO3. K2CO3. CS2CO3. or K3PO4. with o[ without an additive such as 2- (dicyclohexylphosphanyi)biphenyl (DCPB). also affords pyrimidines (I). In a preferred embodiment. coupling is accomplished In the presence o[ Pd(OAc)2 catalyst. DCPB. and NaOtBu in toluene at temperatures from about 100 to about 200 °C in a microwave reactor. SCHEME B Referring to Scheme B. compounds o[ Formula (I) may be prepared by an alternate general route. Protected piperidones (XV). such as 1.4-dk)xa-8-aza- spiro[4.5Jdecane (where PG is -O-(CH2)2-O-). may be converted to aryl amines (XIV) by Sv-aryl substitution or palladium-mediated cross-couplings as described in Scheme A. Deprotection o[ the protecting group using known general procedures. such as concentrated HCI. provides ketones (XV). Ketones (XV) may be processed into compounds o[ Formula (I) generally according to the ring expansion. condensation. activation. and displacements described in Scheme A. Referring to Scheme C. thioethers (XVI). obtained as described in Scheme A. may be oxidized using generally known methods to provide sulfones (XVII). Displacement o[ the sulfone substituent is attained by reaction with alcohols HO- Ch-aalkyl or amines HN(R")Rb in solvents such as MeOH. EtOH. n-BuOH. THF. DMF. DMSO. or toluene. or a mixture thereo[. with or without the presence o[ a suitable base such as NaOMe. NaOEt. KOtBu. NaH. Et3N. (IPr)2EtN. or pyridine. at temperatures between rt and the reflux temperature o[ the solvent. Preferably. displacement with amines HN(R')Rb is performed by heating with sutfonea (XVII) in toluene in a sealed tube at 110 °C. Compounds o[ Formula (I) may be converted to their corresponding salts using methods known to those skilled in the art. For example. amines o[ Formula (I) may be treated with trifluoroacetic acid. HCI. citric acid. H2SO4. methanesuffonic acid (MsOH). benzenesulfonic add. or p-toluenesulfonic acid (TsOH) in a solvent such as EfcO. EtOAc. CH2CI2. THF. or MeOH. or a mixture thereo[. to provide the corresponding salt forms. Compounds prepared according to the schemes described above may be obtained as single enantiomers. diastereomers. or reglolsomere. or as racemtc mixtures or mixtures o[ enantiomers. diastereomers. or regioisomers. Where regioisomeric or diastereomeric mixtures are obtained. isomers may be separated using conventional methods such as chromatography or crystallization. Where racemic (1:1) and non-racemic (not 1:1) mixtures o[ enantiomers are obtained. single enantiomers may be isolated using conventional separation methods known to one skilled in the art. Particularly useful separation methods may include chiral chromatography. recrystallization. diastereomeric salt formation. or derivatization into diastereomeric adducts followed by separation. The following examples are provided to further illustrate aspects o[ the invention and various preferred embodiments. Examples Chemistry: In obtaining the characterization data described in the examples below. the following analytical protocols were followed unless otherwise indicated. NMR spectra were obtained on Bruker model DRX spectrometers. The format o[ 1H NMR data below is: chemical shi(t in ppm downfieJd o[ the tetramethylsilane reference (multiplicity. coupling constant J in Hz. integration). Mass spectra were obtainied on an Agilent series 1100 MSD using electrospray ionlzation (ESI) in either positive or negative modes as indicated. Calculated mass corresponds to the exact mass. Thin-layer chromatography was performed using Merck silica gel 60 F254 2.5 cm x 7.5 cm 250 um or 5.0 cm x 10.0 cm 250 um pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM Science silica gel 60 F294 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone. Normal phase purification was typically done by normal phase flash column chromatography (FCC) with RediSep® silica gel columns using EtOAc)hexanes as eluent unless otherwise specified. Reverse phase high performance liquid chromatography (HPLC) was performed under the following conditions: Instrument. Shimadzu; Column. Phenomenex Gemini column 5 urn C18 (150 x 21.2 mm) or Waters Xterra RP18 OBD 5 urn (100 x 30 mm); Gradient. 95:5 to 0:100 water (0.05% TFAyCH3CN (0.05% TFA); Flow rate. 30 mL)min; Detection. UV at A = 254 nM. Microwave reactions were carried out in either a CEM Discover® or a Biotage Initiator™ Microwave at specified temperatures. Where solutions were "concentrated". they were concentrated using a rotary evaporator under reduced pressure. Unless otherwise specified. reaction solutions were stirred at room temperature (rt) under a N2(g) atmosphere. Hydrochloride salts were obtained by treating the corresponding free bases with HCI (4 N in dioxane) at rt. The mixtures were either concentrated to obtain the HCI salt. or the resulting solid was isolated by filtration. Trifluoroacetic acid salts were obtained by purification o[ the crude reaction product by preparative reverse phase HPLC. To a 0 °C solution o[ 1-BOC-4-piperidone (20 g. 0.10 mol) in E2O (200 mL) was added BF3+Et2O (14 mL. 0.11 mol) followed by drop-wise addition o[ ethyl dlazoacetate (13.7 mL. 0.11 mol) over 1 h. A(ter addition was complete. the mixture was stirred at 0 °C for 1 h. The mixture was diluted with 30% aq. Na2Oa and water at 0 °C and extracted with EtOAc. The combined organic layers were dried (Na2SO0 and concentrated. Purification o[ the residue (FCC) afforded the title compound (25.6 g. 98%). 1H NMR (CDCI3): 4.25-2.03 (m. 11H). 1.47-1.45 (d. J = 7.8 Hz. 9H). 1.31-1.24 (m. 3H). The title compound was prepared analogously to Intermediate A from 3'- triflu6romethyl-2.3.5.6-tetrahydro-[1.2l]bipyridinyl-4-one (see U.S. Pat. Appl. Publ. US 2005)080095). using CH2CI2 instead o[ Et2O. and with a reaction time o[ 12 h at rt. MS (ESI): mass calcd. for C18H17F3N2O3. 330.12; m/z found. 331.1 [M+H]\ 1H NMR (mixture o[ enol and keto forms; CDCI3): 12.75 (s. 1.4H). 8.44-8.41 (m. 1.0H). 8.40-8.38 (m. 1.4H). 7.90-7.83 (m. 2.5H). 7.04-6.99 (m. 1.0H). 6.97-8.92 (m. 1.5H). 4.264+.19 (m. 5.6H). 3.77-3.65 (m. 3.1H). 3.51-3.45 (m. 4.4H). 3.39-3.33 (m. 4.2H). 3.02-2.94 (m. 1.0H). 2.83-2.75 (m. 4.1H). 2.70-2.66 (m. 3.1H). 2.34-2.15 (m. 2.0H). 1.36-1.23 (m. 8.9H). To solution o[ 5-oxo-azepane-1.4-dlcarboxytic acid 1-tert-butyl ester 4-ethyi ester (8.8 g. 30.8 mmol) in EtOH (308 mL) was added NaOEt (21% in EtOH; 38 ml_) followed by formamidine acetate (4.8 g. 45.9 mmol). The mixture was heated at reflux for 2 h. then was concentrated. azeotroping with toluene. The residue was dissolved in water and made basic via addition o[ 50% aq. NaOH. The aqueous layer was extracted with toluene and then acidified to pH = 7 with HOAc (precipitate formed). The mixture was heated at 100 °C for 1 h. cooled to 0 °C. and filtered to give the title compound (2.5 g. 31%). which was used without further purification. To a solution o[ 4-hydroxy-5.6.8.9-tetrahydrc-pyrimido[4.5-d]azepine-7- carboxylic acid tert-butyl ester (1.0 g. 3.77 mmol) in CH2CI2 (14 mL) was added 4 M HCI In dioxane (4 mL. 15 mmol). A(ter 24 h. the mixture was concentrated to afford the HCJ salt (923 mg). The salt (200 mg. 1.0 mmol) was dissolved in MeOH (10 mL) and filtered through quaternary amine resin. carbonate form (1.0 g) and concentrated to provide the title compound (159 mg. 97%). A solution o[ 6.7.8.9-tetrahydro-5H-pyrlmido[4.5-d]azepin-4-ol (353 mg. 1.76 mmol). 2-(luoro-3-trifluoromethyl-pyridine (582 mg. 3.53 mmol). iPr2NEt (0.9 mL. 5.28 mmol). and f-amyf alcohol (5 mL) was heated In a microwave at 180 °C for 5 h. The mixture was concentrated. diluted with water. and extracted with EtOAc. The combined organic layers were dried (Na2O") and concentrated to give the title compound (185 mg. 34%). which was used in the next step without further purification. To a solution o[ 7-(3-trifluoromethyf-pyrkJin-2-y1)-6.7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-ol (185 mg. 0.60 mmol) in CH3CN (2 mL) was added POCI3 (0.11 mL. 1.19 mmol). The reaction mixture was heated at 90 °C for 2 h. The mixture was cooled to rt. diluted with EtOAc. and quenched slowly with saturated (satd.) aq. NaHCOs. The combined organic layers were dried (NaaSOO and concentrated. The crude residue was purified (FCC) to give the title compound (65 mg. 33%). Step E. To a solution o[ 4-chloro-7-(3-trifluoromethyt-pyridin-2-yt)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepine (27 mg. 0.085 mmol) In n-BuOH (1 mL) was added 4-tert-butylaniline (27 uL. 0.17 mmol). A(ter 2 h at 135 °C. the mixture was cooled to rt. quenched with saturated aqueous (satd. aq.) NaHCC with EtOAc. The combined organic layers were dried (Na2SC The residue was purified (FCC) to give the title compound (33 mg. 89%). MS (ESI): mass calcd. for C24H28F3N5. 441.21; m/z found. 442.2 [M+HJ". 1H NMR (CDCI3): 8.50 (s. 1H). 8.40-8.37 (m. 1H). 7.90-7.85 (m. 1H). 7.46-7.36 (m. 4H). 6.98-6.93 (m. 1H). 6.45 (s. 1H). 3.70-3.65 (m. 2H). 3.64-3.60 (m. 2H). 3.26-3.20 (m. 2H). 3.02-2.95 (m. 2H). 1.32 (s. 9H). Alternatively. the reaction o[ this step may be performed in the microwave at 180 °C for 30 min. Example 1A: (4-tert-Butv1-phenyl[7-(3-trifluotomethyl-PVridin-2-yl)-6.7.9.8.9- tetrahydro-5H-pyrimklor4.5-diazepin-4-yl]-arnine hvdrocnloride salt. The following Examples 2-16 were prepared using methods analogous to those described in Example 1. substituting the appropriate amidines in Step A and amines in Stop E. Example 2: 24-Trifluoromethyl-Dhenv1)-[7-)3-trifluoromethyl-Pvridin-2-v1)-6.7.6.9- tetra-hvdro-5H-pyrimido[4.5-d1azepin-4-vf1-amlne. MS (ESI): mass calcd. for C21H17F6N5. 453.14; m/z found. 454.1 [M+H]". 1H NMR (CDCJ3): 8.56 (s. 1H). 8.39-8.36 (m. 1H). 7.89-7.86 (m. 1H). 7.68 (d. J = 8.8 Hz. 2H). 7.59 (d. J = 8.8 Hz. 2H). 6.98-6.94 (m. 1H). 6.65 (s. 1H). 3.68-3.64 (m. 2H). 3.63-3.59 (m. 2H). 3.27-3.22 (m. 2H). 3.04-3.00 (m. 2H). Example 2A: (4-Trifluoromethyt-phenylH7-(3-trifluoromethy tetra-hvdro-5H-pyrimidor4.5-d1azep|n-4-vfl-amlne hvdrochloride salt- Example 3: (4-tert-Butyl-phenv MS (ESI): mass calcd. for C2H2Ns. 481.25; m/z found. 482.2 [M+H]". 1H NMR (CDCI3): 8.38-8.35 (m. 1H). 7.87-7.83 (m. 1H). 7.50-7.45 (m. 2H). 7.36-7.31 (m. 2H). 6.94-6.91 (m. 1H). 6.40 (s. 1H). 3.66-3.53 (m. 4H). 3.21-3.12 (m.2H). 2.94-2.86 (m. 2H). 2.09-2.02 (m. 1H). 1.32 (s. 9H). 1.11-1.06 (m. 2H). 0.97-0.92 (m. 2H). Example 4: (4-Chloro-DhenvlVf2-cvcloDropy 6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1azepin-4-v MS (ESI): mass calcd. for C23H21CIF3N5. 459.14; m/z found. 460.1 [M+H]". 1H NMR (CDCI3): 8.39-8.35 (m. 1H). 7.88-7.83 (m. 1H). 7.50-7.45 (m. 2H). 7.30- 7.26 (m. 2H). 6.97-6.91 (m. 1H). 6.41 (s. 1H). 3.65-3.55 (m. 4H). 3.20-3.15 (m. 2H). 2.94-2.89 (m. 2H). 2.08-2.01 (m. 1H). 1.05-1.01 (m. 2H). 0.97-0.92 (m. 2H). Example 5: t2-Cvclopropyl-7-(3-trifluoromethyl-pyridin-2-v Dvrimido[4.5-dlazepin-4-vf]-(4-trifluo[omethyl-phenyl)-amine. MS (ESI): mass calcd. for C24H21FeN5. 493.17; m/z found. 494.1 [M+H]". 1H NMR (CDCI3): 8.39-8.35 (m. 1H). 7.88-7.85 (m. 1H). 7.73-7.65 (m. 2H). 7.60-7.51 (m. 2H). 6.97-6.92 (m. 1H). 6.59 (s. 1H). 3.66-3.55 (m. 4H). 3.23-3.15 (m. 2H). 2.99-2.90 (m. 2H). 2.12-2.05 (m. 1H). 1.09-O.95 (m. 4H). Example 5A: f2-CvdoproDVl-7-(3-trtfluoromethyt-Pvridin-2-vl)-6.7.8.9-tetrahvdro- 5H-pyrimkto[4.5-d1azepin-4-yl]-[4-trifluorometfrv1-Phenvl)-arnine hydrochloride salt. Example 6: (4-tert-Butyl-Phenyl)-[2-phenyl-7-23-trifluoromethyl-pridin-2-v1V6.7.8.9- tetrahvdro-5H-pyrimldor4.5-d]azepin-4-yl]-amin9. MS (ESI): mass calcd. for C30H30F3N5. 517.25; m/z found. 518.2 [M+H]". 1H NMR (CDCI3): 8.41-8.37 (m. 3H). 7.89-7.86 (m. 1H). 7.65-7.59 (m. 2H). 7.49-7.39 (m. 5H). 6.97-6.91 (m. 1H). 6.54 (s. 1H). 3.73-3.69 (m. 2H). 3.68-3.64 (m. 2H). 3.35-3.29 (m. 2H). 3.06-3.00 (m. 2H). 1.35 (s. 3H). Example 7: f2-Phenv pyrimido[4.5-dlazepir)4-yl]-(4-trifluoromethyl-phenul)-amino. MS (ESI): mass calcd. for C27H21F6N5. 529.17; m/z found. 530.2 [M+H]". 1H NMR (CDCb): 8.41-8.33 (m. 3H). 7.89-7.85 (m. 1H). 7.81 (d. J = 8.5 Hz. 2H). 7.65- 7.63 (d. J = 8.5 Hz. 2H). 7.49-7.43 (m. 3H). 6.98-6.93 (m. 1H). 6.72 (s. 1H). 3.72- 3.67 (m. 2H). 3.66-3.62 (m. 2H). 3.36-3.32 (m. 2H). 3.11-3.02 (m. 2H). Example 8: 24-tert-Buty1-phenylVr2-l30Prooyl-7-(3-trrfluoromethyt-pyridin-2-v1)- 6.7.8.9-tetrahvdro-5H-ovrimtdor4.5-d]lazepln-4-yl]-amine. MS (ESI): mass calcd. for C27H32F3N5. 483.26; m/z found. 484.2 [M+H]". 1H NMR (CDCI3): 8.38-8.35 (m. 1H). 7.87-7.83 (m. 1H). 7.50-7.45 (m. 2H). 7.62-7.57 (m. 2H). 6.94-6.91 (m. 1H). 6.45 (s. 1H). 3.67-3.63 (m. 2H). 3.62-3.58 (m. 2H). 3.21-3.17 (m. 2H). 3.05-2.97 (m. 1H). 2.95-2.90 (m. 2H). 1.34-1.31 (m. 12H). 1.30 (s. 3H). Example 9: [2-lsopropyl-7-(3-trifluoromethyl-PVridin-2-yl)-6.7.8.9-tetrahvdro-5H- PVrimJdo[4.5-dlazepln-4-yl]-(4-trifluoromethyl-phenyl)- amine. MS (ESI): mass calcd. for C24H23F6N5. 495.19; m/z found. 496.1 [M+H]". 1H NMR (CDCI3): 8.39-8.36 (m. 1H). 7.88-7.84 (m. 1H). 7.79 (d. J = 9.1 Hz. 2H). 7.58 (d. J = 8.8 Hz. 2H). 6.97-6.93 (m. 1H). 6.64 (s. 1H). 3.67-3.63 (m. 2H). 3.61-3.57 (m. 2H). 3.24-3.20 (m. 2H). 3.09-3.00 (m. 1H). 3.00-2.95 (m. 2H). 1.31 (d. J = 6.86 Hz. 6H). Example 9A: r2-lsopropy ovrimldo[4.5-dlazepin-4-v+-('4-trifluoromethyl-phenv1)-amine hvdrochtoride salt. 1H NMR (CD3OD): 8.47-8.45 (m. 1H). 8.04 (dd. J = 1.7. 7.8 Hz.1H). 7.82 (d. J = 8.6 Hz. 2H). 7.75 (d. J = 8.6 Hz. 2H). 7.18-7.14 (m. 1H). 3.71-3.67 (m. 2H). 3.65-3.62 (m. 2H). 3.40-3.35 (m. 2H). 3.27-3.23 (m. 2H). 3.12 (td. J = 6.8.13.6 Hz. 1H). 1.32 (d. J = 6.8Hz. 6H). Example 10: r2-lsoDroDv1-7-)3-trifluoromethyl-Dvridin-2-v1V6.7.8.9-tetrahvdro-5H- Dvrimldo[4.5-d1azeoln-4-vr|-(3-trifluoromethyl-DhenvlVamlne. MS (ESI): mass calcd. for C24H23F6N5. 495.19; m/zfound. 496.1 [M+H]". 1H NMR (CDCb): 8.41-8.39 (m. 1H). 8.30 (s. 1H). 7.91-7.88 (m. 1H). 7.69-7.66 (m. 1H). 7.47-7.43 (m. 1H). 7.32-7.31 (m. 1H). 6.99-6.95 (m. 1H). 6.63 (s. 1H). 3.70- 3.66 (m. 2H). 3.64-3.61 (m. 2H). 3.26-3.22 (m. 2H). 3.10-3.02 (m. 1H). 3.01-2.97 (m. 2H). 1.33 (d. J = 6.9 Hz. 6H). Example 11: f2-lsopropy1-7-23-trifluorom9thyt-PVridin-2-vt)-6.7.8.9-t9trahvdro-5H- pyrimido[4.5-d1azep)n-4-vfi-(4-trif1uorcHTi8thoxv-phenyl)-arnine. MS (ESI): mass calcd. for C24H23F8N5O. 511.18; m/z found. 512.1 [M+H]". 1H NMR (CDCb): 8.40-8.37 (m. 1H). 7.89-7.86 (m. 1H). 7.73-7.67 (m. 2H). 7.20 (d. J = 8.3 Hz. 2H). 6.97-6.93 (m. 1H). 6.53 (s. 1H). 3.67-3.64 (m. 2H). 3.63-3.58 (m. 2H). 3.25-3.19 (m. 2H). 3.09-2.93 (m. 3H). 1.31 (d. J = 6.8 Hz. 6H). Example 12: f2-r4-Fluoro-phenv MS (ESI): mass calcd. for CasHa)FtNs. 473.22; m/z found. 474.2 [M+H]"\ 1H NMR (CDCI3): 8.38-8.35 (m. 1H). 7.87-7.84 (m. 1H). 7.19-7.14 (m. 2H). 7.03-8.96 (m. 2H). 6.95-6.90 (m. 1H). 4.65-4.59 (m. 1H). 3.77-3.70 (m. 2H). 3.60-3.54 (m. 4H). 3.16-3.11 (m. 2H). 3.02-2.88 (m. 3H). 2.69-2.64 (m. 2H). 1.30 (d. J = 7.1 Hz. 6H). Example 13: f2-(2-Chloro-ohenyl)-ethylM2-lsoproDvt-7-(3-trff1uoromethyl-pyridin-2- vl)-2.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-vll-amine. MS (ESI): mass calcd. for C25H27CIF3N6. 489.19; m/z found. 490.1 [M+H]". 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.89-7.86 (m. 4H). 3.17-3.07 (m. 4H). 3.02-2.93 (m. 1H). 2.72-2.67 (m. 2H). 1.31 (d. J = 6.9 Hz. 6H). Example 14: (3.4-Dk;hloro-b9nzvtM2-isopropy1-7-(3-trifliic)rornethyl-pyrtdlr)-2-vi)- 6.7.8.9-tetrahvdro-5H-pyrlmkjo[4.5-dlazepin-4-vfl-amtne. MS (ESI): mass calcd. for C24H24CI2F3N5. 509.14; m/z found. 510.1 [M+H]1H NMR (CDCI3): 8.39-6.36 (m. 1H). 7.89-7.86 (m. 1H). 7.50 (d. J = 2.2 Hz. 1H). 7.40 (d. J " 8.2 Hz. 1H). 7.22-7.19 (m. 1H). 6.96-6.93 (m. 1H). 4.99-4.94 (m. 1H). 4.68 (d. J = 6.0 Hz. 2H). 3.64-3.57 (m. 4H). 3.18-3.14 (m. 2H). 2.99-2.91 (m. 1H). 2.82-2.79 (m. 2H). 1.26 (d. J = 6.9 Hz. 6H). Example 15: (4-tert-Butyl-Dhenv 6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-yl]-amin9. MS (ESI): mass calcd. for C25H28F3N5.455.23; m/z found. 456.9 [M+H]\ 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.89-7.86 (m. 1H). 7.53-7.50 (m. 2H). 7.39-7.35 (m. 2H). 6.97-6.93 (m. 1H). 6.50 (s. 1H). 3.66-3.59 (m. 4H). 3.22-3.18 (m. 2H). 2.96-2.93 (m. 2H). 2.55 (s. 3H). 1.34 (s. 9H). Example 16: r2-Methyt-7-(3-trifluoromethyt-PVridin-2-vlV6.7.8.9-tetrahvdro-5H- pyrimido-(4.5-dlazepin-4-vl)-(4-trifluorometr)yl-phenv)Vamlne. MS (ESI): mass calcd. for C22H19F6N5. 467.15; m/z found. 468.1 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.87 (m. 1H). 7.74 (d. J = 8.5 Hz. 2H). 7.60 (d. J = 8.8 Hz. 2H). 7.00-6.95 (m. 1H). 6.66 (s. 1H). 3.67-3.64 (m. 2H). 3.63-3.59 (m. 2H). 3.25-3.20 (m. 2H). 3.02-2.98 (m. 2H). 2.59 (s. 3H). Example 17: (5-Tri(tuoromethyl-ovridin-2-v1)-(7-(3-trifluoromethyl-Dvi1din-2-vlV 6.7.8.9-tetrahvdro-5H-Dvrimldo[4.5Hj]azepin-4-vl|-amine. The title compound was syl]thesized in a manner similar to Example 1 with modifications to Step E as follows: Step E. To a solution o[ 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azeplno (38 mg. 0.12 mmol). 4-trifluorometh2amino- pyridine (28 mg. 0.17 mmol). and NaOtBu (16 mg. 0.16 mmol) in toluene (1.2 ml_) in a microwave vial was added a solution o[ Pd(OAc)2 (0.4 mg. 0.002 mmol) and 2- (dicydohexyiphosphino)biphenyl (DCPB) (1.2 mg. 0.004 mmol) in toluene (1 ml_). The mixture was flushed with N2 The mixture was cooled. filtered through a plug o[ diatomaceous earth. and concentrated. The residue was purified (FCC) to afford the title compound (35 mg. 66%). MS (ESI): mass calcd. for C2oH16F6N6. 454.13; m/z found. 453.2 IM+H]". 1H NMR (CDCI3): 8.65 (s. 1H). 8.61 (d. J = 8.8 Hz. 1H). 8.54-8.51 (m. 1H). 8.41-8.38 (m. 1H). 7.95-7.85 (m. 2H). 7.64 (s. 1H). 7.01-6.95 (m. 1H). 3.67-3.57 (m. 4H). 3.31-3.25 (m. 2H). 3.14-3.07 (m. 2H). The following Examples 18-25 below were prepared using methods analogous to those described in Example 17. substituting the appropriate amkJines in Step A and amines in Step E. Example 18: lsoQuir)olin-1-yl-T7-)3-trifluoromethyl-pyridin-2-vl)-6.7.8.9-tetrahvdro- 5H-pyrimldor4.5-d1azeoln-4-vll-amine. MS (ESI): mass calcd. for C23Hi9F3Ne. 436.16; m/z found. 437.1 [M+H]+. 1H NMR (CDCI3): 8.83 (d. J = 8.0 Hz. 1H). 8.65 (s. 1H). 8.42-8.39 (m. 1H). 7.90-7.86 (m. 1H). 7.69-7 64 (m. 1H). 7.60-7.53 (m. 2H). 7.32-7.29 (m. 1H). 6.97-6.93 (m. 1H). 6.71 (d. J = 6.9 Hz. 1H). 3.64-3.54 (m. 6H). 3.30-3.24 (m. 2H). Example 19: f2-CvcloproDv1-7-(3-trifluoromethyl-pyr1din-2-v pyrimido[4.5-d1azepin-4-v MS (ESI): mass calcd. for C2oFcNs. 494.17; m/z found. 495.1 [M+H]\ 1H NMR (CDCb): 8.54-8.47 (m. 2H). 8.40-8.37 (m. 1H). 7.93-7.84 (m. 2H). 7.54 (3. 1H). 7.00-6.89 (m. 1H). 3.62-3.54 (m. 4H). 3.24-3.19 (m. 2H). 3.04-2.99 (m. 2H). 2.19-2.08 (m. 1H). 1.13-1.08 (m. 2H). 1.05-1.00 (m. 2H). Example 20: f2-lsopropyl-7-(3-trifluoromethyl-Pvrkiin-2-v MS (ESI): mass calcd. for C2HZJFBNB. 496.18; m/z found. 497.1 [M+H]\ 1H NMR (CDCI3): 8.73 (d. J = 9.1 Hz. 1H). 8.50 (s. 1H). 8.40-8.37 (m. 1H). 7.94-7.90 (m. 1H). 7.88-7.85 (m. 1H). 7.60 (s. 1H). 6.98-6.93 (m. 1H). 3.65-3.54 (m. 4H). 3.28-3.20 (m. 2H). 3.14-3.01 (m. 3H). 1.34 (d. J = 6.9 Hz. 6H). Example 20A: f2-l30PfOPV)-7-(3-trffluoronnethyt-pyrkiln-2-v1)-6.7.8.9-tetrahvdro-5H- Pvrimjdo[4.5-d1azeDln-4-yl]-(5-«rifluoromethyt-pyridin-2-vlVannlne hvdrochloride salt Example 21: f2-lsoDroDvt-7-(3-trifluQromethyl-Pvridin-2-vl)-6.7.8.9-tetrahvdro-5H- Pvrimido[4.5-d1azepir)-4-vtl-<:uinohn-3-yl-amine.> MS (ESI): mass calcd. for CM2sFaNs. 478.21; m/z found. 479.1 (M+HJ". 1H NMR (CDCI3): 8.99 (d. J = 2.2 Hz; 1H). 8.86 (d. J = 2.5 Hz. 1H). 8.43-8.40 (m. 1H). 8.07 (d. J = 8.2 Hz. 1H). 7.92-7.88 (m. 1H). 7.83-7.80 (m. 1H). 7.65-7.61 (m. 1H). 7.58-7.54 (m. 1H). 7.00-6.95 (m. 1H). 6.75 (s. 1H). 3.74-3.70 (m. 2H). 3.67-3.63 (m. 2H). 3.29-3.25 (m. 2H). 3.14-3.05 (m. 3H). 1.38 (d. J = 6.9 Hz. 6H). Example 22: f2-Phenvt-7-23-trifluoromethyl-PVridin-2-yl)-6.7.8.9-tetrahvdro-5H- pyrimido[4.5-dlazepin-4-vll-(5-trifluoromethyl-PVridin-2-v1)-amine. MS (ESI): mass calcd. for C2H2Ne. 530.17; m/z found. 531.1 [M+H]". 1H NMR (CDCI3): 8.76 (d. J = 8.8 Hz. 1H). 8.57 (s. 1H). 8.44-8.39 (m. 3H). 8.04-8.00 (m. 1H). 7.91-7.88 (m. 1H). 7.67 (s. 1H). 7.55-7.48 (m. 3H). 7.00-6.96 (m. 1H). 3.72-3.62 (m. 4H). 3.41-3.36 (m. 2H). 3.18-3.11 (m. 2H). Example 23: r2-l3Opropyt-7-(3-trifluoromethyl-Dvridin-2-vl)-6.7.8.9-tetrahvdfx)-5H- PVrimtdo[4.5-d1azepin-4-yl]-(6-trifluoromethylpyr)din-3-v1)-arnlne. MS (ESI): mass calcd. for CajHaFeNa. 496.18; m/z found. 497.1 [M+H]\ 1H NMR (CDC13): 8.86 (d. J = 2.5 Hz. 1H). 8.54-8.51 (m. 1H). 8.42-8.39 (m. 1H). 7.91- 7.90 (m. 1H). 7.69 (d. J =8.5 Hz. 1H). 7.01-6.96 (m. 1H). 6.71 (s. 1H). 3.70-3.67 (m. 2H). 3.64-3.60 (m. 2H). 3.29-3.24 (m. 2H). 3.12-3.02 (m. 3H). 1.33 (d. J = 6.6 Hz. 6H). Example 24: F2-Methyl7-l3-trifluoromethyl-Pvridin-2-vdV6.7.8.9-tetrahvdro-5H- pyrimido[4.5-dlazeoin-4-vi1-(5-trifluorom9thyl-pyridin-2-v MS (ESI): mass calcd. for CjiHieFsNe. 468.15; m/z found. 469.8 {M+H]". 1H NMR (CDCI3): 8.84 (d. J = 2.5 Hz. 1H). 8.47-8.43 (m. 1H). 8.40-8.38 (rti. 1H). 7.90- 7.87 (m. 1H). 7.68 (d. J = 8.8 Hz. 1H). 7.00-6.96 (m. 1H). 6.81 (s. 1H). 3.67-3.63 (m. 2H). 3.62-3.59 (m. 2H). 3.25-3.22 (m. 2H). 3.06-3.03 (m. 2H). 2.58 (s. 3H). Example 25: f2-lsopropy ovrlmidor4.5-d1azepln-4-yl]-)4-phenoxv-phenyl)-amir)0. MS (ESI): mass calcd. for C2SH28F3N5O. 519.22; m/z found. 520.2 [M+HJ". 1H NMR (CDCb): 8.42-8.39 (m. 1H). 7.90-7.87 (m. 1H). 7.67-7.62 (m. 2H). 7.37- 7.32 (m. 2H). 7.12-7.08 (m. 1H). 7.05-7.01 (m. 4H). 6.98-6.94 (m. 1H). 6.48 (s. 1H). 3.70-3.66 (m. 2H). 3.65-3.61 (m. 2H). 3.24-3.21 (m. 2H). 3.07-2.94 (m. 3H). 1.32 (d. J = 6.9 Hz. 6H). Example 26; (4-Trifluoromethy tetrahvdro-5H-pyrimidor4.5-d]azepin-4-vfl-amine. The title compound was syl]thesized a manner simHar to Example 1 with modifications to Step C as follows and using 4-trifiuoromethyIanillne in Step E: Step C. 7-(4-Trifluoromethyi-pyrirnidin-2-v d]azepin-4-ol (60 mg. 0.30 mmol). 2-chtoro-4-tritrifluoropyrimidine (36 pL. 0.30 mmol). and Et3N (0.11 ml_. 0.81 mmol) in DMF (1.2 mL) was heated at 120 °C for 2 h. The mixture was cooled to rt. diluted with water. and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give the title compound (69 mg. 68%). which was used without further purification. Step E. MS (ESI): mass calcd. for C2H2Ne. 454.13; m/z found. 455.1 [M+HJ". "H NMR (CDCI3): 8.56 (s. 1H). 8.53 (d. J = 5.2 Hz. 1H). 7.67 (d. J = 8.2 Hz. 2H). 7.59 (d. J = 8.5 Hz. 2H). 6.80 (d. J = 5.2 Hz. 1H). 6.60 (s. 1H). 4.30-4.26 (m. 2H). 4.13-4.09 (m. 2H). 3.31-3.26 (m. 2H). 2.96-2.90 (m. 2H). Example 27: (7-Pvrimidin-2-v1-6.7.8.9-tetrahvdro-5H-pyrimidor4.S2la7an|n-4-vlW4- trifluoromethyi-phenviVamine. The title compound was prepared analogously to the methodology described In Example 26. substituting 2-chloropyrimidine in Step C. MS (ESI): mass calcd. for C19Hi7F3N6. 386.15; m/z found. 387.1 [M+H]". 1H NMR (CDC13): 8.57 (s. 1H). 8.35 (d. J = 4.8 Hz. 2H). 7.68 (d. J = 8.8 Hz. 2H). 7.59 (d. J = 8.8 Hz. 2H). 6.61 (s. 1H). 6.55-6.52 (m. 1H). 4.28-4.23 (m. 2H). 4.11-4.06 (m. 2H). 3.32-3.25 (m. 2H). 2.95-2.90 (m. 2H). Example 28: r7-Pvrazin-2-yl-6.7.8.9-letrahvdro-5H-Dvrimldor4.5-d1azepin-4-v The title compound was prepared analogously to Example 26. substituting 2-chloropyrazine in Step C. MS (ESI): mass calcd. for CiGH2FaNe. 386.15; m/z found. 387.1 [M+H]". 1H NMR (CDCI3): 8.56 (s. 1H). 8.12-8.10 (m. 1H). 8.08-8.06 (m. 1H). 7.86 (d. J = 2.7 Hz. 1H). 7.67 (d. J = 8.8 Hz. 2H). 7.59 (d. J + 8.8 Hz. 2H). 6.57 (s. 1H). 4.25-4.20 (m. 2H). 3.92-3.88 (m. 2H). 3.38-3.34 (m. 2H). 2.96-2.91 (m. 2H). Example 29: 27-Quinoxalin-2-yl-6.7.8.9-te2rarivdro-5H-Dvrimido[4.5-dlazepin-42vl)- (4-trifluoromethyl-pher|y1)-aminet The title compound was prepared analogously to Example 26. substituting 2-chloroquinoxaline in Step C. MS (ESI): mass calcd. for C23H19F3N8. 436.16; m/z found. 437.1 {M+H]". 1H NMR (CDCI3): 8.58 (d. J = 11.2 Hz. 2H). 7.92-7.89 (m. 1H). 7.73-7.66 (m. 3H). 7.63-7.58 (m. 3H). 7.44-7.39 (m. 1H). 6.61 (s. 1H). 4.42- 4.35 (m. 2H). 4.16-4.07 (m. 2H). 3.46-3.38 (m. 2H). 3.09-3.02 (m. 2H). Example 30; l7-(3-Chloro-Dvridin-2-vl)-6.7.8.9-tetrarivdro-5H-Dvrimidor4.5- dlazepin-4-v11-(4-tnfluoromethyl-Dhenviyamtne. The title compound was prepared analogously to Example 26. substituting ! 2.3-dichloropyridine in Step C. MS (ESI): mass calcd. for C20H17CJF3N5. 419.11; m/z found. 420.1 (M+Hj". 1H NMR (CDCI3): 8.57 (s. 1H). 8.15-8.13 (m. 1H). 7.68 (d. J - 9.3 Hz. 2H). 7.63-7.58 (m. 3H). 6.84-6.79 (m. 1H). 6.65 (s. 1H). 3.77-3.67 (m. 4H). 3.31-3.24 (m. 2H). 3.08-3.01 (m. 2H). Example 31; (4-tert-Butyl-PhenvlK7-(6-chloro-5-methyl-pyrimidin-4-vt)-6.7.8.9- tetrahvdro-5H-Pvrimidor4.5-d1azepin-4-vl]-amlne. The title compound was prepared analogously to Example 26. substituting 4.6-dichloro-5-methylpyrimidine in Step C and 4-tert-butyl-aniline in Step E. MS (ESI-): mass calcd. for C23H27CIN6. 422.20; m/z found. 421.2 [M-HJ". "H NMR (CDCI3): 8.50 (s. 1H). 8.33 (s. 1H). 7.44-7.36 (m. 4H). 6.43 (s. 1H). 3.91-3.84 (m. 2H). 3.81-3.75 (m. 2H). 3.26-3.19 (m. 2H). 3.04-2.98 (m. 2H). 2.31 (s. 3H). 1.32 (s. 9H). Example 32; f4-tert-Butyl-phenv1Vr7-)3-methyl-QUinoxalin-2-vtV6.7.8.9-te The title compound was prepared analogously to Example 26. substituting 2-chloro-3-methylquinoline in Step C and 4-tert-butyl-aniline in Step E. MS (ESI-): mass calcd. for C27H30N6. 438.25; m/z found. 437.2 (M-H]-. 1H NMR (CDC13): 8.51 (s. 1H). 7.90-7.87 (m. 1H). 7.79-7.76 (m. 1H). 7.60-7.55 (m. 1H). 7.53-7.48 (m. 1H). 7.43-7.36 (m. 4H). 6.47 (s. 1H). 3.80-3.76 (m. 2H). 3.74-3.70 (m. 2H). 3.31-3.26 (m. 2H). 3.07-3.02 (m. 2H). 2.75 (s. 3H). 1.32 (s. 9H). Example 33: f4-tert-BuWI-phenviH2-isoproPV tetrahvdro-5H-pyrimido[4.5-d1azepin-4-vfl-amin9. The title compound was prepared analogously to Example 26. substituting 2-ch(oro-3-methylquinoline in Step C and 4-tert-butyl-aniline in Step E. MS (ESI-): mass calcd. for C3oH3eNfl. 480.3; m/z found. 479.3 [M-Hf. 1H NMR (CDCI3): 7.89- 7.86 (m. 1H). 7.78-7.76 (m. 1H). 7.62-7.54 (m. 3H). 7.51-7.47 (m. 1H). 7.37-7.34 (m. 2H). 6.48 (s. 1H). 3.77-3.73 (m. 2H). 3.71-3.67 (m. 2H). 3.29-3.23 (m. 2H). 3.02-2.97 (m. 3H). 2.74 (s. 3H). 1.33-1.32 (m. 12H). 1.31 (s. 3H). Example 34: r2-lsoproDv1-7-(3-methyl-aulnoxalln-2-v1)-6.7.8.9-tetrahvdro-5H- pyrimido-(4.5-d1azepln-4-vlH4-trifluoromethyl-phenv1)-amine. The title compound was prepared analogously to Example 26. substituting 2-chtoro-3-methylquinoline in Step C. MS (ESI): mass calcd. for C2H2)FaNe. 492.22; m/z found. 493.2 [M+H]". 1H NMR (CDCI3): 7.89-7.86 (m. 1H). 7.81-7.75 (m. 3H). 7.61-7.55 (m. 3H). 7.53-7.48 (m. 1H). 6.67 (s. 1H). 3.78-3.75 (m. 2H). 3.72-3.68 (m. 2H). 3.32-3.27 (m. 2H). 3.09-3.02 (m. 3H). 2.75 (s. 3H). 1.32 (d. J = 7.1 Hz. 6H). Example 35: r2-lsopropyl-7-(3-trifluoromethyl-QUinoxalin-2-v1V6.7.8.9-tetrahvdro- 5H-pyrimldo[4.5-d1azepln-4-vlH4-trifluoromethyl-phenyl)-arnine. The title compound was prepared analogously to Example 26. substituting 2-chloro-3-trifluoromethylquinoJine in Step C. MS (ESI): mass calcd. for C27H24F6N6. 546.2; m/z found. 547.2 [M+H]". 1H NMR (CDCI3): 8.06-8.03 (m. 1H). 7.88-7.71 (m. 4H). 7.65-7.57 (m. 3H). 6.66 (s. 1H). 3.87-3.77 (m. 4H). 3.33-3.27 (m. 2H). 3.10-3.00 (m. 3H). 1.32 (d. J = 6.8 Hz. 6H). Example 36: f2-lsoproDVl-7- pyrimidor4.5-d1azeDln-4-vlH4-tf1fluoromethyiH3henvl)-amine. The title compound was prepared analogously to Example 26. substituting 2-chloro-3-(methylsulfony1)pyridine (see. Ponticello. G.S. et al.. J. Org. Chem. 1979. 44(17). 3080-3082) in Step C. MS (ESI): mass calcd. for C2HMFSNSOJS. 505.18; m/z found. 506.1 [M+H]\ 1H NMR (CDCI3): 8.54-8.51 (m. 1H). 8.38-8.34 (m. 1H). 7.80 (d. J = 8.3 Hz. 2H). 7.60 (d. J = 8.6 Hz. 2H). 7.25-7.21 (m. 1H). 6.89 (s. 1H). 3.60-3.55 (m. 2H). 3.54-3.50 (m. 2H). 3.24-3.20 (m. 2H). 3.11-2.99 (m. 6H). 1.32 (d. J = 6.8Hz. 6H). Example 37: (4-tert-Butyl-phenviH7-phthalazin-1-yl-6.7.8.9-tetrahvdro-5H- pyrimido-r4.5-d1azepin-4-v1Vamine. The title compound was syl]thesized In a manner similar to Example 1 with modifications to Step C as follows and using 4-tert-butyl-aniline in Step E: Step C. 7-PhthalazJn-1-vt-6.7.8.9-tetrahvdro-5H-Pvrimido-r4.5-dlazepin-4-ol. A solution o[ 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-ol (50 mg. 0.33 mmol). 1.4-dlchlorophthalazlne (55 mg. 0.28 mmol). and Et3N (0.11 ml_. 0.81 mmol) in DMF (5 mL) was heated at 120 °C for 2 h. The mixture was cooled to rt. diluted with water. and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give 7- 5H-pyrimido{4.5-d]azepin-4-ol (50 mg. 55%). o[ which 23 mg (0.14 mmol) was treated with ammonium formate (116 mg. 1.85 mmol) and PdfOHyC (14 mg. 0.08 mmol) in MeOH)dioxane (1:1; 4 ml_). A(ter 1 h at 100 °C. the mixture was cooled rt. filtered through diatomaceous earth. and concentrated to give the title compound. which was carried on to Step D as in Example 1. MS (ESI-): mass calcd. for C2Hzstyj. 424.24; m/z found. 423.2 [M-H]\ 1H NMR (CDCI3): 9.13 (s. 1H). 8.51 (s. 1H). 8.08-6.04 (m. 1H). 7.91-7.80 (m. 3H). 7.48-7.36 (m. 4H). 6.56 (s. 1H). 4.04-3.97 (m. 2H). 3.96-3.89 (m. 2H). 3.37-3.30 (m. 2H). 3.20-3.08 (m. 2H). 1.32 (s.9H). Example 38: (4-tert-Butyl-phenylH7-(5-methyl-pyrlmldin-4-v 5H-pyrimklor4.5-d1azepin-4-vl|-arnine. The title compound was prepared analogously to Example 37 using 4.6- dlchloro-5-methyl pyrlmkJine in Step C. MS (ESI): mass calcd. for C2H2Ns. 388.24; m/z found. 389.2 [M+H]". 1H NMR (CDCI3): 8.53 (s. 1H). 8.49 (s. 1H). 8.09 (3. 1H). 7.43-7.35 (m. 4H). 6.43 (s. 1H). 3.97-3.94 (m. 2H). 3.88-3.84 (m. 2H). 3.25- 3.21 (m. 2H). 3.03-2.97 (m. 2H). 2.28 (s. 3H). 1.31 (3. 9H). Example 39: f2-Piperidin-1 -yl-7-)3-trifluoromethyl-Dvridin-2-vlV6.7.8.9-tetrahvdro- 5H-pyrimido[4.5-d1a2epin-4-vl1-(4-trifluoromethyl-pr)envlVamine. Step A. 2-Piperidin-1-vi-7-(3-trtfluoromethylH)yl]clin-2-v (32 mL) was added 5-oxo-1- acid ethyl ester (Intermediate B; 1.27 g. 3.85 mmol). followed by piperidine-1- carboximldamide hydrobromide (1.2 g. 5.77 mmol). A(ter heating at reflux for 24 h. the mixture was cooled and concentrated. The residue was dissolved in water and CH2Cfe. The aqueous layer was acidified to pH = 7 with HOAc. The layers were separated and the aqueous layor was extracted with CH2CI2 The combined organic layers were dried (Na2SO4) and concentrated. The residue was triturated with Et2O and filtered. The filtrate was concentrated and the residue was purified (FCC) to give the title compound (776.4 g. 51% - combined filtered and chromatog raphed). Step B. 4-Chk)ro-2-piperidin-1-vt-7-(3-trifluoromethyt-Pvridin-2-vl)-6.7.8.9- tetrahvdro-5H-pyrimido[4.5-dlazepine. To a solution o[ 2-piperidin-1-yl-7-(3- trifluoromethyl-pyridin-2-yl)-€17.8.9-tetrahydro-5hl-pyrimldo[4.5-d]azepln-4-ol(435 mg. 1.11 mmol) in CH3CN (9 mL) was added POCI3 (0.41 mL. 4.43 mmol). A(ter 1.5 h at 80 °C. the mixture was cooled to rt. diluted with EtOAc. and quenched slowly with satd. aq. NaHCC)3. The organic layers were combined. dried (Na2SO4). and concentrated. The crude residue was purified (FCC) to give the title compound (160 mg. 35%). Step C. r2-Pineridin-1-yl-7-(3-trifluoromethyl-pyridir)-2-vt)-6.7.8.9-tetrahvdrp- 5H-pyrimldo[4.5-d1azepln-4-yl1-(4-trifluoromethy chloro-2-piperidin-1-yl-7-(3-trifluoro-methyl-pyridin-2-y1)-6.7.8l9-tetrahydro-5H- pyrimkJo[4.5-d]azepine (50 mg. 0.12 mmol). 4-tri(tuoromethyl aniline (0.02 mL. 0.18 mmol). and NaOtBu (16 mg. 0.17 mmol) in toluene (1.5 mL) in a microwave vial was added a solution o[ Pd(OAc)2 (0.4 mg. 0.002 mmol) and DCPB (1 3mg. 0.004 mmol) in toluene (1 mL). The mixture was flushed with N2) and heated in a microwave at 200 °C for 50 min. The mixture was cooled and filtered through a plug o[ diatomaceous earth. The filtrate was concentrated and the residue was purified (FCC) to afford the titlo compound (48 mg. 89%). MS (ESI): mass calcd. for CsoHMFeNe. 536.21; m/z found. 537.2 [M+Hf. 1H NMR (CDC13): 8.40-8.37 (m. 1H). 7.87 (d. J = 1.8 Hz. 1H). 7.65 (d. J = 8.6 Hz. 2H). 7.55 (d. J = 8.8 Hz. 2H). 6.97-6.91 (m. 1H). 6.49 (s. 1H). 3.77-3.71 (m. 4H). 3.62-3.54 (m. 4H). 3.10-3.06 (m. 2H). 2.89-2.84 (m. 2H). 1.70-1.56 (m. 6H). Example 39A: r2-Piperidin-1-yl-7-(3-trifluoromethyi-Dvrldin-2-v1)-6.7.8.9-tetrahvdro- 5H-ovrimidor4.5-dlazepin-4-vl1-(4-trifluoromethy 1H NMR (CD3OD): 8.47-8.45 (m. 1H). 8.05 (dd. J = 7.8. 1.8 Hz. 1H). 7.74 (q. J = 8.8 Hz. 4H). 7.16 (dd. J = 7.8. 4.8 Hz. 1H). 3.74-3.69 (m. 4H). 3.64-3.59 (m. 2H). 3.57-3.54 (m. 2H). 3.31-3.27 (m. 2H). 3.13-3.02 (m. 2H). 1.80-1.72 (m. 2H). 1.72-1.65 (m.4H). Example 39B: r2-Piperidin-1-vi-7-(3-trifluoromethyt-PVridin-2-v1)-6.7.8.9-tetrahvdro- 5H-PVrimido[4.5-dlazepin-4-v11-(4-trifluoromethyl-phenviyamine sulfate satt. 1H NMR (CD3OD): 8.48-8.45 (m. 1H). 8.05 (dd. J = 7.8. 1.6 Hz. 1H). 7.78- 7.68 (m. 4H). 7.19-7.13 (m. 1H). 3.75-3.69 (m. 4H). 3.65-3.59 (m. 2H). 3.58-3.53 (m. 2H). 3.33-3.28 (m. 2H). 3.13-3.09 (m. 2H). 1.79-1.62 (m. 6H). The following Examples 40-45 were prepared using methodology similar to that described in Example 39. substituting the appropriate carboximfdamides in Step A. Example 40: f2-Morpholln-4-v 5H-Pvrimido[4.5-d1azepin-4-v)l-(4-trifluoromethy)-phenv1V-amine. MS (ESI): mass calcd. for Cah2FeNeO. 538.19; m/z found. 539.2 [M+H]". 1H NMR (CDCJ3): 8.40-8.37 (m. 1H). 7.89-7.85 (m. 1H). 7.63 (d. J = 9.1 Hz. 2H). 7.57 (d. J = 9.1 Hz. 2H). 6.98-6.92 (m. 1H). 6.53 (s. 1H). 3.80-3.71 (m. 8H). 3.63- 3.54 (m. 4H). 3.13-3.06 (m. 2H). 2.92-2.86 (m. 2H). Example 40A: f2-Morpholln-4-vt-7-(3-trifluoromethyl-Dvrkiin-2-v tetfahvdro-5H-pyrimldo[4.5-d]ozep 1H NMR (CD3OD): 8.49-8.46 (m. 1H). 8.05 (dd. J = 1.7. 7.4 Hz. 1H). 7.75 (s. 4H). 7.17 (dd. J = 4.9. 7.4 Hz. 1H). 3.79-3.75 (m. 4H). 3.73-3.71 (m. 4H). 3.65-3.62 (m. 2H). 3.59-3.55 (m. 2H). 3.31-3.29 (m. 2H). 3.15-3.11 (m. 2H). Example 41: f2-Morpholin-4-vt-7-(3-trifluoromethyl-pyridin-2-vl)-6.7.8.9-tetrahvxiro- 5H-pyrimidQf4.S-d1azepln-4-vfl-(5-trifluoromethy MS (ESI): mass calcd. for C24H23F6N7O. 539.19; m/z found. 540.2 [M+H]". 1H NMR (CDCI3): 8.52-8.51 (m. 1H). 8.42-8.40 (m. 1H). 8.38 (d. J = 8.8 Hz. 1H). 7.92-7.87 (m. 2H). 7.49-7.46 (m. 1H). 6.99-6.95 (m. 1H). 3.84-3.77 (m. 8H). 3.60- 3.54 (m. 4H). 3.15-3.10 (m. 2H). 2.97-2.94 (m. 2H). Example 42: (4-tert-Butyl-phQnvlM2-piperidirv1-yl-7- 6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-vri-amine. MS (ESI): mass calcd. for C22Na. 524.29; m/z found. 525.3 [M+H]". 1H NMR (CDCI3): 8.39-8.36 (m. 1H). 7.87-7.84 (m. 1H). 7.50-7.46 (m. 2H). 7.35-7.31 (m. 2H). 6.94-6.89 (m. 1H). 6.31 (s. 1H). 3.76-3.71 (m. 4H). 3.63-3.55 (m. 4H). 3.09-3.03 (m. 2H). 2.86-2.81 (m. 2H). 1.67-1.57 (m. 6H). 1.32 (s. 9H). Example 43; N2.N2-Dlmethyi-N4-(6-trifluoromethy methyl-pyridin-2.vlV-6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-dlazeDine-2.4-diamine. Example 43B: N2.N2-Dimethyl-N4-l6-tiifluoromethyl-pyridtn-3-vl)-7-(3-trifluoro- methyl-ovrldin-2-v1V6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1azepine-2.4-diamlne trifluoroacetic add salt. MS (ESI): mass calcd. for C22H21F6N7. 497.18; m/z found. 498.8 [M+HJ". "H NMR(CDC13): 9.04 (d. J = 1.9 Hz.1H). 8.76 (s. 1H). 8.39 (d. J = 4.4 Hz. 1H). 8.16- 8.13 (m. 1H). 8.03-8.00 (m. 1H). 7.74 (d. J = 8.2 Hz. 1H). 7.12-7.08 (m. 1H). 3.67- 3.62 (m. 4H). 3.38-3.33 (m. 2H). 3.22 (s. 6H). 3.12-3.08 (m. 2H). Example 44: N2.N2-Dlmethyl-N4-(5-trffluoromethyl-pyridin-2-vlV7-l3-tii(tuoro- methy MS (ESI): mass calcd. for C2HaiFoNr. 497.18; m/z found. 498.8 [M+HJ". "H NMR (CDCb): 8.58 (d. J = 9.1 Hz. 1H). 8.51-8.49 (m. 1H). 8.42-8.40 (m. 1H). 7.90- 7.86 (m. 2H). 7.48 (s. 1H). 6.98-6.94 (m. 1H). 3.59-3.54 (m. 4H). 3.21 (s. 6H). 3.14- 3.10 (m. 2H). 2.95-2.92 (m. 2H). Example 45: N4-(3-Chloix)4-trifluoromethyt-ohenvl)-N2.N2-dimetfivt-7-(3-trifluo[io- methy The title compound was syl]thesized like Example 39 with modifications to Step C as follows: Step C. A mixture o[ [4-chloro-7-(3-trmuoromethyl-pyrtdin-2-y1)-6.7.8.9- tetrahydro-5H-pyrfmldo-[4.5-d]8zepln-2-yrj-dimethyl-amine (50 mg. 0.14 mmol). 3- chloro-4-trifluoro-methylanlline (40 mg. 0.20 mmol). and p-toluenesulfonic acid (51 mg. 0.27 mmol) in toluene (2 mL) was heated in a sealed tube at 120 °C for 18 h. The mixture was cooled. diluted with satd. aq. NaHCO3. and extracted with CH2CI2. The organic layer was dried (MgSO") and concentrated. The residue was purified (FCC) to give the title compound (55 mg. 78%). MS (ESI): mass calcd. for C23H21CIF8N0. 530.14; m/z found. 531.8 [M+H]". 1H NMR (CD3OD): 8.43-8.40 (m. 1H). 8.25 (d. J = 1.9 Hz. 1H). 8.08-7.98 (m. 1H). 7.66-7.62 (m. 1H). 7.57 (d. J = 8.8 Hz. 1H). 7.11-7.08 (m. 1H). 3.45-3.39 (m. 4H). 3.33-3.31 (m. 1H). 3.13 (s. 6H). 3.06-3.03 (m. 2H). 2.97-2.93 (m. 2H). Example 46: f4-Bromo-ohenvlU2-{80ProDyl-7-(3-ti1f1uoromethyl-pyridin-?.y|)- 6.7.8.9-tetrahvdro-5H-pyiimiclo[4.5-d1azopln-4-vll-amlne. The title compound was prepared using methods similar to those in Example 1 with modifications to Step E as follows: gtep E. A mixture o[ 4-chloro-2-isopropyl-7-(3-trifluoromothyl-pyridin-2-yi)- 6.7.8.9-tetrahydro-5H-pyrimido{4.5-d]azepine (50 mg. 0.14 mmol). 4-bromoan!llne (35 mg. 0.36 mmol). and p-toluenesulfonic acid (51 mg. 0.27 mmol) in toluene (2 mL) was heated in a sealed tube at 130 °C for 18 h. The mixture was cooled. diluted with satd. aq. NaHCOa. and extracted with EtOAc. The organic layer was dried (N82SO4) and concentrated. The residue was purified (FCC) to give the title compound (57 mg. 77%). MS (ESI): masscalcd. for CaH2BrFaNs. 505.11; m/z found. 506.1 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.87 (m. 1H). 7.61- 7.56 (m. 2H). 7.48-7.43 (m. 2H). 6.99-6.95 (m. 1H). 6.49 (s. 1H). 3.68-3.65 (m. 2H). 3.63-3.60 (m. 2H). 3.25-3.21 (rn. 2H). 3.08-2.99 (m. 1H). 2.98-2.94 (m. 2H). 1.32 (d. J = 6.9 Hz. 6H). Example 47: (4-tert-BuM-phenylH2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2- yl)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-dlazepln-4-vfl-arnine. The title compound was syl]thesized in accordance with Example 39 with modifications to Step C as follows: Step C. To a solution o[ 4-cMoro-2-morpholiiv4-yl-7-(3-trtfluorometliyf- pyridin-2-yl)-6)7.8.9-tetrahydro-5H-pyi1m!do[4.5-d]azepjne (30 mg. 0.08 mmoJ) in n- BuOH (2 mL) was added 4-tert-butylaniline (23 uL. 0.15 mmol). The mixture was heated In the microwave at 180 °C for 90 min. then was cooled to rt. diluted with MeOH. and filtered through quaternary amine resin. carbonate form (500 mg). The filtrate was concentrated and the residue was purified (FCC) to give the title compound (39 mg. 99%). MS (ESI): mass calcd. for C28H33F3N6O. 526.27; m/z found. 527.2 [M+Hf. 1H NMR (CDCI3): 8.40-6.37 (m. 1H). 7.87 (d. J = 1.8 Hz. 1H). 7.48-7.43 (m. 2H). 7.37-7.31 (m. 2H). 6.96-6.89 (m. 1H). 6.35 (s. 1H). 3.80-3.70 (m. 8H). 3.64-3.54 (m. 4H). 3.11-3.04 (m. 2H). 2.88-2.82 (m. 2H). 1.33 (s. 9H). The following Examples 48-51 were prepared analogously to the methods used in Example 47. substituting the appropriate carboximidamides in Step A and amines in Step C. Example 48: N"-(4-tert-Butyl-phenv1)-N2.N2-dimethyl-7-(3-trifluoromethyl-Dvridin-2- vt)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-dlazepine-2.4-diamine. MS (ESI): mass calcd. for C26H31F3N6. 484.26; m/z found. 485.9 [M+H]". Example 48: N"-(4-tert-Butv)-phenyl)-N2.N2-dlrnethyt-7-(3-trifluoromethyl-pyridin-2- v salt.' 1H NMR (CD3OD): 8.47-8.45 (m. 1H). 8.05-8.02 (m. 1H). 7.51-7.47 (m. 2H). 7.46-7.42 (m. 2H). 7.17-7.13 (m. 1H). 3.64-3.60 (m. 2H). 3.57-3.53 (m. 2H). 3.30- 3.27 (m. 2H). 3.18 (s. 6H). 3.11-3.06 (m. 2H). 1.35 (s. 9H). Example 49: N'.N2Dimethyl-N2-l2trifiuoromethyi-phenylW-O-trifluoromethyt- pyridin-2-vl)-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazeplne-2.4-diamine. MS (ESI): mass calcd. for C23H22F6N6. 496.18; m/z found. 497.8 [M+H]\ 1H NMR (CDCb): 8.41-8.39 (m. 1H). 7.89-7.86 (m. 1H). 7.73 (d. J = 8.8 Hz. 2H). 7.57 (d. J = 8.8 Hz. 2H). 6.97-6.93 (m. 1H). 6.55 (s. 1H). 3.62-3.56 (m. 4H). 3.18 (s. 6H). 3.13-3.09 (m. 2H). 2.90-2.87 (m. 2H). Example 508: N4-(4-Chloro-phenyl)-N2.N2-dimethyl-7-(3-trifluoromethy y|)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azeplne-2.4-dlamirtetrif1uoroaceticacid salt. MS (ESI): mass calcd. for C22H22CIF3N6. 462.15; m/z found. 463.8 [M+H)". 1H NMR (CD3OD): 8.47-6.45 (m. 1H). 8.05-8.02 (m. 1H). 7.57-7.53 (m. 2H). 7.42- 7.38 (m. 2H). 7.17-7.13 (m. 1H). 3.63-3.59 (m. 2H). 3.57-3.53 (m. 2H). 3.31-3.27 (m. 2H). 3.18 (s. 6H). 3.10-3.06 (m. 2H). Example 51: N4-(4-Trifluoromethyl-phenylV7- 6.7.8.9-tetrahvdro-5H-pyr1mldor4.5-dla7epine-2.4-diamlne. MS (ESI): mass calcd. for C2iH18F6N6. 468.15; m/z found. 469.1 [M+H]". 1H NMR (CDCb): 8.41-8.39 (m. 1H). 7.90-7.87 (m. 1H). 7.67 (d. J = 8.2 Hz. 2H). 7.58 (d. J = 8.5 Hz. 2H). 6.99-6.95 (m. 1H). 6.55 (s. 1H). 4.73 (s. 2H). 3.63-3.57 (m. 4H). 3.11-3.07 (m. 2H). 2.93-2.89 (m. 2H). Example 52: f2-Methylsu(fanvt-7-[3-ti1fluoromethyl-Dvridir)-2-vlV6.7.8.9-tetrahvdro- 5H-pyrimldo[4.5-d1azepln-4-vf1-24-trifluoroTTiethyl-Dhenvl)-arnlne. Step A. 2-Methylsulfanv)-7-(3-trifluoromethyl-Dvridlr)-2-vl)-6.7.8.9-tetrahvdro- 5H-pyrimido[4.5-d1azepin~4-ol. To solution o[ 5-oxo-1-(3-trifluoromethyl-pyridin-2- yl)-azepane-4-carboxylic add ethyl ester (3.0 g. 9.09 mmol) in EtOH (40 ml_) was added NaOEt (1.97 g. 29.1 mmol) and thiourea (1.1 g. 13.6 mmol). The mixture was heated at reflux for 12 h. The mixture was cooled. treated with Mel (0.74 mL. 11.8 mmol) drop-wise. and stirred at rt for 1 h. The mixture was concentrated and the residue was dissolved in water and acidified to pH « 7 with HOAc (a precipitate formed). The solid was filtered to give the title compound (3.3 g. )99%). which was used in the next step without further purification. Step B. 4-Chloro-2-methylgulfanyl-7-(3-trifluoromethyl-pyridin-2-vl)-6.7.8.9- tetrahvdro-5H-pyrimido[4.5-dlazeplne. To a solution o[ 2-methyJsuffanyl-7-(3- trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrirnJdo[4.5-d]azepin-4-ol (1.8 g. 4.92 mmol) in CH3CN (40 mL) was added POCI3 (1.4 mL. 14.8 mmol). A(ter 15 min at 80 °C. the mixture was cooled to rt. diluted with EtOAc. and quenched slowly with satd. aq. NaHCCb. The organic layer was separated. dried (MgSO4). and concentrated. The crude residue was purified (FCC) to give the title compound (1.6 g. 89%). Step C. To a solution o[ 4-chloro-2-methylsulfany1-7-(3-trifIuoromethyl- pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine (830 mg. 2.22 mmol) in n-BuOH (5 mL) was added 4-trifluoromethylaniline (0.4 mL. 3.30 mmoJ). The mixture was heated in the microwave at 160 °C for 30 min. then was cooled to rt. quenched with satd. aq. NaHCO3. and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound (950 mg. 86%). MS (ESI): mass calcd. for C22H.«F6N5S. 499.13; m/z found. 500.1 [M+H]". 1H NMR (CDCIj): 8.40-8.37 (m. 1H). 7.89-7.86 (m. 1H). 7.69 (d. J = 8.6 Hz. 2H). 7.58 (d. J = 9.1 Hz. 2H). 6.99-8.94 (m. 1H). 6.65 (s. 1H). 3.66-3.62 (m. 2H). 3.60-3.56 (m. 2H). 3.21-3.16 (m. 2H). 2.99-2.94 (m. 2H). 2.53 (s. 3H). Example 53: r2-Methanesulfonyl-7-(3-trifluoromethyt-pyridin-2-vl)-6.7.8.9- tetrahvdfo-5H-pyrimidor4.5-d]azepin-4-vfl-l'4-trifluoromethyl-Dhenvl)-amine. . To a solution o[ [2-methylsulfanyl-7- tetrahydro-5H-pyrimido[4.5-d]azepln-4-yf]-(4-trifluo[omethyl-phenyl)-amine (Example 52; 513 mg. 1.02 mmol) in CH2CI2 (10 mL) was added m-CPBA (77%; 480 mg. 2.22 mmol). A(ter 2 h. the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2CI2- The combined organic layers wero dried (MgSO4) and concentrated. The residue was purified (FCC; MeOH)CH2CI2) to afford the title compound (500 mg. 92%). MS (ESI): mass calcd. for C22HieF0N3O2S. 531.12; m/z found. 532.8 [M+H]". 1H NMR (CD3OD): 8.46-8.44 (m. 1H). 8.04-8.01 (m. 1H). 7.88 (d. J = 8.8 Hz. 2H). 7.66 (d. J = 8.5 Hz. 2H). 7.15-7.11 (m. 1H). 3.60-3.54 (m. 4H). 3.37-3.31 (m. 2H). 3.28-3.23 (m. 5H). Example 54: N2-Phen\22V4-trifluoromethy vl)-6.7.8.9-tetrahvdro-5H-Pvrimldo[4.5-dlazepine-2.4-diarnlne. A solution o[ [2-methanesulfony1-7- tetrahydro-5H-pyrimido[4.6-d]azepin-4-yf]-(4-trifluoromethyl-phenyJ)-amine (Example 53; 30 mg. 0.06 mmol). aniline (8 mg. 0.09 mmol). and p-toluenesulfonic acid (21.3 mg. 0.11 mmol) in toluene (2 mL) was heated at 125 °C for 12 h. The mixture was cooled and directly purified using Preparative HPLC to give the title compound (20 mg. 67%). MS (ESI): mass calcd. for C27H22F8N6. 544.18; m/z found. 545.9 [M+H]\ 1H NMR (CD3OD): 8.46-8.44 (m. 1H). 8.00-7.97 (m. 1H). 7.66-7.58 (m. 4H). 7.48 (S. 1H). 7.45-7.42 (m. 2H). 7.24-7.19 (m. 2H). 7.16-7.11 (m. 2H). 3.63-3.59 (m. 2H). 3.57-3.53 (m. 2H). 3.29-3.25 (m. 2H). 3.11-3.07 (m. 2H). Example 55: N2-Cvclopropyt-N"-(4-trifluoromethy|-ohenvt)-7-(3-trif1uorDmethyl- pyridin-2-vl)-6.7.8.9-tetrahydro-5H-Pvrimidor4.5-d]azepine-2.4- The title compound was prepared using methods analogous to those described in Example 54. with n-butanol or t-amyi alcohol as the solvent. in a sealed tube at 130 °C. and without the addition o[ p-toluenesuffonic acid. Example 55B: 2-Cvdooropyt-r2-2-trifluoromethyH-Phenvi2-(S-trifluorornethyt- pyridin-2-vdV6.7.8.9-tetrahvdro-5H-pyrimldo[4.5-d1azeDlne-2.4-diamine trifluoroacetlc acid salt. MS (ESI): mass calcd. for Ca2zjFsN". 508.18; m/z found. 509.8 [M+H]". 1H NMR (CD3OD): 8.49-8.44 (m. 1H). 8.04 (d. J = 7.7 Hz. 1H). 7.92 (s. 2H). 7.69 (d. J = 8.8 Hz. 2H). 7.18-7.13 (m. 1H). 3.68-3.61 (m. 2H). 3.59-3.54 (m. 2H). 3.31-3.24 (m. 2H). 3.15-3.11 (m. 2H). 2.76-2.66 (m. 1H). 0.94-0.86 (m. 2H). 0.69-0.64 (m. 2H). The compounds in Examples 56-61 were prepared using methods analogous to those described in Example 55. Example 56: T2-Azetldin-1 -vt-7-(3-trtfluoromethyt-pyridin-2-vl)-6.7.8.9-tetrahvdro- 5H-pyrimldor4.5-d]azepln-4-yl]-(4-trifluoromethyl-phenv1)-amine. Example 56B: [2-Azetidin-1 -v 5H-pyrimido[4.5-dlazepin-4-vf]-(4-trifluoromethyi-phenyl)-amine trifluoroacetic add salt. MS (ESI): mass calcd. for C2HaFeNe. 508.18; m/z found. 509.8 [M+H]". 1H NMR (CD3OD): 8.47-8.45 (m. 1H). 8.05-8.02 (m. 1H). 7.85 (d. J = 8.5 Hz. 2H). 7.69 (d. J = 8.8 Hz. 2H). 7.17-7.13 (m. 1H). 4.32-4.22 (m. 4H). 3.64-3.60 (m. 2H). 3.57- 3.53 (m. 2H). 3.26-3.22 (m. 2H). 3.13-3.09 (m. 2H). 2.53-2.45 (m. 2H). Example 57: 1 -(4-(4-Trifluorornethyl-phenvtarrilno)-7-(3-t!ifluc)romethyl-Pvridin-2-v1)- 6J.8.9-tetrahvdro-5H-pyrimldor4.5-d1azepin-2-vfl-plpei1dine-4-carboxvflcacld. Example 57B: 1 -(4-(4-Trifluoromethyt-phenylamino)-7-{3-trtfluoromethyt-Dvridin-2- y1)2.7.8.9-tetrahvdro-5H-pyrimido[4.5 MS (ESI): mass calcd. for C27H2eF6N8O2. 580.2; m/z found. 581.9 [M+H]". 1H NMR (CD3OD): 8.49-8.44 (m. 1H). 8.07-8.02 (m. 1H). 7.74-7.72 (m. 4H). 7.18- 7.13 (m. 1H). 4.30-4.22 (m. 2H). 3.65-3.61 (m. 2H). 3.58-3.54 (m. 2H). 3.34-3.25 (m. 4H). 3.14-3.09 (m. 2H). 2.74-2.66 (m. 1H). 2.08-2.01 (m. 2H). 1.80-1.68 (m. 2H). Example 58: N2-(2-Piperidin-1 -yl-ethylV-N4-(4-trifluoromethyl-phenv1)-7-(3-trifluoro- methyl-Pvridin-2-vl)-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-d1azenine-2.4-dlamine. Example 56B: N2-(2-Piperidin-i-v«-ethyl)-N4-(4-trifluore)methyl-phenyl)-7-(3- trifluoro-methyl-pyridin-2-vl)-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1a2epine-2.4- diamine trifluoroacetic acid salt. MS (ESI): mass calcd. for CaeHa-iFeNz. 579.25; m/z found. 581.0 [M+Hf. 1H NMR (CD3OD): 8.47-8.44 (m. 1H). 8.05-8.01 (m. 1H). 7.79-7.70 (m. 4H). 7.18-7.12 (m. 1H). 3.76-3.71 (m. 2H). 3.64-3.59 (m. 2H). 3.57-3.52 (m. 2H). 3.44-3.36 (m. 2H). 3.24-3.17 (m. 4H). 3.13-3.07 (m. 2H). 2.81-2.70 (m. 2H). 1.82-1.32 (m. 6H). Example 59: 1 -[4-(4-Trifluoromethyl-Dhenvtamlno)-7-(3-trifluoromethyl-ovridin-2-v1)- 6.7.8.9-tetrahvdro-5H-Dvrimiclo[4.5-cl)azepin-2-v)l-piperidin-4-ol. Example 59B: 1 -(4-(4-Trifluoromethyl-Dhenvlamino)-7-(3-trifluoromethyl-Dvridin-2- vl)-6.7.8.9-tetrahydro-5H-pyl]mkio[4.5- MS (ESI): mass calcd. for C-2H2FeNeO. 552.21; m/z found. 553.9 [M+HJ". nH NMR (CD3OD): 8.47-8.43 (m. 1H). 8.05-8.00 (m. 1H). 7.75-7.68 (m. 4H). 7.17- 7.11 (m. 1H). 4.07-3.98 (m. 2H). 3.97-3.88 (m. 1H). 3.64-3.57 (m. 2H). 3.56-3.42 (m. 4H). 3.32-3.25 (m. 2H). 3.13-3.06 (m. 2H). 1.98-1.87 (m. 2H). 1.64-1.49 (m. 2H). Example 60: f2-(4-lsopropy1-pi'perazin-1 -vl)-7-(3-trjfluoromethyl-pyridin-2-vl)- 6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-vl1-(4-trifluoromethyt-phenv))-amlne. Example 60B: f2-(4-lsopropyl-piperazin-1-vO-7-(3-trrfluoromethyl-DvridJr)-2-vt)- 6T.8.94etrehvdrcv5H-Dvrimido[4.5-d1azepin-4-vlW4-trifluoromethy«-DhenvtVamine tri(tuoroacetlc add salt. MS (ESI): mass calcd. for Ca2FeN). 579.25; m/z found. 581.0 [M+HJ". 1H NMR (CD3OD): 8.47-8.44 (m. 1H). 8.05-8.01 (m. 1H). 7.73-7.71 (m. 4H). 7.18-7.12 (m. 1H). 3.66-3.24 (m. 15H). 3.18-3.07 (m. 2H). 1.38 (d. J = 6.3 Hz. 6H). Example 61: N2-rretrahvdfo-pyran-4-vl)-N4-(4-trif1uoromethyl-phenv1V7-23-tr1fluoro- methy Example 61B: N2-n'etrahvdrD-Pvran-4-v trifluQfo-methy diamine trtfluoroacetic acid salt. MS (ESI): mass calcd. for C28H2«F6N«O. 552.21; m/z found. 553.9 [M+H]1H NMR (CD3OD): 8.48-8.45 (m. 1H). 8.06-8.03 (m. 1H). 7.77 (d. J = 8.5 Hz. 2H). 7.72 (d. J = 8.8 Hz. 2H). 7.18-7.14 (m. 1H). 3.98-3.84 (m. 3H). 3.64-3.60 (rh. 2H). 3.58-3.54 (m. 2H). 3.43-3.35 (m. 2H). 3.21-3.17 (m. 2H). 3.12-3.09 (m. 2H). 1.92- 1.84 (m. 2H). 1.65-1.54 (m. 2H). Example 62: f2-Methoxv-7-(3-trifluoromethyl-pyridin-2-vl)-6.7.8.9-tetrahvdro-5H- pyrim1do[4.5-dtezepln-4-vlH4-trifluoromethyl-Dhenv1)-amine. A solution o[ [2-methanesulfonyl-7- tetrahydix)-5H-pyrimido[4.5-cl]azepin-4-y(]-(4-trifIuoromethyl-phenyl famine (Example 53; 44 mg. 0.08 mmol) and NaOMe (100 mg. 0.25 mmol) in MeOH (1.5 mL) was heated at 60 °C for 1 h. The mixture was cooled. acidified with HOAc (3 drops). and directly purified using Preparative HPLC (conditions as in Example 54) to give the title compound (35 mg. 89%). MS (ESI): mass calcd. for CaHieFoNsO. 483.15; m/z found. 484.8 [M+H]". 1H NMR (CDCI3): 9.63 (s. 1H). 8.39 (d. J = 3.3 Hz. 1H). 7.89 (d. J " 7.7 Hz. 1H). 7.73 (d. J = 8.5 Hz. 2H). 7.63 (d. J = 8.5 Hz. 2H). 7.06-7.02 (m. 1H). 3.88 (s. 3H). 3.50-3.44 (m. 4H). 3.26-3.22 (m. 2H). 3.11-3.07 (m. 2H). The following Examples 63-109 were prepared using methods analogous to those described in the preceding examples. Exarnple 63: N4-23.4-Dichloro-phenyl)-N2.N2-dimethy4-7- yl)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepine-2.4-diamlne. MS (ESI): mass calcd. for Cjs-HaiCbFaNe. 496.12; m/z found. 497.8 [M+H]Example 63B: N4-(3.4-Dichloro-phenyl]-N2.N2-dimethyl-7-(3-trifluorDmethyl-pyridin- 2-v1)-6.7.8.9-tetrahvdro-5H-pyrimldo[4.5-dlazeplne-2.4-diamlnetrifluoroaceticacld salt. 1H NMR (CD3OD): 8.46 (dd. J = 4.7. 1.4 Hz. 1H). 8.03 (dd. J + 7.8. 1.8 tiz. 1H). 7.93-7.92 (m. 1H). 7.53-7.52 (m. 2H). 7.17-7.12 (m. 1H). 3.64-3.58 (m. 2H). 3.56-3.52 (m. 2H). 3.32-3.29 (m. 2H). 3.22 (s. 6H). 3.11-3.06 (m. 2H). Example 64: N4-(4-Methoxv-3-trifluoromethyl-PhenvlVN2.N2-dimethyi-7-23- trifluQfomethyl-pyridin-2-v1)-6.7.8.9-tetrahvdro-5H-Pvrimldor4.5-d1azepine-2.4- diamlne. MS (ESI): mass calcd. for C24H24FeN6O. 526.19; m/z found. 527.9 [M+H]". 1H NMR (CD3OD): 8.42 (dd. J = 4.7. 1.6 Hz. 1H). 8.13 (d. J = 2.7 Hz. 1H). 7.90 (dd. J = 7.8. 1.8 Hz. 1H). 7.56 (dd. J = 8.9. 2.7 Hz. 1H). 7.04-6.93 (m. 2H). 6.35 (s. 1H). 3.94 (s. 3H). 3.66-3.57 (m. 4H). 3.16 (s. 6H). 3.14-3.09 (m. 2H). 2.90-2.85 (m. 2H). Example 65: 2-l4-r2-Dimethylamino-7-(3-trifluoronnethyt-pyridin-2-v1V€.7.8.9- tetrahvdro-5H-Pvrimldo[4.5-d1azeDlr)-4-ylaminoI-Dhenvl)-2-methyl+Dropionttrfle. MS (ESI): mass calcd. for C26H28F3N7. 495.24; m/z found. 496.9 [M+H]Example 65B: 2-|4-(2-Dimethylamino-7-(3-trifluoromethyt-Pvridin-2-v1V6.7.8.9- tetrahvdro-5H-Pvrimldo[4.5-dlaz&pin-4-vlamir)o1-phenyl)-2-methy trifluoroacetic acid salt. 1H NMR (CD3OD): 8.45 (dd. J = 4.7. 1.4 Hz. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.66-7.60 (m. 2H). 7.58-7.53 (m. 2H). 7.17-7.11 (m. 1H). 3.64-3.58 (m. 2H). 3.56-3.51 (m. 2H). 3.30-3.25 (m. 2H). 3.18 (s. 3H). 3.11-3.06 (m. 2H). 1.73 (s. 6H). Example 66: (4-tert-Butv1-phenv1)-[2-piperidin-1-vlmethyl-7-(3-trifluorometfivf- pyrtdin-2-v1)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-dlazepin-4-yl]-amlne. MS (ESI): mass calcd. for C30H37F3N6. 538.30; m/z found. 540.0 [M+H]". Example 66B: (4-tert-Butv1-Dhenv)Vr2-PiP8ridin-1-vlmethyt-7-23-trtfluoromethy Pvrklin-2-v1)-6.7.8.9-tetrahvdro-5H-Pvrinnldor4.5-d1a2epin-4-vf|-amlneUtfluoroacetic acid salt. 1H NMR (CD3OD): 8.46 (dd. J = 4.7. 1.4 Hz. 1H). 8.04 (dd. J = 7.8. 1.7 Hz. 1H). 7.53-7.49 (m. 2H). 7.39-7.35 (m. 2H). 7.17-7.13 (m. 1H). 4.41 (s. 2H). 3.65- 3.60 (m. 4H). 3.33-3.31 (m. 2H). 3.23-3.18 (m. 2H). 1.80-1.69 (m. 4H). 1.68-1.58 (m. 2H). 1.36 (s. 9H). 1.29-1.21 (m. 2H). Example 67; (4-tert-Butvt-phenv vl)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-yl]-amine. MS (ESI): mass calcd. for C28H30F3N5O. 485.24; m/z found. 468.9 [M+HJExample 67B: (4-tert-Butyl-pheny1)-r2-methoxvmethyl-7-)3-trifluoromethyt-pyl]din- 2-vt)2.7.8.9-tetrahvdro-6H-pyrimido[4.5-d1azepin-4-vl1-amlne trifluoroacetk; acid salt. 1H NMR (CD3OD): 8.66 (d. J = 8.9 Hz. 1H). 8.52 (s. 1H). 8.40 (dd. J «4.7. 1.5 Hz. 1H). 7.93 (dd. J = 8.9. 2.3 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.63 (s. 1H). 7.00-6.95 (m. 1H). 3.65-3.56 (m. 4H). 3.28-3.21 (m. 2H). 3.09-3.03 (m. 2H). 2.63 (s. 3H). Example 68: N4-r2.3-Dihvdro-benzon.41dloxin-6-v1VN2.N2Hdimethy 2rifluoromethyl-pyridii)2-v1)-6.7.8.9-tetrahvdro-5H-ovrimidor4.5-d1azepine-2.4- diamlne. MS (ESI): mass calcd. for C24H25F3N6O2.486.20; m/z found. 487.8 [M+H]". Example 68B: N4-)2.3-Dihvdro-benzon.41dioxin-6-vtVN2.N2-dlmethyl-7-(3- trifluoromethyl-pyridin-2-vl)-6.7.8.9-tetrahvdro-5H-PViim)do[4.5-d1azeplne-2.4- diamine trifiuoroacetic acid salt. 1H NMR (CD3OD): 8.46-8.44 (m. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.16- 7.12 (m. 1H). 7.11 (d.J = 2.4Hz. 1H). 6.98 (dd. J = 8.7. 2.5 Hz. 1H). 6.84 (d. J = 8.7 Hz. 1H). 4.25 (s. 4H). 3.62-3.58 (m. 2H). 3.55-3.51 (m. 2H). 3.29-3.24 (m. 2H). 3.17 (s. 6H). 3.07-3.02 (m. 2H). Example 69: r2-Methyl-7-(3-trifluoromethyl-pyridin-2-vl)-6.7.8.9-tetrahvdro-5H- pyrlmldor4.5-dlazepin-4-v1R5-trif]uoromethyl-pyridin-2-vl famine. MS (ESI): mass calcd. for C2IHI8FBN6. 468.15; m/z found. 469.8 (M+HJ". "H NMR (CDCI3): 8.66 (d. J = 8.9 Hz. 1H). 8.52 (s. 1H). 8.40 (dd. J = 4.7. 1.5 Hz. 1H). 7.93 (dd. J = 8.9. 2.3 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.63 (s. 1H). 7.00-6.95 (m. 1H). 3.65-3.56 (m. 4H). 3.28-3.21 (m. 2H). 3.09-3.03 (m. 2H). 2.63 (s. 3H). Example 70: N2-Benzyl-N'.N'-dlmetfivi2-O-trifluoromethyl-ovridin2-vlVe2.S.g- tetrahvdro-5H-pyrimido[4.5-d1azepine-2.4-diafnir MS (ESI): mass calcd. for C23H25F3N6. 442.21; m/z found. 443.8 [M+H]". Example 70B: N4-Benzvt-N2.N2-dimethyl-7-(3-trifluoromethyl-Dvridin-2-v tetrahydro-5H-pyrinnldo[4.5- 7.25-7.20 (m. 1H). 7.10-7.06 (m. 1H). 4.70 (s. 2H). 3.60-3.56 (m. 2H). 3.54-3.50 (m. 2H). 3.26-3.20 (m. 2H). 3.15 (s. 6H). 2.97-2.93 (m. 2H). Example 71: 4-(2-Dlmettiviamino-7-(3-trifluoromethyl-pyridin-2-v tetrahvdro-5H-Pvrlmldo[4.5-dla7epin-4-vlaminol-benzenesulfonamide. MS (ESI): mass calcd. for C22H24F3N7O2S. 507.17; m/z found. 508.8 [M+H]". Example 71B: 4-(2-Dlmethytamino-7-)3-trif1uoromethyt-Dvridin-2TV tetrahydrch5H-pyrimido[4.5-d]azepin-4-vlanriinol-penzenesulfonarntdeti1flu9roacetic ackj salt. 1H NMR (CD3OD): 8.47-8.45 (m. 1H). 8.04 (dd. J = 7.8. 1.7 Hz. 1H). 7.94- 7.91 (m. 2H). 7.81-7.77 (m. 2H). 7.19-7.11 (m. 1H). 3.66-3.58 (m. 2H). 3.58-3.52 (m. 1H). 3.34-3.29 (m. 2H). 3.21 (s. 6H). 3.13-3.10 (m. 2H). Example 72: N2.N2-Dlmethyl-N4-l4-n)tro-Dhenv 6.7.8.9-tetrahvdro-5H-Dvrlmidor4.5-d1azepine-2.4-diamine. MS (ESI): mass calcd. for C22H22F3N7O2. 473.18; m/z found. 474.8 [M+H]". Example 72B; N2.N2-Dimethyl-N4-24-nltro-Dhenv 6.7.8.9-tetrahvdro-5H-pyrimkio[4.5-d1azeplno-2.4-d(amlne trifluoroacetlc acid salt. 1H NMR (CD3OD): 8.48-8.45 (m. 1H). 8.31-8.26 (m. 2H). 8.04 (dd. J - 7.8. 1.8 Hz. 1H). 7.92-7.87 (m. 2H). 7.19-7.12 (m. 1H). 3.66-3.59 (m. 2H). 3.58-3.54 (m. 2H). 3.37-3.33 (m. 2H). 3.24 (s. 3H). 3.16-3.12 (m. 2H). Example 73: N4-(3.4-Dichloro-beazvl)-N2.N2-climethyl-7-(3-trifluoromethyt-Dvridin-2- vl)-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-cnazeDine-2.4-diamlne. MS (ESI): mass calcd. for C23H23CI2F3N6. 510.13; m/z found. 511.1 [M+H]Example 73B: N4-23.4-Dlchloro-benzv1)-N2.N2-2lmethyt-7-(3-trifluoromethy 2-v1V6.7.8.9-tetrahvdro-5H-pyrimidor4.5-cl1azeplne-2.4-dlamlne trifluoroacetlc acid salt 1H NMR (CD3OD): 8.40 (dd. J = 4.7. 1.3 Hz. 1H). 7.99 (dd. J = 7.8. 1.8 Hz. 1H). 7.48-7.46 (m. 1H). 7.44 (s. 1H). 7.24 (dd. J = 8.3. 2.0 Hz. 1H). 7.12-7.06 (m. 1H). 4.65 (s. 2H). 3.61-3.55 (m. 2H). 3.54-3.49 (m. 2H). 3.25-3.18 (m. 2H). 3.14 (s. 6H). 2.97-2.91 (m. 2H). Example 74: f2-Methy MS (ESI): mass calcd. for C2iHieF6N6S. 500.12; m/z found. 501.8 [M+HJ". Example 74B; f2-Methylsulfanyl-7-(3-trmuoromethyl-pyridin-2-vl)-6.7.8.9- tetrahvdro-5H-Dvrimido[4.5- 1H NMR (CD3OD): 8.84-8.81 (m. 1H). 8.35 (dd. J " 8.0. 1.5 Hz. 1H). 8.19 (s. 1H). 7.75-7.65 (m. 2H). 6.71 (d. J = 9.0 Hz. 1H). 4.32-4.24 (m. 2H). 3.90-3.84 (m. 2H). 3.30-3.23 (m. 2H). 2.98 (t. J = 6.3 Hz. 2H). 2.32 (s. 3H). Example 75: T2-Methylsulfanv1-7-(3-trifluorometrivf-Dvridin-2-y 5H-pyrimido[4.5-dlazepin-4-v)H6-trtfluoromethy MS (ESI): mass calcd. for C2HioFeNoS. 500.12; m/z found. 501.8 [M+HJ". Example 75B: f2-Methylsutfanyt-7-(3-trifluoromethyl-Pyl]'din-2-v tetrahvdro-5H-pyrlmido[4.5-d]azepln-4-vf)-(6-trifluoromethyl-pyridin-3-vlVamine trtfluoroacetlc acid salt. 1H NMR (CD3OD): 9.00 (d. J = 2.4 Hz. 1H). 8.46-8.43 (m. 1H). 8.36 (dd. J = 8.6. 2.4 Hz. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.78 (d. J = 8.6 Hz. 1H). 7.16-7.10 (m. 1H). 3.56-3.48 (m. 4H). 3.20-3.10 (m. 4H). 2.50 (s. 3H). Example 76: r2-Methoxvmethyl.7-23-trtfluoromethyt-pyridin-2-vl)-6.7.8.9-tetrahvdro- 5H-pyrim)do[4.5-dlazepln-4-vfl-24-trlfluoromethyl-phenyl)-emin9. MS (ESI): mass calcd. for C23H21F6N5O. 497.17; m/z found. 489.3 [M+H]Example 76B: f2+Methoxymethyl-7- tetrahvdro-5H-DVrimldo[4.5-d1azepin-4-vfl-(4-trifluQromethyt-Dhenvl)-am)ne trifluoroacetic acid salt. 1H NMR (CD3OD): 8.46-8.44 (m. 1H). 8.03 (dd. J = 7.9. 1.7 Hz. 1H). 7.79- 7.68 (m. 4H). 7.18-7.11 (m. 1H). 4.57 (s. 2H). 3.68-3.59 (m. 4H). 3.52 (s. 3H). 3.46- 3.42 (m. 2H). 3.28-3.23 (m. 2H). Example 77: 4-(2-Dlmethylamlno-7-(3-trtf)uoromethyl-pyridin-2-vl)-6.7.8.9- tetrahvdro-5H-pyrimido[4.5-dlazeDln-4-vlamlno1-benzoic add methyt ester. MS (ESI): mass calcd. for 024"2322. 486.20; m/z found. 487.8 [M+H]Example 77B: 4-(2-Dlmethylamlno-7- tetrahvdro-5H-Pvrim)do[4.5-dlazepln-4-vtamino1-benzoic acid methyl ester frtf|uoroacotlc acid salt. : 1H NMR (CD3OD): 8.47 (dd. J = 4.7. 1.5 Hz. 1H). 8.08-8.04 (m. 2H). 8.04 (d. J = 1.8 Hz. 1H). 7.75-7.72 (m. 2H). 7.18-7.13 (m. 1H). 3.92 (s. 3H). 3.64-3.60 (m. 2H). 3.58-3.53 (m. 2H). 3.32-3.29 (m. 2H). 3.22 (s. 6H). 3.15-3.09 (m. 2H). Example 78: 4-(2-Dimethylamino-7-23-trifluoromethyl-Pvridin-2-vl)-6.7.8.9- tetrahvdro-5H-Dvrimidor4.5-dlazepin-4-v MS (ESI): mass calcd. for C23H22F3N7. 453.19; m/z found. 454.8 [M+HJ". Example 78B: 4-(2-Dimettivlamlno-7-(3-1rifluoromethyl-Dvridin-2-vt)-6.7.8.9- tetrahydro-5H-Dvrimldo[4.5-d1azeDfn-4-vlamino1-benzonttrHe trifluoroacetfc ackl salt. 1H NMR (CD3OD): 8.46 (dd. J = 4.7. 1.4 Hz. 1H). 8.04 (dd. J = 7.8.1.8 Hz. 1H). 7.85-7.81 (m. 2H). 7.79-7.76 (m. 2H). 7.18-7.13 (m. 1H). 3.65-3.59 (m. 2H). 3.57-3.52 (m. 2H). 3.34-3.32 (m. 2H). 3.23 (s. 6H). 3.15-3.09 (m. 2H). Example 79: N4-(4-Dimethylamino-pheov pyridin-2-v1)-6.7.8.9-letrahvdro-5H-Pvrimklo[4.5-d1azeDine-2.4-dlamine. MS (ESI): mass calcd. for C24H28F3N7. 471.24; m/z found. 472.2 [M+H]". Example 79B: N4-(4-Dlmethy)amino-phenyl)-N2.N2-dimethyt-7-(3-trTfluoromethyt- pyridin-2-vlV6.7.8.9-tetrahvdro-5H-Pvr : 1H NMR (CD3OD): 8.46-8.43 (m. 1H). 8.02 (dd. J = 7.8. 1.7 Hz. 1H). 7.82- 7.76 (m. 2H). 7.62-7.58 (m. 2H). 7.17-7.10 (m. 1H). 3.64-3.57 (m. 2H). 3.56-3.51 (m. 2H). 3.31-3.28 (m. 2H). 3.27 (s. 6H). 3.19 (s. 6H). 3.12-3.06 (m. 2H). Example 80: (3-Chloro-4-trtfluoromethyl-Dhenvl)-r2-methoxvmethyl-7-(3- trifluoromethyl-pyridin-2-vt)-6.7.8.9-tetrahvdix)-5H-PVrimldor4.5-d1azepin-4-yl]- amine. MS (ESI): mass calcd. for C23H20C!FoN90. 531.13; m/z found. 532.3 (M+H)"Example 80B: f3-Chloro-4-trifluoromethy trifluoromethy trrfluoroacetic acid salt. 1H NMR (CD3OD): 8.44 (dd. J = 4.8. 1.4 Hz. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.44-7.38 (m. 2H). 7.16-7.10 (m. 1H). 6.96-6.91 (m. 2H). 3.80 (s. 3H). 3.62- 3.57 (m. 2H). 3.56-3.50 (m. 2H). 3.29-3.23 (m. 2H). 3.14 (s. 3H). 3.08-3.02 (m. 2H). Example 81: N4-(4-Methoxv-phenyl)-N2.N2-dlmethyi-7-(3-trifluor9methyl-pyridin-2- v0-6.7.8.9-tetrahvdro-5H-pyrimkJor4.5-d]azepine-2.4-diamlne. MS (ESI): mass calcd. for C2HzsFaNcO. 458.20; m/z found. 459.8 [M+HJ". Example 81B: N4-(4-Methoxv-phenv ylV6.7.8.9-tetrahvdro-5H-pyrimkk)r4.5-dlazepine-2.4-diamlne trtfluoroacetlc ackl salt. 1H NMR (CD30D): 8.44 (dd. J +4.8. 1.4 Hz. 1H). 8.02 (dd. J « 7.8. 1.8 Hz. 1H). 7:44-7.38 (m. 2H). 7.16-7.10 (m. 1H). 6.96-6.91 (m. 2H). 3.80 (3. 3H). 3.62- 3.57 (m. 2H). 3.56-3.50 (m. 2H). 3.29-3.23 (m. 2H). 3.14 (s. 3H). 3.08-3.02 (m. 2H). Example 82: N4-lndan-2-v1-N2.N2-dimethy tetrahvdfo-5H-pyrimhioF4.5-dlazepine-2.4-di?fnine. MS (ESI): mass calcd. for C25H27F3Ne. 468.22; m/z found. 469.0 [M+H]Example 82B: N 6.7.8.9-tetrahvdrc)5H-pyrimido[4.5-cr]azepine-2.4-dlamine trifluoroacetic acid salt. 1H NMR (CD3OD): 8.44-8.41 (m. 1H). 8.02 (dd. J = 7.8. 1.7 Hz. 1H). 7.25- 7.20 (m. 2H). 7.18-7.15 (m. 2H). 7.15-7.11 (m. 1H). 5.04-4.95 (m. 1H). 3.60-3.54 (m. 2H). 3.47-3.43 (m. 2H). 3.42-3.35 (m. 2H). 3.24 (s. 6H). 3.23-3.20 (m. 2H). 3.10-3.02 (m. 2H). 2.95-2.90 (m. 2H). Example 83: r7-C5-Amlno-3-methy pyrimido[4.5-dlazepin-4-vt1-(4-trifluoromethyt-phenyl)-amine. MS (ESI): mass caJcd. for C24H27F3N6. 456.22; m/z found. 455.2 [M-HT. 1H NMR (CDCI3): 7.79 (d. J « 8.6 Hz. 2H). 7.67 (d. J = 2.9 Hz. 1H). 7.58 (d. J = 8.7 Hz. 2H). 6.90-6.85 (m. 1H). 6.69-6.65 (m. 1H). 3.46-3.37 (m. 2H). 3.34-3.29 (m. 2H). 3.26-3.22 (m. 2H). 3.21-3.17 (m. 2H). 3.10-3.03 (m. 1H). 2.96-2.90 (m. 2H). 2.27 (s. 3H). 1.34 (d. J = 6.9 Hz. 6H). Example 84: r7-(2-Amlno-oh8nv d1azepin-4-vll-(4-trifluoromethyl-phenv1Vamin9. MS (ESI): mass calcd. for C2«H26F3N5. 441.21; m/z found. 442.2 [M+H]". 1H NMR (CDCb): 7.44-7.33 (m. 2H). 7.17-7.09 (m. 2H). 6.89-6.81 (m. 2H). 6.67-6.59 (m. 2H). 4.10-3.97 (m. 2H). 3.60-3.47 (m. 2H). 3.13-3.03 (m. 2H). 3.02-2.92 (m. 1H). 2.90-2.85 (m. 2H). 1.28-1.26 (m. 6H). Example 85: f2-lsopropyt-7-(2-nHro-Phenvl)-6.7.8.9-tetrahvdro-5H-pyrimldor4.5- d1azepin-4-y MS (ESI): mass calcd. for Ca-2FaNsOa. 471.19; m/z found. 472.1 [M+HJ". 1H NMR (CDCI3): 7.99 (dd. J = 8.2. 1.5 Hz. 1H). 7.66-7.56 (m. 1H). 7.42-7.35 (m. 2H). 7.34-7.28 (m. 2H). 6.67-6.51 (m. 2H). 4.22-4.02 (m. 2H). 3.62-3.47 (m. 2H). 3.15-3.04 (m. 2H). 2.96-2.83 (m. 3H). 1.21 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C2H2Ne. 442.21; m/z found. 443.1 [M+H]". 1H NMR (CDCI3): 7.86-7.72 (m. 3H). 7.64-7.57 (m. 2H). 7.04-6.95 (m. 1H). 6.90-6.85 (m. 1H). 6.71-6.67 (m. 1H). 3.89-3.77 (m. 2H). 3.47-3.40 (m. 2H). 3.39-3.35 (m. 2H). 3.26-3.21 (m. 2H). 3.13-3.04 (m. 1H). 3.01-2.94 (m. 2H). 1.36 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C24H25F3N6O2. 486.20; m/z found. 487.1 [M+H]". 1H NMR (CDCI3): 8.93 (d. J = 2.6 Hz. 1H). 8.16-8.05 (m. 1H). 7.81 (d. J = 8.5 Hz. 2H). 7.62 (d. J = 8.4 Hz. 2H). 7.35-7.28 (m. 1H). 6.76-6.60 (m. 1H). 4.04-3.90 (m. 2H). 3.89-3.82 (m. 2H). 3.35-3.22 (m. 2H). 3.12-3.02 (m. 3H). 2.41 (s. 3H). 1.33 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C23H23F3N6O2. 472.18; m/z found. 473.1 [M"H]". 1H NMR (CDCI3): 8.41-8.28 (m. 1H). 8.15-8.12 (m. 1H). 7.36-7.21 (m. 4H). 6.84- 6.69 (m. 1H). 3.81-3.67 (m. 4H). 3.47-3.37 (m. 2H). 3.36-3.30 (m. 2H). 3.22-3.07 (m. 1H). 1.32 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C2sH28F3NsO2S. 519.19; m/z found. 520.1 [M+H]+. 1H NMR (CDCI3): 9.03-8.84 (m. 1H). 7.63-7.54 (m. 1H). 7.43-7.37 (m. 2H). 7.32- 7.28 (m. 2H). 6.69-6.57 (m. 2H). 4.18-4.01 (m. 2H). 3.65-3.52 (m. 2H). 3.13-2.97 (m. 3H). 2.93-2.84 (m. 4H). 1.31 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C23H23F6N7O. 551.19; m/z found. 552.9 [M+H]". Example 90B: 4-r4-(4-Trifluoromethyt-Dheny acid salt. 1H NMR (CDCI3): 8.41 (dd. J=4.8. 1.4HZ.1H). 7.91 (dd. J = 7.8. 1.8 Hz. 1H). 7.70 (d. J = 8.7 Hz. 2H). 7.61 (d. J = 8.6 Hz. 2H). 7.34-7.31 (m. 1H). 7.05-7.01 (m. 1H). 6.53-6.45 (m. 1H). 4.39-4.31 (m. 2H). 4.14-4.09 (m. 2H). 3.65-3.57 (m. 4H). 3.57-3.52 (m. 2H). 3.40-3.31 (m. 2H). 3.02-2.90 (m. 2H). Example 91: (Rl-1-(4-)4-Trif1uorDmettiyl-phenv1amin9V7-(2-trtfluoromethyt-ovridin- 2-v MS (ESI): mass calcd. for CajHrcFeNeO. 552.21; m/zfound. 553.9 [M+H]". Example 91B: (R)-1-(4-(4-Trifluoromethyl-phenv trifluoroacetic acid salt. 1H NMR (CDCI3): 8.42-8.38 (m. 1H). 7.89 (dd. J «= 7.8. 1.6 Hz. 1H). 7.67- 7.59 (m. 5H). 7.02 (dd. J = 7.7. 4.8 Hz. 1H). 4.33-4.23 (m. 1H). 4.20-4.11 (m. 1H). 4.08-4.00 (m. 1H). 3.63-3.49 (m. 5H). 3.39-3.33 (m. 2H). 3.31-3.22 (m. 1H). 2.99- 2.90 (m.2H). 2.03-1.90 (m. 1H). 1.89-1.73 (m. 2H). 1.58-1.49 (m. 1H). Example 92: F2-(4-Methyi-piperazin-1 -y1)-7-(3-trifluoromethyl-pyodin-2-vl)-6.7.8.9- tetrahvdro-5H-pyrimidor4.5-dlazepin-4-vlH4-trifluoromethyl-phenv MS (ESI): mass calcd. for CjeH2FsN). 551.22; m/z found. 552.9 [M+H]". Example 92B: f2-(4-Methyl-piperazin-1-v tetrahvdro-5H-pyrfmidor4.5-d1azepln-4-vfl-(4-trffluonomethy trifluoroacetic acki salt. =•H NMR (CDCI3): 8.38 (dd. J « 4.6. 1.4 Hz. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.64 (d. J + 8.6 Hz. 2H). 7.56 (d. J = 8.7 Hz. 2H). 6.97-6.91 (m. 1H). 6.52 (s. 1H). 3.83-3.75 (m. 4H). 3.62-3.53 (m. 4H). 3.13-3.04 (m. 2H). 2.90-2.84 (m. 2H). 2.52-2.42 (m. 4H). 2.34 (s. 3H). Example 93: N2-(2-Methoxv-ethyl)-N2-methyl-N4-24-trifluoromethyt-phenylV7-)3- trifluoromethyl-ovridin-2-vlV6.7.8.9-tetrahvdro-5H-Dvrirriido[4.5- MS (ESI): mass calcd. for Czs2sFeNeO. 540.21; m/z found. 541.3 [M+H]". Example 93B: N2-(2-Methoxv-ethyl)-N2-methyl-N4-(4-trifluoromethyl-Dhenvl)-7-)3- trifluoromethyl-pyridin-2-y dlamine trifluoroacetic acid salt. 1H NMR (CD3OD): 8.45 (dd. J = 4.8. 1.3 Hz. 1H). 8.03 (dd. J = 7.8. 1.8 Hz. 1H). 7.76 (d. J = 8.6 Hz. 2H). 7.70 (d. J = 8.7 Hz. 2H). 7.17-7.11 (m. 1H). 3.78-3.76 (m. 2H). 3.64-3.59 (m. 2H). 3.59-3.52 (m. 4H). 3.21 (s. 3H). 3.13-3.08 (m. 2H). Example 94: (SV1 -r4-(4-Trifluo[omethyt-phenylamlnoV7-(3-tf1fluoromethyt-Pvr(din- 2-vl)-6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1azepin-2-vtl-p|peridin-3-ol. MS (ESI): mass calcd. for CajHajFeNaO. 552.21; m/z found. 553.3 [M+H]". Example 94B: fS)-1-(4-(4-Trifluoromethyl-phenylafnlno)-7-23-trtfluorom9thyt- PVridin-2-yl]2T.8.9-tetrahvdr trifluoroacetic acid salt. 1H NMR (CD3OD): 8.45 (dd. J = 4.7. 1.4 Hz. 1H). 803 (dd. J = 7.8. 1.8 Hz. 1H). 7.77-7.68 (m. 4H). 7.14 (dd. J = 7.6. 4.8 Hz. 1H). 3.8B-3.76 (m. 2H). 3.70-3.51 (m. 7H). 3.30-3.25 (m. 2H). 3.13-3.07 (m. 2H). 2.00-1.86 MS (ESI): mass calcd. for Czsh2FsNe. 522.20; m/z found. 523.3 (M+H]Example 95B: N2-CvcloproDvlmethyl-N"-(4-trifluoromethy diamine trifluopoacytk; add salt. 1H NMR (CD3OD): 8.45 (dd. J = 4.7. 1.4 Hz. 1H). 8.04-8.01 (m. 1H). 7.81- 7.67 (m. 4H). 7.16-7.11 (m. 1H). 3.65-3.51 (m. 4H). 3.26-3.13 (m. 4H). 3.11-3.06 (m. 2H). 1.10-1.00 (m. 1H). 0.52-0.45 (m. 2H). 0.22-0.15 (m. 2H). MS (ESI): mass calcd. for C25H26F3N5O. 469.21; mJz found. 470.2 [M+H]1H NMR (CDCI3): 8.40-8.37 (m. 1H). 8.00-7.95 (m. 2H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.81-7.77 (m. 2H). 6.98-6.94 (m. 1H). 6.73 (s. 1H). 3.68-3.57 (m. 4H). 3.25- 3.21 (m. 2H). 3.10-3.03 (m. 1H). 3.02-2.96 (m. 2H). 2.59 (s. 3H). 1.34 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C24H23F3NB. 452.19; m/z found. 453.1 [M+H]". 1H NMR (CDCI3): 8.41-6.38 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.85-7.81 (m. 2H). 7.662-7.61 (m. 2H). 7.00-6.95 (m. 1H). 6.72 (s. 1H). 3.69-3.57 (m. 4H). 3.28-3.23 (m. 2H). 3.13-3.04 (m. 1H). 3.03-2.98 (m. 2H). 1.34 (d. J = 6.9 Hz. 6H). 1 MS (ESI): mass calcd. for C2oCbFaNsS. 513.08; m/z found. 514.0 [M+H]". 1H NMR (CDCI3): 8.38-8.34 (m. 1H). 7.88-7.84 (m. 1H). 7.43-7.38 (m. 2H). 7.18- 7.14 (m. 1H). 6.96-6.91 (m. 1H). 6.05-4.97 (m. 1H). 4.66 (d. J = 5.7 Hz. 2H). 3.63- 3.50 (m. 4H). 3.14-3.08 (m. 2H). 2.80-2.76 (m. 2H). 2.44 (s. 3H) Example 99: f2-Piperazin-1-vt-7-(3-trifluoromethyl-DVfklln-2-v1V€.7.8.9-tetrahvdro- 5H-Pvrimido[4.5-cflazepir)-4-vfl-(4-trifluoromethyl-phenyl)-amine. MS (ESI): mass calcd. for CabHzsFeNr. 537.21; m/z found. 538.2 [M+HJ". Example 99B: [2-Plperazln-1 -v1-7-(3-trffluoromethyl-pyridin-2-yl]-6.7.8.9-tetrahvdro- 5H-ovrimidor4.5-dlazepln-4-vl)-(4-trifluoromethyl-phenv1)-amlne trifluoroacetlc acid salt 1H NMR (CD3OD): 8.47-8.44 (m. 1H). 8.03 (dd. J « 7.8.1.8 Hz. 1H). 7.74- 7.67 (m. 4H). 7.17-7.13 (m. 1H). 4.02-3.93 (m. 4H). 3.59-3.50 (m. 4H). 3.35-3.21 (m. 6H). 3.13-3.07 (m. 2H). Example 100: f2-Thtomorpholin-4-yl-7-{3-trinuoromethy4-Pvridin-2-vlV6.7.8.9- tetrahvdrQ-5H-Dvrimldo[4.5-cnazepln-4-yl]-(4-trifluoromethyt-prienv1)-amin9. MS (ESI): mass calcd. for Cas2FeNeS. 554.17; m/z found. 555.2 [M+H]". 1H NMR (CDCb): 8.44-8.41 (m. 1H). 7.91 (dd. J = 7.8. 1.8 Hz. 1H). 7.67-7.57 (m. 4H). 7.02-6.96 (m. 1H). 6.56 (3. 1H). 4.20-4.08 (m. 4H). 3.68-3.57 (m. 4H). 3.16- 3.08 (m. 2H). 2.95-2.89 (m. 2H). 2.71-2.66 (m. 4H). Example 101: 2-IsoproDVl-T2a-tfifluoromethyl-Dvridin-Z-vlV2.).a.Q-tetrahvclro'SH- pyrimtdo[4.5-dlazepin-4-v MS (ESI): mass calcd. for C24H23F6N5O2S. 559.15; m/z found. 560.1 [M+H]Example 101B: r2-lsoproDyl-7-[3-tfffluoromettiv 5H-pyrimido[4.5-dlazepln-4-yf]-(4-tnfluoromeVianesulfpnyl-phenyl)-amine triflugroacetic acid salt. 1H NMR (CD3OD): 8.44-8.42 (m. 1H). 8.02-7.94 (m. 3H). 7.88-7.84 (m. 2H). 7.14-7.09 (m. 1H). 3.83-3.76 (m. 1H). 3.69-3.60 (m. 6H). 3.29-3.22 (m. 2H). 1.32- 1.27 (m.6H). Example 102: f2-(4-Benzyl-oiperazin-1 -vl)-7-(3-trifluoromethyl-Pvridin-2-vl)-6.7.8.9- tetrahydro-5H-Pvrimldor4.5-d1azepin-4-vlM4-trifluoromethyl-phenv1)-amine. MS (ESI): mass calcd. for C32H31F6N7. 627.25; m/z found. 628.2 [M+H]". nH NMR (CDCI3): 8.41-8.38 (m. 1H). 7.88 (dd. J = 7.8. 1.9 Hz. 1H). 7.66-7.61 (m. 2H). 7.57-7;53 (m. 2H). 7.39-7.28 (m. 5H). 6.98-6.93 (m. 1H). 6.51 (s. 1H). 3.82-3.76 (m. 4H). 3.63-3.55 (m. 6H). 3.12-3.07 (m. 2H). 2.91-2.86 (m. 2H). 2.54-2.49 (m. 4H). Example 103: 4-(2-lsoDroDvt-7-(3-trifluoromethyl.Dvridin-2-v1V€.7.8.9-tetrahvdro- 5H-Dvrimldo[4.5-d1azeDln-4-vtamlno1-benzo)c ackl methyl ester. MS (ESI): mass caJcd. for C25H2oF3N502. 485.20; m/z found. 486.2 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 8.07-8.02 (m. 2H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.80-7.75 (m. 2H). 6.99-6.95 (m. 1H). 6.71 (s. 1H). 3.92 (s. 3H). 3.68-3.59 (m. 4H). 3.27-3.22 (m. 2H). 3.11-3.03 (m. 1H). 3.02-2.98 (m. 2H). 1.35 (d. J = 6.9 Hz. 6H). Example 104: f2-l30Dropyt-7- pyrjmido[4.5-d1azepin-4-yl]-)4-trif1uorom9thyl3ulfanv1-phenvi)-amine. MS (ESI): mass calcd. for C2HaFeNsS. 527.16; m/z found. 528.1 [M+Hf. 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.81-7.77 (m. 2H). 7.65-7.61 (m. 2H). 6.99-6.95 (m. 1H). 6.65 (s. 1H). 3.70-3.58 (m. 4H). 3.27- 3.22 (m. 2H). 3.12-3.03 (m. 1H). 3.02-2.97 (m. 2H). 1.34 (d. J - 6.9 Hz. 6H). Example 105: r2-lsopropyl-7-)3-ti1fluoromethyt-Dyridin-2-v1)-6.7.8.9-tetrahvdro-5H- pyrimido[4.5-dlazepin-4-vf|-pyrimldirt-4-yl-amine. MS (ESI): mass cated. for C2iH22F3N7. 429.19; m/z found. 430.1 [M+HJ". 1H NMR (CDQa): 8.83-8.81 (m. 1H). 8.60 (d. J " 5.9 Hz. 1H). 8.58-8.55 (m. 1H). 8.42- 8.40 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.51 (s. 1H). 7.01-8.97 (m. 1H). 3.65- 3.56 (m. 4H). 3.29-3.25 (m. 2H). 3.17-3.10 (m. 1H). 3.08-3.04 (m. 2H). 1.38 (d. J = 6.9 Hz. 6H). Example 106; r2-PvTTOlidirv1-v27-(3-trifluoromethyl-DVTidin-2-y1V-6.7.8.9-t9trahvdro- 5H-pyrimido[4.5-d1azepin-4-vf1-(4-trifluorom9thyl-phenv = MS (ESI): mass calcd. for Czs22Ne. 522.20: m/z found. 523.1 [M+H]". 1H NMR (CDCI3): 8.41-8.38 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.82-7.77 (m. 2H). 7.59-7.54 (m. 2H). 6.97-6.92 (m. 1H). 6.55 (s. 1H). 3.64-3.53 (m. 8H). 3.13-3.08 (m. 2H). 2.91 -2.87 (m. 2H). 2.02-1.94 (m. 4H). Example 107: f2-lsopropyl-7-23-triflLioromethyl-pyridin-2-v1V6.7.8.9-t9lrahvdro-5H- Pvrimido[4.5-d1azepin-4-vri-Pvrimidin-2-v1-aiTiine. MS (ESI): mass calcd. for C21H22F3N7.429.19; m/z found. 430.1 [M+H]\ 1H NMR (CDCI3): 8.45 (d. J = 4.8 Hz. 2H). 8.43-8.41 (m. 1H). 7.88 (dd. J = 7.8.1.8 Hz. 1H). 7.36 (s. 1H). 7.00-6.95 (m. 1H). 6.85-6.83 (m. 1H). 3.65-3.58 (m. 2H). 3.55- 3.50 (m. 2H). 3.35-3.30 (m. 2H). 3.14-3.06 (m. 1H). 2.93-2.88 (m. 2H). 1.33 (d. J = 6.9 Hz. 6H). MS (ESI): mass calcd. for C2SH26CI2F3N5. 523.15; m/z found. 524.1 [M+H]". 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.38 (d. J = 8.2 Hz. 1H). 7.32 (d. J = 2.0 Hz. 1H). 7.06 (dd. J =8.1. 2.0 Hz. 1H). 6.96-6.92 (m. 1H). 4.68-4.63 (m. 1H). 3.80-3.70 (m. 2H). 3.61-3.57 (m. 4H). 3.18-3.13 (m. 2H). 3.03- 2.95 (m. 1H). 2.95-2.89 (m. 2H). 2.72-2.68 (m. 2H). 1.32 (d. J = 6.8 Hz. 6H). Example 1 Q9; (3.4-Dichloro-phenvtM2-isopropy1-7-(3-trifluoromethyl-pyridin-2-vt)- 6.7.8.9-tetrahvdro-5H-pyrlmldo[4.5-d1azepln-4-yl]-amine. MS (ESI): mass calcd. for CaHzjCfeFsNs. 495.12; m/z found. 496.1 [M+H]": 1H NMR (CDCI3): 8.41-8.38 (m. 1H). 8.10 (d. J = 2.4 Hz. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.43-7.37 (m. 2H). 6.99-6.95 (m. 1H). 6.50 (s. 1H). 3.69-3.57 (m. 4H). 3.26-3.21 (m. 2H). 3.10-3.01 (m. 1H). 2.98-2.94 (m. 2H). 1.34 (d. J = 6.9 Hz. 6H). The following compounds in Examples 110-114 are prepared according to the procedures described above. Example 110: N-)2-(2-lsoDroDyl-4-(4-trif1uoromethyl-DhenvtaminoV5.6.8.9- tetrahvdro-ovrimidor4.5-d1azepin-7-v Example 111: N-22-(2-lsopropyt-4-(4-trifluoromethyl-DhenvlamlnoV5.6.8.9- tetrahvdro-pyrimidor4.5-d1azepin-7-yl]-phenviymethanesulfonarnide. Example 112: 2-(4-(2-Azetidin-1-yl-7-(3-trifluoromethy tetrahvdro-5H-pyrimldor4.5-d1a2epin-4-vlamlrtol-phenvt}-propan-2-ol. Example 113: 2-(4-(2-Azepan-1-y tetrahydro-5H-Pvr1mldo[4.5-dlazepfn-4-ylaminoI-phenv1)-propan-2-ol. Example 114; N2-(2-Dlmethylamino-ethytVN2-methyt-N4-)4-ti1fluoromethyt-phenvt)- 7-(3-trifluoromethyi-Pvridin-2-vlV-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-dlazeplne-2.4- diamine. The title compound was prepared using known procedures (See: US Pat 4.160;834). The title compound was prepared from 2.6-dichloro-3-trifluoromethyl-pyrkline using methods analogous to Intermediate C (See: Hirokawa et al. Chem. Pharm. Bull. 2001. 49(12). 1621; Katritzky. A. R. et al. J. Org. Chem. 1997. 62. 6412). Intermediate E: 6-Methoxv-5-trifluorornethyl-Dvridin-2-vtamine. The title compound was prepared as described by Hirokawa et a). Chem. Pharm. Bull. 2001. 49(12). 1621 and WO 2006)081388. Intermediate F: 1-Methyt-1.2.3.4-tetrahvdro-ouinolirv7-v1amine. The title compound was prepared using methods analogous to those described by Hamann. L.G. et al. J. Med. Chem. 1998. 41. 623 and Higuchi. R.I. et al. Bloorg. Med.Chem. Lett. 1999. 9.1335. Intermediate G: 1.4.4-Trimethyi-1.2.3.4-tetrahvdro-ouinolin-7-v1amine. The title compound was prepared using methods analogous to Intermediate F. Intermediate H: 2-(4-Amino-phenv1)-2-methyi-proptonic acid methyl ester. Step A: 2-Methyl-2-(4-nttrophenv1Vpropionic acid methyl ester. To a solution o[ 2-methyt-2-(4-nltrophenyl)-propionic acid (1.0014 g. 4.76 mmoi) in 10% McOH)benzene (20 ml_) was added dropwise (trimethy!silyt)-diazomethane (2.0 M in hexanes. 3.5 ml_. 7.0 mmol). The reaction mixture was stirred at rt until evolution o[ N2 ceased ( purified (FCC) to give the title compound (937.6 mg. 88%). Step B. To a solution o[ 2-methyl-2-(4-nitrophenyl)-propionic acid methyl ester (932.2 mg. 4.16 mmol) and ammonium formate (1.58 g. 25.1 mmol) in MeOH was added Pd)C (10%. 441.2 mg. 0.414 mmol). The reaction mixture was stirred at rt until gas evolution ceased. then filtered through a plug o[ diatomaceous earth and concentrated. The residue was red is solved in H2O and extracted with EtOAc. The organic layers were combined. dried. and concentrated to provide the title compound which was used without further purification. The following Examples 115-126 were prepared using methods analogous to those described in Example 1. substituting the appropriate amidines in Step A and amines in Step E. Example 115: N4f4-Chloro-3-(trifluoromethyhDhenvr|metfiv1)-2-M-methylethy MS (ESI): mass calcd. for C25H24CIF6N5. 543.16; m/z found. 544.1 (M+H)". 1H NMR (CDCI3): 8.37-8.35 (m. 1H). 7.87-7.84 (m. 1H). 7.73-7.71 (m. 1H). 7.49- 7.43 (m. 2H). 6.95-6.91 (m. 1H). 5.05-4.99 (m. 1H). 4.72 (d. J = 5.8 Hz. 2H). 3.63- 3.55 (m. 4H). 3.18-3.12 (m. 2H). 2.98-2.89 (m. 1H). 2.82-2.77 (m. 2H). 1.22 (d. J = 6.9 Hz. 6H). Example 116: 2-21-MethylethylV7-[3-(trifluoromethyl2DVridin-2-vll-N-lf6- (trifluoromethy amine. MS (ESI): mass calcd. for C24H24F6N6. 510.20; m/z found. 511.1 [M+H]". "H NMR (CDCI3): 8.75-8.73 (m. 1H). 8.38-8.35 (m. 1H). 7.89-7.84 (m. 2H). 7.62 (d. J = 8.1 Hz. 1H). 6.95-6.92 (m. 1H). 5.11-5.07 (m. 1H). 4.81 (d. J = 5.8 Hz. 2H). 3.62- 3.55 (m. 4H). 3.18-3.13 (m. 2H). 2.97-2.87 (m. 1H). 2.84-2.79 (m. 2H). 1.20 (d. J = 6.9 Hz. 6H). Example 117: 2-n-MethylethylVN-(f4-)trifluoromethyl]phenyl]nnethytW7-(a- rtrifluoromethyl)pyridin-2-vl1-6.7.8.9-tetrahydrc)-5H-Dvrim)do[4.5-d1a2eoin-4-amlne. MS (ESI). mass calcd. for CaHwFeNs. 509.20; mlz found. 510.1 [M+H]". 1H NMR (CDCI3): 8.37-8.35 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.58 (d. J - 8.1 Hz. 2H). 7.47 (d. J = 8.1 Hz. 2H). 6.95-6.91 (m. 1H). 5.00-4.95 (m. 1H). 4.79 (d. J = 5.7 Hz. 2H). 3.63-3.56 (m. 4H). 3.17-3.13 (m. 2H). 2.98-2.88 (m. 1H). 2.82-2.77 (m. 2H). 1.23 (d. J = 6.9Hz. 6H). Example 118: N-(2-r2-Fluorophenv rtrffluoromethyl)Pyl]din-2-vll-6.7.6.9-tetrahvdro-5H-pyrimido[4.5-d1a2epln-4-amlne. MS (ESI): mass calcd. for C2H2N.. 473.22; m/z found. 474.1 [M+H]". 1H NMR (CDCI3): 8.38-8.36 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.24-7.17 (m. 2H). 7.10-7.02 (m. 2H). 6.95-6.91 (m. 1H). 4.73-4.69 (m. 1H). 3.78-3.74 (m. 2H). 3.59- 3.56 (m. 4H). 3.14-3.12 (m. 2H). 3.01-2.93 (m. 3H). 2.69-2.67 (m. 2H). 1.30 (d. J = 6.9 Hz. 6H). Example 119: N-r2-(2-Bromophenv+ethyfl-2-21-methylethylV7-[3- (trtfluoromethyl)pyridin-2-vtl-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-cllazepln-4-amlne. MS (ESI): mass calcd. for C25H27BrF3N3. 534.14; m/z found. 536.1 [M+HJ". 1H NMR (CDCI3): 8.38-8.36 (m. 1H). 7.85 (dd. J = 7.8. 1.8 Hz. 1H). 7.57-7.54 (m. 1H). 7.25-7.20 (m. 2H). 7.11-7.07 (m. 1H). 6.94-6.90 (m. 1H). 4.70-4.67 (m. 1H). 3.82-3.77 (m. 2H). 3.60-3.54 (m. 4H). 3.16-3.08 (m. 4H). 3.02-2.93 (m. 1H). 2.71- 2.68 (m. 2H). 1.31 (d. J = 6.9 Hz. 6H). Example 120: N-((2.6-Dlchtoropheny1)methyf1-2-n-methylethyl)-7-(3- (trifluoromethyl)Pvrkiln-2-2-6.7.8.9-tetrah\2fo-5H-Dvr1midor4.5-d1azepln-4-amine. MS (ESI): mass calcd. for C24H24CI2F3N6. 509.14; m/z found. 510.1 [M+H]1H NMR (CDCI3): 8.36-8.34 (m. 1H). 7.84 (dd. J = 7.8. 1.8 Hz. 1H). 7.33 (d. J = 8.0 Hz. 2H). 7.20-7.16 (m. 1H). 6.93-6.90 (m. 1H). 5.05 (d. J = 5.5 Hz. 2H). 4.95-4.92 (m. 1H). 3.61-3.54 (m. 4H). 3.16-3.10 (m. 2H). 3.01-2.94 (m. 1H). 2.75-2.72 (m. 2H). 1.31 (d. J = 6.9 Hz. 6H). Example 121: N-K2-Chtorophenv+methy (trifluoromethyl2pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-PVrimldo[4.5-d1azQPin-4-amine trifluoroacetlc acid salt. MS (ESI): mass calcd. for C24H2SCIF3N5.475.18; m/z found. 477.1 [M+H]"H NMR (CD3OD): 8.40-8.38 (m. 1H). 8.02-7.98 (m. 1H). 7.42-7.39 (m. 1H). 7.29- 7.20 (m. 3H). 7.10-7.06 (m. 1H). 3.67-3.64 (m. 2H). 3.61-3.57 (m. 2H). 3.31-3.28 (m. 4H). 3.09-3.06 (m. 2H). 3.01-2.92 (m. 1H). 1.20 (d. J = 6.8 Hz. 6H). Example 122: N-r4-)1.1-Dimethy MS (ESI): mass calcd. for C27H38F3N5. 489.31; m/z found. 490.2 [M+HJ". 1H NMR (CDCI3): 8.38-8.36 (m. 1H). 7.85 (dd. J = 7.8. 1.8 Hz. 1H). 6.94-6.90 (m. 1H). 4.34-4.31 (m. 1H). 3.96-3.86 (m. 1H). 3.64-3.64 (m. 4H). 3.14-3.09 (m. 2H). 2.96- 2.89 (m. 1H). 2.74-2.69 (m. 2H). 2.25-2.18 (m. 2H). 1.88-1.80 (m. 2H). 1.27 (d. J = 6.9 Hz. 6H). 1.25-0.95 (m. 5H). 0.89 (s. 9H). Example 123: N-(2-l3-Chlorophenv (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-Dvrimk)o[4.5-d]azepin-4-amlne. MS (ESI): mass calcd. for CzsHzrCIFaNj. 489.19; m/z found. 490.1 [M+Hf. 1H NMR (CDCI3): 8.39-8.36 (m. 1H). 7.85 (dd. J = 7.8. 1.8 Hz. 1H). 7.25-7.20 (m. 3H). 7.11-7.08 (m. 1H). 6.95-6.90 (m. 1H). 4.68-4.60 (m. 1H). 3.77-3.73 (m. 2H). 3.61-3.55 (m. 4H). 3.18-3.11 (m. 2H). 3.02-2.88 (m. 3H). 2.69-2.64 (m. 2H). 1.31 (d. J = 6.9 Hz. 6H). Example 124: N-(2-M-ChloroDhenvl)ethy 1H NMR (CDCI3): 8.38-8.36 (m. 1H). 7.86-7.85 (m. 1H). 7.29-7.26 (m. 2H). 7.15- 7.13 (m. 2H). 6.95-6.92 (m. 1H). 4.64-4.61 (m. 1H). 3.73 (dd. J = 13.2. 6.7 Hz. 2H). 3.61-3.54 (m. 4H). 3.16-3.11 (m. 2H). 3.00-2.93 (m. 1H). 2.91 (t. J = 7.1 Hz. 2H). 2.68-2.65 (m. 2H). 1.31 (d. J = 6.9 Hz. 6H). Example 125: N-(2-r2.6-DichloroDhenvltethyl]-2-ri-methylethytW743- (trif1uoromethyl)pyridin-2-vf1-6.7.8.9-tetrahydro-5H-DVi1midQf4.5-dlazepln-4-amlne. MS (ESI): mass calcd. for C25H26CI2F3N5. 523.15; m/z found. 524.4 (M+HJ". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.29 (d. J = 8.0 Hz. 2H). 7.11-7.07 (m. 1H). 6.95-6.91 (m. 1H). 4.79-4.75 (m. 1H). 3.85 (dd. J = 6.8. 12.8 Hz. 2H). 3.62-3.54 (m. 4H). 3.30 (t. J = 13.8. 6.9 Hz. 2H). 3.14-3.10 (m. 2H). 2.96-2.90 (m. 1H). 2.74-2.70 (m. 2H). 1.28 (d. J = 6.9 Hz. 6H). Example 126: 2-ri-MethylethyiVN-)2-(2-)methyloxv)Dhenvflethy(t-7-(3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9rtetrahvdro-5H-Dvrimldo[4.5-dlazepin-4-amine. : MS (ESI): mass calcd. for C28H30F3N5O. 485.24; m/z found. 486.5 [M+H]". 1H NMR (CDCI3): 8.37-8.35 (m. 1H). 7.85 (dd. J = 7.8. 1.7 Hz. 1H). 7.25-7.20 (m. 1H). 7.16-7.14 (m. 1H). 6.94-6.87 (m. 3H). 5.03-4.99 (m. 1H). 3.86 (s. 3H). 3.72- 3.68 (m. 2H). 3.58-3.56 (m. 4H). 3.13-3.10 (m. 2H). 2.97-2.90 (m. 3H). 2.69-2.65 (m. 2H). 1.29 (d. J = 6.9 Hz. 6H). Example 127: N.N-Dlmethyl-4- 6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1aizepin-4-vl)amlno)benzamlde. The title compound was prepared using methods analogous to those described in Example 1. using isobutyramidine in Step A. 4-amino-N.N-dimethyi- benzamide in Step E. and substituting t-amyl alcohol for n-butanol in Step E. MS (ESI): mass calcd. for CasHagFaNeO. 498.24; m/z found. 499.3 [M+H]\ 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.75-7.72 (m. 2H). 7.47 7.44 (m. 2H). 6.99-6.95 (m. 1H). 6.63 (s. 1H). 3.72-3.60 (m. 4H). 3.27-3.21 (m. 2h 3.16-3.02 (m. 7H). 3.00-2.97 (m. 2H). 1.34 (d. 6.9 Hz. 6H). The following Examples 128-175 were prepared using methods analogous to those described in Example 46. substituting the appropriate amidines in Step A and amines in Step E. Example 128: N-[3-Chloro-4-qrifluoromethylk)henv1l-2-(1-methylethytt-7-(3- (trifluoromethyl)pyridin-2-vtl-6.7.8.9-tetrarivdro-5H2Pvrimidor4.5-d1azeDin-4-amlne. MS (ESI): mass calcd. for C2HjaCIFsNs. 529.14; m/z found. 530.1 [M+H]". 1H NMR (CDCI3): 8.39-8.38 (m. 1H). 8.16 (d. J = 2.0 Hz. 1H). 7.88 (dd. J = 7.8. 1.1 Hz. 1H). 7.62 (d. 8.7 Hz. 1H). 7.55-7.52 (m. 1H). 6.99-6.95 (m. 1H). 6.66 (s. 1H). Example 129: 2-Methyf-2-(4-a2-n-methylethy 6.7.8.9-tetrahvdro-5H-pyr MS (ESI): mass calcd. for C27H29F3N6. 494.24; m/z found. 495.2 [M+H]". "H NMR (CDCI3): 8.39-8.38 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.74-7.70 (m. 2H). 3.06-3.01 (m. 1H). 2.98-2.94 (m. 2H). 1.74 (s. 6H). 1.32 (d. J " 6.9 Hz. 6H). Example 130: 4-a2-(1-MethylethylV7-(32trifluoromethyl2DVi1din-2-vl1-6.7.8.9- tetfahvdro-5H-pyrimidor4.5-d1azeDln-4-vl')amlno')benzolcactd. MS (ESI): mass calcd. for C24H24F3N6O2l 471.19; m/z found. 472.1 [M+H]". 1H NMR (CD3OD): 8.46-8.43 (m. 1H). 8.07-8.01 (m. 3H). 7.76-7.72 (m. 2H). 7.16- 7.12 (m. 1H). 3.68-3.58 (m. 4H). 3.34-3.30 (m. 2H). 3.24-3.20 (m. 2H). 3.12-3.05 (m. 1H). 1.31 (d. J = 6.8 Hz. 6H). Example 131: N-Bipheny 6.7.8.9-tetrahvdro-5H-pyrimido[4r5-d1azepin-4-amine. MS (ESI): mass calcd. for CaoHajFaNs. 503.23; m/z found. 504.5 [M+HJ". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.89-7.86 (m. 1H). 7.77-7.74 (m. 2H). 7.64-7.58 (m. 4H). 7.46-7.42 (m. 2H). 7.35-7.30 (m. 1H). 6.97-6.93 (m. 1H). 6.57 (s. 1H). 3.70-3.65 (m. 2H). 3.64-3.60 (m. 2H). 3.24-3.20 (m. 2H). 3.08-3.01 (m. 1H). 2.99- 2.96 (m. 2H). 1.34 (d. J = 6.9 Hz. 6H). Example 132: N24-CvclohexvlDh9nv1V2-21-methytethylV7-[3- (trif1uCHT?methyl22dlrv2-vfl-6.7.8.9-tetrahvdrD-5H-Dvrinrildor4.5-tflazeDin-4-amtne. MS (ESI): mass calcd. for 2BH2FSNS. 509.27; m/z found. 510.5 tM+H]". fH NMR (CDCI3): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8.1.8 Hz. 1H). 7.60-7.57 (m. 2H). 7.20-7.16 (m. 2H). 6.95-6.92 (m. 1H). 6.44 (s. 1H). 3.68-3.58 (m. 4H). 3.22-3.18 (m. 2H). 3.05-2.97 (m. 1H). 2.95-2.91 (m. 2H). 2.52-2.44 (m. 1H). 1.93-1.80 (m. 4H). 1.78-1.70 (m. 2H). 1.46-1.36 (m. 4H). 1.31 (d. J = 6.9 Hz. 6H). Example 133: 2-(1-Methylethyl)-N-(4-DiDerldin-1-v MS (ESI): mass calcd. for CaHuFsNe. 510.27; m/z found. 511.5 [M+H]". 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.88-7.85 (m. 1H). 7.53-7.49 (m. 2H). 6.97-6.91 (m. 3H). 6.35 (s. 1H). 3.68-3.57 (m. 4H). 3.22-3.17 (m. 2H). 3.15-3.09 (m. 4H). 3.03-2.95 (m. 1H). 2.93-2.88 (m. 2H). 1.76-1.71 (m. 4H). 1.60-1.54 (m. 2H). 1.29 (d. J = 6.9 Hz. 6H). Example 134: 2-M-MethylethylVN-(4-morDholin-4-viDhenv1V7-(3- (trifluoromethyl)pyrtdin-2-v11-6.7.8.9-tetrahvdro-5H-Pvrimidor4.5-d1azep MS (ESI): mass calcd. for C27H31F3N6O. 512.25; m/z found. 513.5 [M+H]". 1H NMR (CDCb): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.57-7.53 (m. 2H). 6.95-6.90 (m. 3H). 6.37 (s. 1H). 3.90-3.86 (m. 4H). 3.67-3.59 (m. 4H). 3.21- 3.17 (m. 2H). 3.15-3.12 (m. 4H). 3.03-2.96 (m. 1H). 2.93-2.90 (m. 2H). 1.29 (d. J = 6.9 Hz. 6H). Example 135: 2-M-MethylethylVN-r4-(nriethylsulfanvl)Dhenyl]-7-[3- (trifiLK?romethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-d1azepin-4-amine. MS (ESI): mass calcd. for C24H26F3NsS. 473.19; m/z found. 474.4 [M+H]"H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.63-7.60 (m. 2H). 7.30-7.26 (m. 2H). 6.97-6.92 (m. 1H). 6.46 (s. 1H). 3.69-3.57 (m. 4H). 3.24- 3.18 (m. 2H). 3.06-2.97 (m. 1H). 2.95-2.92 (m. 2H). 2.49 (3. 3H). 1.31 (d. J = 6.9 Hz. 6H). Example 136: 2-)1-Methylethyl VN-(4-nttropfienvl)-7-(3-(trifluoromethyl)pyridin-2-vl1- 6.7.8.9-tetrahvdro-5H-Dvrlm(do[4.5-d1azepir)-4-arnine. MS (ESI): mass calcd. for C2H2NsC2. 472.18; m/z found. 473.4 [M+H]+. 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 8.26-8.23 (m. 2H). 7.89-7.84 (m. 3H). 6.98- 6.95 (m. 1H). 6.85 (s. 1H). 3.66-3.63 (m.2H). 3.61-3.59 (m. 2H). 3.27-3.23 (m. 2H). 3.12J-3.05 (m. 1H). 3.04-2.99 (m. 2H). 1.34 (d. J = 6.9 Hz. 6H). Example 137: 2-n-Methylethyl)-N-r4-n-methylethyhphenyl]-7-[3- arifllioromethyl)pyridin'2-yl]-6.7.8.9-tetrahvclro-5H-pyrimidor4.5-cnazeDin-4-amine. MS (ESI): mass calcd. for C2BH30F3N5. 469.25; m/z found. 470.2 [M+H]+. "H NMR (CDCIg): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.60-7.57 (m. 2H). 7.23-17.18 (m. 2H). 6.96-6.92 (m. 1H). 6.45 (s. 1H). 3.69-3.58 (m. 4H). 3.24-3.17 (m. 2H). 3.06-2.97 (m. 1H). 2.96-2.85 (m. 3H). 1.32 (d. J = 6.9 Hz. 6H). 1.26 (d. J = 6.8. 6H). Example 138: 2-( 1.1 -Dimethylethyl)-N-r4-(1.1 -dimethylethyl]phenyll-7-(3- (trifluoromethyl]pyridin-2-vll-6.7.8.9-tetrahvdro-5H-Pvrimidor4.5-d1azepln-4-amlne. \ MS (ESI): mass calcd. for CzaH2FaNs. 497.28; m/z found. 498.2 [M+Hf. 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.86 (d. J = 7.8.1.8 Hz. 1H). 7.64-7.60 (m. 2H). 7.39-7.33 (m. 2H). 6.96-6.91 (m. 1H). 6.43 (s. 1H). 3.71-3.58 (m. 4H). 3.24-3.18 (m. 2ti). 2.96-2.92 (m. 2H). 1.38 (s. 9H). 1.33 (s. 9H). Example 139: 2-H. 1 -Dlmethy)ethyl]-N-[4-(trifluoromethyl)phenyl]-7-[3- rtrifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d]azepin-4-amine. MS (ESI): mass calcd. for C29H2sFeN5. 509.20; m/z found. 510.1 [M+HJ". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.90-7.86 (m. 1H). 7.80 (d. J + 8.5 Hz. 2H). 7.59 (d. J = 8.6 Hz. 2H). 6.98-6.93 (m. 1H). 6.62 (s. 1H). 3.69-3.64 (m. 2H). 3.63-3.58 (m. 2H). 3.27-3.21 (m. 2H). 3.02-2.95 (m. 2H). 1.38 (s. 9H). Example 140: NI-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-n-methylethy))-7-)3- (tflfluoromethyl)Pvridin-2-vf)-6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1azepirv4-amir)e. MS (ESI): mass calcd. for CJMH2FTNS. 513.18; m/z found. 514.1 [M+Hf. 1H NMR (CDCI3): 8.39-8.38 (m. 1H). 8.05-8.00 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.54-7.49 (m. 1H). 7.27-7.25 (m. 1H). 6.99-6.94 (m. 1H). 6.71 (s. 1H). 3.69-3.57 (m. 4H). 3.27-3.21 (m. 2H). 3.12-3.03 Example 141: N-)2.3-Dihvdro-1H-lnden-5-yl]-2-)1-methylethylV7-(3- (trifluoromethyHpyridin-2-vfl-6.7.8.9-tetrahvdro-5H-ovr|mldo('4.5-dlazepln-4-amin9 hvdrochloride salt. MS (ESI): mass calcd. for CajHajFaNs. 467.23; m/z found. 468.2 [M+H]f. 1H NMR (CD3OD): 8.46-8.43 (m. 1H). 8.02 (dd. J «= 7.8. 1.7 Hz. 1H). 7.40-7.38 (m. 1H). 7.26-7.21 (m. 2H). 7.14-7.11 (m. 1H). 3.66-3.63 (m. 2H). 3.61-3.57 (m. 2H). 3.19-3.14 (m. 2H). 3.06-2.97 (m. 1H). 2.96-2.90 (m. 6H). 2.15-2.08 (m. 2H). 1.26 (d. J a 6.8 Hz. 6H). Example 142: 2-d-Methyiettiyl)-N-(4-(1.3-oxazol-5-v1bhenv (trtfliK?rometh2)DVridin-2-vt]-6.7.8.9-tetrahvdro-5H-pyrirnidor4.5-d1azeplrv4-amine. MS (ESI): mass calcd. for C2H2NsC). 494.20; m/z found. 495.1 [M+HJ". 1H NMR (CDC".): 8.40-8.38 (m. 1H). 7.90-7.86 (m. 2H). 7.78-7.75 (m. 2H). 7.66- 7.62 (m. 2H). 7.30 (s. 1H). 6.98-6.93 (m. 1H). 6.61 (s. 1H). 3.70-3.58 (m. 4H). 3.26- 3.19 (m. 2H). 3.10-2.94 (m. 3H). 1.33 (d. J = 6.9 Hz. 6H). Example 143: N-(4-n.1-DlmethylethylV-3-nitrophGnvll-2-n-methylethylV7-(3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimldo[4.5-cnazepin-4-amine. MS (ESI): mass calcd. for C27H3iF3N6O2. 528.24; m/z found. 529.2 [M+HJ". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 8.10 (d. J = 2.4 Hz. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.53 (dd. J = 8.8. 2.4 Hz. 1H). 7.47 (d. J = 8.8 Hz. 1H). 6.99-6.94 (m. 1H). 6.57 (s. 1H). 3.68-3.56 (m. 4H). 3.26-3.17 (m. 2H). 3.07-2.99 (m. 1H). 2.98-2.93 (nr\ 2H). 1.41 (s. 9H). 1.31 (d. J = 6.9 Hz. 6H). Example 144: 2-F2ran-2-vt-N-(4- (trifluoromethyl)Pvrldin-2-vi1-6.7.8.9-tetrahvdro-5H-pyrimkio[4.5 MS (ESI): mass calcd. for CzsHtgFeNjO. 519.15; m/z found. 520.1 [M+Hf. 1H NMR (CDCI3): 8.32-8.31 (m. 1H). 7.81 (dd. J = 7.8. 1.8 Hz. 1H). 7.73 (d. J = 8.6 Hz. 2H). 7.56 (d. J = 8.6 Hz. 2H). 7.53-7.52 (m. 1H). 7.14-7.11 (m. 1H). 6.92-6.87 (m. 1H). 6.68 (s. 1H). 6.49-6.46 (m. 1H). 3.64-3.52 (m. 4H). 3.30-3.23 (m. 2H). 3.01-2.95 (m. 2H). Example 145: N-(4-n.1-Dimethylethyt)phenv1]-2-(uran-2-y127-(3- rtrifluoromethyt)Dvridin-2-v MS (ESI): mass calcd. for C2«H28F3NsO. 507.22; m/z found. 508.2 [M+H]". 1H NMR (CDCI3): 8.33-8.31 (m. 1H). 7.80 (dd. J = 7.8. 1.9 Hz. 1H). 7.54-7.50 (m. 3H). 7.35-7.31 (m. 2H). 7.13-7.11 (m. 1H). 6.89-6.85 (m. 1H). 6.48 (s. 1H). 6.46- 6.44 (m. 1H). 3.63-3.53 (m. 4H). 3.27-3.21 (m. 2H). 2.96-2.90 (m. 2H). 1.27 (s. 9H). Example 146: 2-Furan-3-v)-N-(4-(tpfluoromethyl)phenv .MS (ESI): mass calcd. for CasHigFoNsO. 519.15; m/z found. 520.1 [M+H]". 1H NMR (CDCI3): 8.33-8.31 (m. 1H). 8.10-8.08 (m. 1H). 7.81 (dd. J = 7.8. 1.8 Hz. 106 1H). 7.70 (d. J = 8.5 Hz. 2H). 7.55 (d. J = 8.7 Hz. 2H). 7.41-7.39 (m. 1H). 6.94-6.92 (m. 1H). 6.91-6.87 (m. 1H). 6.62 (s. 1H). 3.64-3.52 (m. 4H). 3.24-3.17 (m. 2H). 2.99-2.93 (m. 2H). Example 147: N-(4-n.1-D)methylothyl)phenyl]-2-(uran-3-vt-7-(3- (trlfliK3rDmetti2)Dvridin-2-vfl-6.7.8.9-tetrah\AJit)5H-ovrimldo[4.5-d1a2epir)-4-amlne1 . MS (ESI): mass calcd. for C28H28F3N9O. 507.22; m/z found. 508.2 [M+H]". 1H NMR (CDQa): 8.33-8.31 (m. 1H). 8.09-8.07 (m. 1H). 7.80 (dd. J = 7.8. 1.8 Hz. 1H). 7.52-7.48 (m.2H).1.28(s.9H). Example 148: BenzoFI .2.51thladiazol-5-yl-r2-isopropy vlH).7.8.9-4etrahvdro-5H-pyrimldor4.5-dIazepin-4-vfl-am?ne- MS (ESI): mass calcd. for C23H22F3N7S. 485.16; m/z found. 486.1 [M+H]+. 1H NMR (CDCI3): 8.56-8.53 (m. 1H). 8.34-8.31 (m. 1H). 7.85 (d. J + 9.4 Hz. 1H). 7.81 (dd. J = 7.8. 1.8 Hz. 1H). 7.59 (dd. J = 9.4. 2.2 Hz. 1H). 6.91-6.87 (m. 1H). 6.68 (s. 1H). 3.63-3.59 (m. 2H). 3.57-3.54 (m. 2H). 3.21-3.16 (m. 2H). 3.07-2.99 (m. 1H). 2.98-2.95 (m. 2H). 1.30 (d. J = 6.9 Hz. 6H). Example 149: 2-22-Thlenvl)-N-r4-(trif\uoromethyl)phenvfl-7-(3- (trifluorornethyhpyrkJln-2-yl]-6.7.8.9-tetrahvdro-5H-PVrimidot4.5-dlazeplr)-4-am|ne. MS (ESI): mass calcd. for C2HieFeNsS. 535.13; mtz found. 536.1 [M+H]". 1H NMR (CDCI3): 8.33-8.31 (m. 1H). 7.86-7.83 (m. 1H). 7.81 (dd. J = 7.8. 1.8 Hz. 1H). 7.76 (d. J = 8.5 Hz. 2H). 7.57 (d. J = 8.6 Hz. 2H). 7.37-7.34 (m. 1H). 7.06-7.04 (m. 1H). 6.91-6.87 (m. 1H). 6.64 (s. 1H). 3.65-3.53 (m. 4H). 3.26-3.20 (m. 2H). 3.00-2.94 (m. 2H). Example 150: 2-l3-Thienv1)-N-(4-(trTfluQromethy (trifluoromethyl)pyridin-2-vl)-6.7.8.9-tetrahvdro-5H-Dyrimido[4.5-dlazepin-4-amine. MS (ESI): mass calcd. for CasH-2FeNsS. 535.13; m/z found. 536 [M+H]". 1H NMR (CDCb): 8.40-8.38 (m. 1H). 8.20-8.18 (m. 1H). 7.90-7.86 (m. 1H). 7.84-7.78 (m. 3H). 7.65-7.63 (m. 2H). 7.36-7.34 (m. 1H). 6.99-6.94 (m. 1H). 6.69 (s. 1H). 3.72-3.60 (m. 4H). 3.35-3.26 (m. 2H). 3.08-3.02 (m. 2H). Example 151: 2-21-MethytethylVN-(4-methylPhenvt)-7-(3-ltrtf1uoromethyl)pyridin-2- vtl-6.7.8.9-tetrahvdro-SH-pyrimido[4.5-d1azeDin-4-amlne h.vdrochlorkte salt. MS (ESI): mass calcd. for C24H+F3N3. 441.21; m/z found. 442.2 [M+HJ". 1H NMR (CD3OD): 8.46-8.44 (m. 1H). 8.03 (dd. J - 7.8. 1.7 Hz. 1H). 7.42-7.39 (m. 2H). 7.24-7.22 (m. 2H). 7.17-7.13 (m. 1H). 3.68-3.58 (m. 4H). 3.35-3.30 (m. 2H). 3.21-3.15 (m. 2H). 3.10-3.00 (m. 1H). 2.37 (s. 3H). 1.26 (d. J = 6.8 Hz. 6H). Example 152: 2-(1-MQthytethy (trif1uoromethyl)pyrkJin-2-v MS (ESI): mass calcd. for C27H3iF3N8O2S. 560.22; m/z found. 561.1 [M+H]". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.90-7.85 (m. 3H). 7.82-7.78 (m. 2H). 6.99- 6.94 (m. 1H). 6.74 (s. 1H). 3.66-3.57 (m. 4H). 3.29-3.21 (m. 6H). 3.11-2.97 (m. 3H). 1.81-1.74 (m. 4H). 1.34 (d. J = 6.9 Hz. 6H). Example 153: 2-(2-MethyM =3-thlazol-4-vlVN-r4-artfluoromethyl)phenv+-7-[3- (trifluoromethy trif uoroacetic acid salt. MS (ESI): mass calcd. for C2H2NeS. 550.14; m/z found. 551.2 [M+H]". 1H NMR (CD3OD): 8.48-8.44 (m. 1H). 8.34 (s. 1H). 8.07-8.02 (m. 1H). 7.89-7.86 (m. 2H). 7.82-7.77 (m. 2H). 7.18-7.13 (m. 1H). 3.72-3.62 (m. 4H). 3.56-3.53 (m. 2H). 3.33-3.30 (m. 2H). 2.84 (s. 3H). Example 1 54: N.N-Dlmethyt-4-(l2-21-methylethyl)-7-[3-(tnfluorornetriyl]pyrklin-2-vri- 6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazeDin-4-y MS (ESI): mass calcd. for C25H29F3N6O2S. 534.20; mVz found. 535.3 [M+H]". 1H NMR (CDCI3): 8.42-8.40 (m. 1H). 7.92-7.89 (m. 3H). 7.78-7.75 (m. 2H). 7.01- 6.96 (m. 1H). 6.77 (s. 1H). 3.69-3.60 (m. 4H). 3.29-3.24 (m. 2H). 3.14-3.00 (m. 1H). 3.04-3.00 (m. 2H). 2.74 (s. 6H). 1.36 (d. 6.9 Hz. 6H). Example 155: N-r2-Fluoro-4-2trifluoromethyl]phenvH-2-(iHrn6thylethy+-7-(3- (tri(tuoromethyl)pyi1din-2-v MS (ESI): mass calcd. for C2H2FrNs. 513.18; m/z found. 514.2 [M+HJ". 1H NMR (CDCIj): 8.93-8.88 (m. 1H). 8.42-8.40 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.49.7.46 (m. 1H). 7.41-7.38 (m. 1H). 7.00-6.97 (m. 2H). 3.70-3.67 (m. 2H). 3.63- 3.60 (m. 2H). 3.28-3.25 (m. 2H). 3.13-3.06 (m. 1H). 3.04-3.01 (m. 2H). 1.36 (d. J = 6.9 Hz. 6H). Example 156: 1 -r4-22-PlDeridin-1-vt-7-(3-(trifluoromethyt)Pvri2ip-2-yl]-6.7.8.9- tetrahvdro-5H-Pvrimido[4.5-d1azeD 1H NMR (CDCb): 8.41-8.39 (m. 1H). 7.98-7.95 (m. 2H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.66-7.64 (m. 2H). 6.98-6.94 (m. 1H). 6.60 (s. 1H). 3.81-3.74 (m. 4H). 3.64- 3.55 (m. 4H). 3.14-3.08 (m. 2H). 2.92-2.86 (m. 2H). 2.60 (s. 3H). 1.71-1.60 (m. 6H). Example 157: N-[3-Fluoro-4-)trifluoromethyl)DhenvlI-2-DiDeridirv1-v (trifluoromethyl)Pvridin-2-vll-6.7.8.9-tetrahvdrc)-5H-Pvrimkior4.5- MS (ESI): mass calcd. for CajKfesFyNe. 554.20; m/z found. 555.2 [M+H]". "H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.84-7.81 (m. 1H). 7.50 (t. J = 8.4 Hz. 1H). 7.18-7.14 (m. 1H). 6.98-8.95 (m. 1HJ. 6.57 (s. 1H). 3.81- 3.73 (m. 4H). 3.63-3.55 (m. 4H). 3.13-3.07 (m. 2H). 2.91-2.85 (m. 2H). 1.73-1.60 (m. 6H). Example 158: N.N-Dimethyl-4-(f2-piperidin-1-v1-7-[3-Ctrifluoromethyl)DVfidin-2-v MS (ESI): mass calcd. for CzrHazFaNjOzS. 575.23; m/z found. 576.3 [M+H]". "H NMR (CDCI3): 8.42-8.40 (m. 1H). 7.90-7.88 (m. 1H). 7.76-7.72 (m. 4H). 6.98- 6.95 (m. 1H). 6.60 (s. 1H). 3.79-3.75 (m. 4H). 3.61-3.56 (m. 4H). 3.12-3.08 (m. 2H). 2.92-2.87 (m. 2H). 2.73 (s. 6H). 1.72-1.63 (m. 6H). Example 159: N-(4-l1.1-Dlmethylethyl)-3-nitroDhenvl]-2-piperidin-1-v rtrifluorometrivhPVridin-2-vl1-6i.7.8.9-tetrahvdro-5H-Pvrim)do[4.5-d]azepin-4-amine. ; MS (ESI): mass calcd. for C29H34F3N7O2. 569.27; m/z found. 570.3 [M+H]+. 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 8.08 (d. J = 2.5 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.45 (d. J = 8.8 Hz. 1H). 7.31-7.28 (m. 1H). 6.97-6.93 (m. 1H). 6.42 (s. 1H). 3.77-3.71 (m. 4H). 3.64-3.55 (m. 4H). 3.11-3.06 (m. 2H). 2.88-2.83 (m. 2H). 1.7121.59 (m.6H). 1.41 (s. 9H). Example 160: N-(4-(Methylsulfanvl)phenylT-2-Diperldin-1-yl-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-Pvrinnidor4.5-d1azepin-4-amine. I MS (ESI): mass calcd. for C26H2gF3NeS. 514.21; m/z found. 515.2 [M+H]+. 1H NMR (CDCI3): 8.40-8.39 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.52-7.47 (m. 2H). 7.30-7.26 (m. 2H). 6.97-6.92 (m. 1H). 6.32 (s. 1H). 3.77-3.70 (m. 4H). 3.65- 3.56 (m. 4H). 3.11-3.06 (m. 2H). 2.87-2.84 (m. 2H). 2.50 (s. 3H). 1.69-1.57 (m. 6H). Example 161: f2-lsopropyl-7-(3-trifluoromethyl-pyridin-2-yl]-6.7.8.9-tetrahvdro-5H- Pvrimido[4.5-d1azepin-4-yl]-n-metriyl-1.2.3.4-tetrarivdro-auinolin-7-vlVamin9. MS (ESI): mass calcd. for C27H31F3N6. 496.26; m/z found. 497.3 [M+H]+. iH NMR (pDCI3): 8.39-8.36 (m. 1H). 7.86 (dd. J « 7.8. 1.8 Hz. 1H). 7.20 (d. J = 2.0 Hz. 1H). 6.96-6.86 (m. 2H). 6.68 (dd. J = 8.0. 2.1 Hz. 1H). 6.40 (s. 1H). 3.72-3.56 (m. 4H). 3.27-3.16 (m. 4H). 3.05-2.90 (m. 6H). 2.74 (t. J = 6.4 Hz. 2H). 2.02-1.94 (m. 2H). 1.32 (d. J = 6.9Hz. 6H). Example 162:12-lsopropyt-7-(3-trifluoromethyl-Dvridin-2-v)V-6.7.8.9-tetrahvdrD-5H- PVrimidor4.5-dlazepin-4-yil-(1.4.4-trimethy MS (ESI): mass calcd. for C29H35F3N8. 524.29; m/z found. 525.3 [M+H]". 1H NMR (CDCb): 8.40-8.38 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.23 (d. J = 2.2 Hz. 1H). 7.14 (d. J = 8.3 Hz. 1H). 6.97-6.92 (m. 1H). 6.78 (dd. J = 8.2. 2.2 Hz. 1H). 6.43 (s. 1H). 3.70-3.60 (m. 4H). 3.29-3.25 (m. 2H). 3.23-3.20 (m. 2H). 3.06-3.00 (m. 1H). 2.98-2.93 (m. 5H). 1.80-1.77 (m. 2H). 1.35 (d. J = 6.9 Hz. 6H). 1.30 (s. 6H). Example 163: (1-Methyl-1.2.3.4-tetrahvdro-quinolin-7-viW2-pip«ridin-1-v1-7-)3- tfifluQromethyl-Pvrldin-2-vlV6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepiri-4-vfl2amine hvdrochlorlde salt. MS (ESI): mass calcd. for C2H2Nr. 537.28; m/z found. 538.3 (M+H]". ?H NMR(CDCI3): 8.41-8.39 (m. 1H). 7.89 (dd. J = 7.8. 1.7 Hz. 1H). 7.02-6.98 (m. 1H). 6.97-6.94 (m. 2H). 6.75-6.72 (m. 1H). 6.66-6.62 (m. 1H). 4.09-3.78 (m. 6H). 3.69- 3.61 (m. 4H). 3.31-3.25 (m. 2H). 2.92-2.87 (m. 5H). 2.80-2.75 (m. 2H). 2.04-1.97 (m. 2H). 1.74-1.66 (m.6H). Example 164: r2-Piperidin-1-v 5H-pyrimido[4.&-d1azepin-4-vt]-(1.4.4-trifnethy amine hvdrochlotide salt. MS (ESI): mass calcd. for C3iH3aF3N7. 565.31; m/z found. 566.3 [M+HJ". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.88 (m. 1H). 7.19 (d. J = 8.2 Hz. 1H). 7.02- 6.93 (m. 2H). 6.78-6.69 (m. 2H). 4.10-3.90 (m. 4H). 3.87-3.80 (m. 2H). 3.69-3.61 (m. 4H). 3.33-3.26 (m. 2H). 2.94-2.87 (m. 5H). 1.82-1.77 (m. 2H). 1.75-1.67 (m. 6H). 1.31 (s. 6H). Exarnple 165: f2-lsopropyt-7-(3-trifluoromethy Pvrimido[4.5- MS (ESI): mass calcd. for CasHaoFaN?. 497.25; m/z found. 498.3 tM+Hf. 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 8.20 (d. J = 2.6 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.85 (dd. J = 9.0. 2.7 Hz. 1H). 6.98-6.94 (m. 1H). 6.41 (d. J = 9.0 Hz. 1H). 6.21 (s. 1H). 3.70-3.66 (m. 2H). 3.64-3.62 (m. 2H). 3.50-3.48 (m. 4H). 3.23-3.18 (m. 2H). 2.99-2.92 (m. 3H). 2.07-2.01 (m. 4H). 1.27 (d. J = 6.9 Hz. 6H). Example 166: 22-Fluoro-4-trifluoromethy trifluoromethyt-pyridin-2-v1V-6.7.a.9-tfltrahvdro-5H-pyrimldor4.5-d1azeDin-4-yl]- amlnq. MS (ESI): mass calcd. for Cae2sFrN... 554.25; m/z found. 555.2 [M+H]". 1H NMR (CDCb): 8.40-8.36 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.84-7.78 (m. 1H). 7.48 (t. J =8.4 Hz. 1H). 7.16-7.11 (m. 1H). 6.97-6.91 (m. 1H). 6.55 (s. 1H). 3.78- 3.70 (m. 4H). 3.61-3.52 (m. 4H). 3.11-3.05 (m. 2H). 2.88-2.83 (m. 2H). 1.72-1.56 (m. 6H). Example 167: 2-Pvridin-4-yl-N-(4-(trifluoromethy MS (ESI): mass calcd. for CMH2oF6N6. 530.17; m/z found. 531.5 [M+H]". 1H NMR (MeOD): 8.90 (d. J = 6.6 Hz. 2H). 8.81 (d. J = 6.7 Hz. 1H). 8.45-8.42 (m. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.87 (d. J = 8.5 Hz. 2H). 7.69 (d. J = 8.6 Hz. 2H). 7.12 (dd. J = 7.7. 4.9 Hz. 1H). 3.62-3.56 (m. 4H). 3.42-3.37 (m. 2H). 3.29-3.25 (m. 2H). Example 168: N-(4-M.1-Dimethyiethy+phenyl]-2-PVTidin-4-yl-7r[3- (trifluoromethyl)pyrtdin-2-v trifluoroacetic acid salt. MS (ESI): mass calcd. for C2BH29F3N7. 518.24; m/z found. 519.5 [M+H]". 1H NMR (MeOD): 8.89 (d. J = 6.6 Hz. 2H). 8.72 (d. J = 6.7 Hz. 2H). 8.44 (dd. J = 4.7. 1.4 Hz. 1H). 8.02 (dd. J + 7.8. 1.8 Hz. 1H). 7.58-7.54 (m. 2H). 7.47-7.44 (m. 2H). 7.12 (dd. J = 7.8. 4.8 Hz. 1H). 3.63-3.57 (m. 4H). 3.40-3.35 (m. 2H). 3.26-3.21 (m. 2H). 1.36 (s. 9H). Example 169; N-[3-Chloro-4-(trifluoromethyl)phenv11-2-Pvridin-4-v (trifluoromethy2)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-ovrimido[4.5- MS (ESI): mass calcd. for CajHieCIFgNg. 564.13; m/z found. 565.4 [M+H]1H NMR (CDCI3): 8.76 (d. J = 5.1 Hz. 2H). 8.40 (d. J = 3.7 Hz. 1H). 8.22 (d. J = 5.3 Hz. 2H). 8.09 (s. 1H). 7.91-7.87 (m. 1H). 7.70 (d. J = 8.8 Hz. 1H). 7.58 (d. J = 9.0 Hz. 1H). 7.01-6.95 (m. 1H). 6.81 (s. 1H). 3.75-3.61 (m. 4H). 3.41-3.32 (m. 2H). 3.13-3.06 (m. 2H). Example 170: 2-Pvridin-4-v1-7-[3-(trifluoromethy+Pvridin-2-yl]-N-(6- (triflyioromethyl)Dvrklin-3-2-617.8.9-tetrahvdro-5H-PvriiTildo[4.5-d1azepirv-4-arnine trifluoroacetic acid salt. MS (ESI): mass calcd. for C2sH19F6N7. 531.16; m/z found. 532.1 [M+H]". 1H NMR (CDCI3): 9.04 (d. J = 2.3 Hz. 1H). 8.90 (d. J = 6.4 Hz. 2H). 8.73 (d. J = 6.4 Hz. 2H). 8.43-8.41 (m. 1H). 8.21 (dd. J = 8.5. 2.3 Hz. 1H). 7.94 (dd. J + 7.8. 1.6 Hz. 1H). 7.79 (d. J = 8.6 Hz. 1H). 7.33 (s. 1H). 7.06-7.02 (m. 1H). 3.77-3.72 (m. 2H). 3.71-3.65 (m. 2H). 3.43-3.38 (m. 2H). 3.25-3.19 (m. 2H). Example 171: N-(4-)1.1-Dimethytethylk)rienyl]-2-Dvrldin-2-v (tfifluoromethyl)pyridin-2-vlV6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d]azepln-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C2W2No. 518.24; m/z found. 519.5 [M+H]". 1H NMR (MeOD): 8.84-8.82 (m. 1H). 8.45 (dd. J = 4.7. 1.5 Hz. 1H). 8.27-8.23 (m. 1H). 8.09-8.00 (m. 2H). 7.72-7.65 (m. 1H). 7.54 (s. 4H). 7.16-7.12 (m. 1H). 3.72-3.63 (m. 4H). 3.57-3.52 (m. 2H). 3.30-3.26 (m. 2H). 1.39 (s. 9H) Example 172: 2-Pvridin-2-v1-N-r4-(trifluoromethyl)Dhenv11-7-[3- (triflL|oromethyl)pyridir)-2-vll-6.7.8.9-tetrahvdro-5H-ovrimldo[4.5-cflazepln-4-amlne le 1 trifluoroacetic acid salt. MS (ESI): mass calcd. for C2H2Ns. 530.17; m/z found. 531.5 [M+H]". 1H NMR (MeOD): 8.88-8.81 (m. 1H). 8.47-8.44 (m. 1H). 8.34-8.31 (m. 1H). 8.16 (dt. J = 7.8. 1.6 Hz. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.86 (d. J = 8.6 Hz. 2H). 7.80 (d. J = 8.6 Hz. 2H). 7.77-7.73 (m. 1H). 7.17-7.12 (m. 1H). 3.71-3.64 (m. 4H). 3.60-3.55 (m. 2H). 3.35-3.31 (m. 2H). Example 173: N-(3-Chloro-4-(trifluoromethy (trifliJoromethyl)pyrldin-2-vf]-6.7.8.9-tBtrahvdro-5H-Dvrirnidor4.5-dlazeDln-4-arnlne trlfluoroacetlc add salt. MS (ESI): mass calcd. for C2HiBCIFeNe. 564.13; m/z found. 565.1 [M+HJ". 1H NMR (MeOD): 8.92-8.82 (m. 1H). 8.47-6.44 (m. 1H). 8.44-8.41 (m. 1H). 8.27 (dt. J = 7.8. 1.6 Hz. 1H). 8.05-3.01 (m. 2H). 7.88 (d. J = 8.7 Hz. 1H). 7.84-7.80 (m. 2H). 7.17-7.13 (m. 1H). 3.70-3.62 (m. 4H). 3.60-3.55 (m. 2H). 3.35-3.31 (m. 2H). Example 174: Methyi 2-methyl-2-(4-d2-21-mettivlethylV7-(3-(trifluoromethyttovrldin- 2-vfl-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-d1azepln-4-vf)amlno)phenvt|propar)oat9. MS (ESI): mass calcd. for C2H2NsC2. 527.25; m/z found. 528.2 (M+HT. 1H NMR (CDCI3): 8.40-8.39 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.69-7.65 (m. 2H). 7.35-7.31 (m. 2H). 6.98-6.94 (m. 1H). 6.51 (s. 1H). 3.70-3.60 (m. 7H). 3.25- 3.20 (m. 2H). 3.08-3.00 (m. 1H). 2.98-2.95 (m. 2H). 1.61 (s. 6H). 1.34 (d. J = 6.9 Hz. 6H). Example 175: Methyl 2-methyl-2-(4-({2-p|penttln-1-yl-7-(3-(trffluoromethyl]pwklln-2- yl]-6.7.8.9-tetrahvdro-5H-pyrimld MS (ESI): mass calcd. for C30H35F3N6O2. 568.27; m/z found. 569.3 [M+Hf. "H NMR (CDCI3): 8.40-8.39 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.56-7.52 (m. 2H). 7.32-7.28 (m. 2H). 6.97-6.92 (m. 1H). 6.36 (s. 1H). 3.78-3.72 (m. 4H). 3.67 (s. 3H). 3.64-3.56 (m. 4H). 3.11-3.05 (m. 2H). 2.88-2.83 (m. 2H). 1.70-1.58 (m. 12H). Example 176: 2-Pvr1din-3-v1-N-(4-2trifluoromethyl)phenyl]-7-(3- (trifluoromethyl)pyrkiln-2-v)l-6.7.8.9-tetrahvdro-5H-Pvrimidor4.5- A microwave vial containing [2-methylsulfanyl-7-(3-trifluoromethyl-pyrkjin-2- yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-ylH4-trifluoromethyl-phenyl)- amine (Example 53; 100 mg. 0.20 mmcrf). Pd2(dbah (7.3 mg. 0.008 mmol). trt-(2- furyl)phosphine (7.4 mg. 0.032 mmol). copper(l)thiophene-2-cart)oxylate (49 mg. 0.260 mmoJ). and 3-pyridyf boronic acid (27 mg. 0.22 mmol) was sealed and evacuated under N2. Upon complete flushing with N2l THF (3 mL) was added. Th« reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was filtered through a plug o[ diatomaceous earth. ooncentrated. and purified directly using Preparative HPLC (conditions as in Example 54) to give the title compound (40 mg. 40%). MS (ESI): mass calcd. for Ca)H2oF6Ne. 530.17; m/z found. 531.2 [M+H]". 1H NMR (MeOD): 9.32-9.28 (m. 1H). 8.54-8.36 (m. 1H). 8.03 (dd. J = 7.8. 1.6 Hz. 1H). 7.88 (d. J = 8.0 Hz. 2H). 7.73-7.69 (m. 1H). 7.17-7.11 (m. 1H). 3.64-3.57 (m. 4H). 3.42-3.37 (m. 2H). 3.29-3.24 (m. 2H). Example 177: 2-(4-({2-Piperidin-1 -v1-7-(3-(ti1fluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahvdro-5H-pyrimidor4.5-dlazepin-4-vl}amino')phenyl1propan-2-ol. To a solution o[ methylmagnesium bromide (170 mL o[ a 3.0 M solution in Et20. 0.51 mmol) in THF at 0 °C was added a solution o[ 1-[4-({2-piperidir+-1-y1-7- [S2trifluoromethylJpyridin2-yll-ej.S.g-tetrahydro-SH-pyrimido2.S-dlazepin2- yf}amino)phenyl]ethanone (Example 156; 59.8 mg. 0.117 mmol) In THF. The solution was allowed to warm to rt over 1 h. and stirred at rt for an additional 5 min. The reaction mixture was then quenched with satd. aq. NH4CI and extracted with EtOAc. The organic layers were combined. dried. and concentrated. The crude residue was purified (FCC) to give the title compound (51 mg. 83%). MS (ESI): mas6 calcd. for C28H33F3N6O. 526.27; m/z found. 527.3 [M+H]". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.55-7.51 (m. 2H). 7.46-7.41 (m. 2H). 6.94-6.90 (m. 1H). 6.35 (s. 1H). 3.77-3.69 (m. 4H). 3.63-3.53 (m. 4H). 3.10- 3.03 (m. 2H). 2.87-2.80 (m. 2H). 1.70 (s. 1H). 1.66-1.60 (m. 6H). 1.54 (s. 6H). Example 178: 2-(4-(22-M-MethylethylV7-(3-)trifluoromethyl)pyridin-2-vfl-6.7.8.9- tetrahvdro-5H-Pvrimido[4.5-d1azepin-4-v0aminok3henvllpropan-2-ol. The title compound was prepared using methods analogous to those described in Example 167. starting with1-{4-{{2-(1-methylethyl)-7-[3- (trinuoromethyl)pyl] MS (ESI): mass calcd. for CMHSOFSNSO. 485.24; m/z found. 486.2 [M+HJ". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.68-7.63 (m. 2H). 7.48- 7.45 (m. 2H). 6.97-6.92 (m. 1H). 6.50 (s. 1H). 3.69-3.58 (m. 4H). 3.25-3.17 (m. 2H). 3.08-2.98 (m. 1H). 2.98-2.92 (m. 2H). 1.61 (s. 6H). 1.32 (d. J = 6.9 Hz. 6H). Example 179: 1.1.1-Trifluoro-2-(4-a2-(1-methylethyl)-7-[3-(trifluoromethyHovrtdin-2- yl]-6t7.8.9-tetrahvdro-5H-Dvrlmkior4.5-d1azepln-4-vr}amlno)phenyl]propan-2-ol. The title compound was prepared using methods analogous to those described In Example 167. starting with 2l2.2-trifluoro-1-{4-[2-isopropyJ-7-(3- trifluoromethyJ-pyridin-2-yl)-6.718.9-tetrahydro-5H-pyrimido{4.5-d]azepin-4-ylamino)- phenylj-ethanone (prepared analogously to Example 1). MS (ESI): mass calcd. for CbsHezFeNsO. 539.21; m/z found. 540.1 [M+H]\ 1H NMR (CDCI3): 8.41-8.40 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.77-7.73 (m. 2H). 7.59-7.54 (m. 2H). 6.99-6.95 (m. 1H). 6.58 (s. 1H). 3.71-3.60 (m. 4H). 3.27-3.21 (m. 2H). 3.09-3.02 (m. 1H). 3.01-2.96 (m. 2H). 2.42 (s. 1H). 1.82 (s. 3H). 1.34 (d. J «= 6.9 Hz. 6H). Example 180:1.1.1-Trifluoro-2-(4-r22-piPeridin-1-yl-7-(3- The title compound was prepared using methods analogous to those described in Example 167. starting with 2.2.2-trifluoro-1-{4-{2-isopropy1-7-(3- trifluorornethyl-pyridin-2-y1)-6.7.8.9-tetrahydro-5H-pyrlmldo[4.5-dlazepin-4-yJarnino]- pheny)}-ethanone (prepared analogously to Example 1). MS (ESI): mass calcd. for CzaHMFeNaO. 580.24: m/z found. 581.3 IM+Hf. 1H NMR (CDC13): 8.40-8.38 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.63-7.60 (m. 2H). 7.54-7.51 (m. 2H). 6.97-6.92 (m. 1H). 6.42 (s. 1H). 3.80-3.71 (m. 4H). 3.66-3.56 (m. 4H). 3.12-3.06 (m. 2H). 2.90-2.84 (m. 2H). 2.37 (s. 1H). 1.81 (s. 3H). 1.70-1.59 (m. 6H). Example 181:2-Methyt-2-(4-a2-n-methylethyl)-7-(3-rtrir1uoromethyl2Dvridin-2-vf1- 6.7.8.9-tetrahvdro-5H-pyrimido[4.5-dlazepin-4-vl)amino)phenyl]propan-1-ol. To a solution o[ methyl 2-methyl-2-[4-({2-(1-methylethyl)-7-(3- (trifluoromethyl)pyridin-2-yI}-6.7.8.9-tetrahydro-5H-pyrimldo[4.5-d]azepin-4- yt}arhino)phenyT]propanoate (Example 174. 73 mg. 0.14 mmol) In THF Was added UAIH4 (14.2 mg. 0.374 mmol). A(ter stirring at rt for 4 h. the reaction mixture was quenched with satd. aq. Na2SC\+. The reaction mixture was then filtered through a plug o[ diatomaceous earth and concentrated. The crude residue was purified (FCC) to give the title compound (45.4 mg. 66%). MS (ESI): mass calcd. for C27H32F3N5O. 499.26; m/z found. 500.3 [M+H]+. 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.89 (dd. J =7.8. 1.8 Hz. 1H). 7.70-7.66 (m. 2H). 7.40-7.36 (m. 2H). 6.98-6.94 (m. 1H). 6.51 (s. 1H). 3.70-3.60 (m. 6H). 3.26-3.20 (m. 2H). 3.08-3.00 (m. 1H). 2.98-2.94 (m. 2H). 1.37 (s. 6H). 1.34 (d. 6.9 Hz. 6H). Example 182; 1-r4-((2-(1-Methylethyl]-7-(3-(trifluoromethyt)pyridin-2-yl]-(i 7.8Q- tetrahvdro-5H-Pvrimidor4.5- To a solution o[ 1-{4- 6.7.8.9-tetrahydix)-5H-pyrimido[4.5-d]azepin-4-yl}amino)phenyf]ethanone (Example 96; 37 mg. 0.079 mmol) in MeOH was added NaBH" (4.1 mg. 0.11 mmol). The mixture was stirred at rt for 4 h. then concentrated. The residua was redissolved in water and extracted with EtOAc. The organic layers were combined. dried. and concentrated. The crude residue was purified (FCC) to give the title compound (32.1 mg. 86%). MS (ESI): mass calcd. for C2sH2eF3N3O. 471.22; m/z found. 472.2 [M+HJ". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.67- 7.64 (m. 2H). 7.38-7.34 (m. 2H). 6.97-6.92 (m. 1H). 6.51 (s. 1H). 4.93-4.88 (m. 1H). 3.69-3.60 (m. 4H). 3.24-3.18 (m. 2H). 3.06-2.98 (m. 1H). 2.98-2.94 (m. 2H). 1.76 (d.J = 3.6Hz. 1H). 1.52 (d. J = 6.4 Hz. 3H). 1.31 (d. J = 6.9 Hz. 6H). Example 183: 2.2.2-Trir1uoro-1-(4-22-n-methylethylV7-(3-(trif1uoromethyl2Pvrldlh-2- yr)-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-vi)amino)phenvflethanol. : The title compound was prepared using methods analogous to those described in Example 172. starting with 2.2.2-trifluoro-H4-{2-isopropyl-7-(3- trifluoromethyl-pyridin-2-y1)-€.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepln-4-y1amino]- phenyf}-ethanone (prepared analogously to Example 1). MS (ESI): mass calcd. for C26H26F6N5O. 525.20; m/z found. 526.1 [M+H]". 1H NMR (CDCI3): 8.32-8.30 (m. 1H). 7.80 (dd. J = 7.8. 1.8 Hz. 1H). 7.69-7.65 (m. 2H). 7.40-7.36 (m. 2H). 6.90-6.86 (m. 1H). 6.51 (s. 1H). 4.97-4.91 (m. 1H). 3.59-3.56 (m. 2H). 3.54-3.51 (m. 2H). 3.17-3.12 (m. 2H). 3.00-2.92 (m. 1H). 2.90-2.87 (m. 2H). 2.66-2.60 (m. 1H). 1.26- 1.23 (m.6H). Example 184: 2-Methyl-2-r4-((2-(1-methylethy To a solution o[ methyl 2-methyl-2-[4-({2-(1-methyiethyl)-7-[3- (trifluoromethyI)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrlmJdo[4.5-d]azepin-4- yl}amino)phenyf]propanoate (Example 174; 63 mg. 0.12 mmol) in 1:2 THF:H2O (3 mL:6 mL) was added lithium hydroxide monohydrate (8.0 mg. 0.19 mmol). The mixture was heated at 60 °C for 5 h. The THF was removed under reduced pressure. and the resulting solution was acidified to neutral pH with 10% aq. HC1. The solution was then extracted with EtOAc. The organic layers were combined. dried. and concentrated. The crude residue was purified (FCC) to give the title compound (37 mg. 60%). MS (ESI): mass calcd. for C27Hx)F3N6O2. 513.24; m/z found. 514.1 [M+H]". 1H NMR (CD3OD): 8.45-8.42 (m. 1H). 8.01 (dd. J « 7.9. 1.7 Hz. 1H). 7.69-7.63 (m. 2H). 7.38-7.33 (m. 2H). 7.13-7.09 (m. 1H). 3.57-3.50 (m. 4H). 3.21-3.16 (m. 2H). 3.13-3.08 (m. 2H). 3.01-2.93 (m. 1H). 1.57 (s. 6H). 1.28 (d. J = 6.9 Hz. 6H). Example 185: 4-(C2-(1 -MethylethylV7-(3-(trrfluorornethyl)pyrtdin-2-yl1-6.7.8.9- tetrahvdro-5H-pyrlmldor4.5-d1azepin-4-yf)amino)benzolc add trlfluoroacetic acid salt. The title compound was prepared using methods analogous to those described In Example 184. starting with methyl 4-({2-(1-methylethyl)-7-[3- (trinuoromethylJpyridin2-yij-a.).a.Q-tetrahydro-SHHayrimldoK.S-dlazepin2- yl}amino)benzoate (Example 103) and purified using preparative HPLC. MS (ESI): mass calcd. for C24H2"F3N5O2. 471.19; m/z found. 472.1 [M+H]". 1H NMR (CD3OD): 8.46-8.43 (m. 1H). 8.07-8.01 (m. 3H). 7.76-7.72 (m. 2H). 7.16-7.12 (m. 1H). 3.68- 3.58 (m. 4H). 3.34-3.30 (m. 2H). 3.24-3.20 (m. 2H). 3.12-3.05 (m. 1H). 1.31 (d. J = 6.8 Hz. 6H). Example 186: 2-Methyt-2-r4-((2-piperidin-1-v1-7-(3-(trifluoromethyl)pyrk)in-2-vfl- 6.7.8.9-tetrahydro-5H-pyrlmido[4.5-d1azepin-4-v : The title compound was prepared using methods analogous to those described in Example 184. starting with o[ methyl 2-methyl-2-[4-({2-(1-methylethyl)- 7-[3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimtdo[4.5- C2flH33F3N6O2. 554.26; m/z found. 555.3 [M+H]". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.56-7.52 (m. 2H). 7.37-7.32 (rn. 2H). 6.95-6.90 (m. 1H). 6.35 (s. 1H). 3.76-3.70 (m. 4H). 3.62-3.54 (m. 4H). 3.07-3.03 (m. 2H). 2.85-2.80 (m. 2H). 1.68-1.56 (m. 12H). The following Examples 187-190 were prepared using methods analogous to those described in Example 17. substituting the appropriate amidines in Step A and amines in Step E. Example 187: 2-n-Methylethyl)-N-)5-methy hvdrochloride salt. MS (ESI): mass calcd. for C22H24F3N7. 443.20; m/z found. 444.1 [M+H]". "H NMR (CD3OD): 9.15-9.13 (m. 1H). 8.44-8.41 (m. 1H). 8.39-8.38 (m. 1H). 8.00 (dd. J = 7.8. 1.6 Hz. 1H). 7.15-7.09 (m. 1H). 3.66-3.53 (m. 4H). 3.39-3.33 (m. 2H). 3.27- 3.21 (m. 2H). 3.19-3.09 (m. 1H). 2.55 (s. 3H). 1.32 (d. J = 6.8 Hz. 6H). Example 188: N-(6-Chloro-5-2trifluoromethyl)pyridin-2-yl]-2-(1-methylethylV-7-(3- (trifl29ro[pettivi)pyridin-2-v hydrochloride salt. MS (ESI): mass calcd. for C23H2iCIF6N8. 530.14; m/z found. 531.2 [M+H]". 1H NMR (CDCI3): 8.57-8.52 (m. 1H). 8.47-8.44 (m. 1H). 8.18 (d. J = 8.6 Hz. 1H). 8.12 (s. 1H). 7.95-7.91 (m. 1H). 7.02-7.07 (m. 1H). 4.09-3.99 (m. 1H). 3.93-3.84 (m. 2H). 3.71-3.64 (m. 4H). 3.21-3.13 (m. 2H). 1.48 (d. J = 6.7 Hz. 6H). I Example 189: f2-lsopropyf-7-(3-trifluorQmethyl-pyridin-2-v1)-6.7.8.9-tetrahvdro-5H- pyrimido[4.5-dla2epir)-4-v11-(6-metfioxv-5-trifluoromethyl-Pviidin-2-v1Vamine hvdrochloride salt. MS (ESI): mass calcd. for C2H2NeO. 526.19; m/z found. 527.2 [M+H]1H NMR (CD3OD): 8.48-8.45 (m. 1H). 8.10-8.02 (m. 2H). 7.89-7.85 (m. 1H). 7.19- 7.14 (m. 1H). 4.06 (s. 3H). 3.71-3.66 (m. 2H). 3.64-3.59 (m. 2H). 3.44-3.39 (m. 2H). 3.34-3.28 (m. 2H). 3.24-3.17 (m. 1H). 1.41-1.39 (m. 6H). Example 190: 2-Pvridin-4-vi-7-[3-)trffluoromethyl)DVridlr)-2-vfl-N-(5- rtriflyiQromethyl)DVridin-2-\4]-6.7.8.9-tetrahvdro-5H-DVrimldo[4.5- MS (ESI): mass calcd. for CzjH2FeN). 531.16; m/z found. 532.5 [M+H]\ "H NMF" (MeOD): 8.96-8.92 (m. 2H). 8.92-8.89 (m. 2H). 8.66-8.63 (m. 1H). 8.44 (dd. J +4.8. 1.4 Hz. 1H). 8.30 (d. J + 8.8 Hz. 1H). 8.12 (dd. J = 9.0. 2.3 Hz. 1H). 8.02 (dd. J " 7.9. 1.8 Hz. 1H). 7.15-7.10 (m. 1H). 3.64-3.55 (m. 4H). 3.48-3.40 (m. 2H). 3.30- 3.27 (m. 2H). Examples 191-192 were prepared using methods analogous to those described in Example 17. substituting the appropriate amidines in Step A. amines in Step E. and substituting Pd2(dba)3 (5 mol %) for Pd(OAc)2 and 1.2.3.4.5- pentaphenyl-1'-(di-tbutylphosphlno)ferrocene (Qphos. 10 mol %) for DCPB. Example 191: f2-lsoproDvt-7-(3-trifluoromethyl-pyridin-2-vl)-6.7.8.9-tetrahvdro-5H- pyrimldor4.5-d1azepin-4-yl]-(5-trifluoromethyl-pyrazln-2-vl)-amine. MS (ESI): mass calcd. for C22H21F8N7. 497.18; m/z found. 498.2 [M+HJ". 1H NMR (CDCI3): 10.02-10.01 (m. 1H). 8.56-8.55 (m. 1H). 8.40-8.38 (m. 1H). 7.88 (dd. J « 7.8. 1.8 Hz. 1H). 7.56 (s. 1H). 7.01-6.96 (m. 1H). 3.67-3.55 (m. 4H). 3.31-3.24 (m. 2H). 3.16-3.04 (m. 3H). 1.36 (d. J = 6.9 Hz. 6H). Example 192: r2-Piperidin-1-yl-7- 5H-Pvrimido[4.5-d1azepin-4-yl]-25-trifluoromethyl-pyra2in-2-vl)-amlne. ; MS (ESI): mass calcd. for C2Ha-vFeNa. 538.20; m/z found. 539.2 [M+H]+. 1H NMR (CDCI3): 9.76-9.73 (m. 1H). 8.56-8.54 (m. 1H). 8.42-8.40 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.43 (s. 1H). 6.99-6.95 (m. 1H). 3.81-3.75 (m. 4H). 3.62-3.53 (m. 4H). 3.15-3.09 (m. 2H). 2.98-2.92 (m. 2H). 1.75-1.58 (m. 6H). i The following Examples 193-197 were prepared using methods analogous to thpse described in Example 39. substituting the appropriate carboximidamidines . in Step A and amines in Step C. Example 193: 2-(4-Methylpiperazin-1 -yl]-7-[3-(trifluoromethyl]pyridin-2-yl]-N-(5- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d]azepin-4-amine. j MS (ESI): mass calcd. for C25H26FSN8. 552.22; m/z found. 553.2 [M+H]+. 1H NMR (CDCI3): 8.50-8.48 (m. 1H). 8.41-8.38 (m. 2H). 7.90-7.86 (m. 2H). 7.44 (s. 1H).i6.97-6.94 (m. 1H). 3.86-3.79 (m. 4H). 3.58-3.52 (m. 4H). 3.13-3.08 (m. 2H). 2.95|2.91 (m. 2H). 2.51-2.47 (m. 4H). 2.35 (s. 3H). Example 194: 2-Azepan-1-yl-7-(3-(trifluoromethyl]pyridin-2-yl]-N-r5- (trifluoromethyl)pyridin-2-vll-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin'4-amine. MS (ESI): mass calcd. for C26H27F6N7. 551.22; m/z found. 552.2 [M+H]". 1H NMR (CDCI3): 8.80 (d. J = 8.8 Hz. 1H). 8.49-8.48 (m. 1H). 8.40-8.38 (m. 1H). 7.88- 7.84 (m. 2H). 7.44 (s. 1H). 6.96-6.92 (m. 1H). 3.81-3.72 (m. 4H). 3.59-3.52 (m. 4H). 3.12-3.08 (m. 2H). 2.94-2.90 (m. 2H). 1.84-1.78 (m. 4H). 1.59-1.55 (m. 4H). Example 195: N242-(Dimethylamino)ethyl]-N2-methyl-7-[3-(trifluoromethyl)Dvridin-2- vl]-N4-(5-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-ovrimidor4.5-dlazepine- 2.4-diamine. MS (ESI): mass calcd. for C25H28FBN8l 554.23; m/z found. 555.2 [M+H]". 1H NMR (CDCI3): 8.56 (d. J = 8.9 Hz. 1H). 8.49-8.48 (m. 1H). 8.40-8.38 (m. 1H). 7.87 (dd.;J = 7.8.1.8 Hz. 1H). 7.84-7.82 (m. 1H). 7.45 (s. 1H). 6.96-6.94 (m. 1H). 3.79- 3.73. (m. 2H). 3.57-3.52 (m. 4H). 3.19 (s. 3H). 3.11-3.09 (m. 2H). 2.93-2.90 (m. 2H). 2.55-2.50 (m. 2H). 2.30 (s. 6H). Example 196: N2-Methyl-N2-(2-(methyloxvtethyl]-743-(trifluorornethyl]pyridin-2-vll- N4-r5-(trifluoromethyl')pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-cnazepin9- 2.4-diamine. MS (ESI): mass calcd. for C24H25F6N7O. 541.20; m/z found. 542.1 [M+H]1H NMR (CDCl3): 8.55 (d. J = 8.8 Hz. 1H). 8.49-8.48 (m. 1H). 8.40-8.39 (m. 1H). 7.88-7.84 (m. 2H). 7.46 (s. 1H). 6.97-6.94 (m. 1H). 3.84-3.80 (m. 2H). 3.64-3.61 (m. 2H). 3.56-3.53 (m. 4H). 3.38 (s. 3H). 3.23 (s. 3H). 3.11-3.09 (m. 2H). 2.93-2.91 (m. 2H). Example 197: 2-Azetidin-1 -yl-7-[3-(trifIuoronnethyl]pyridin-2-vll-N-r5- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazeDln-4-amine trifluoroacetic acid salt. I | MS (ESI): mass calcd. for C23H2iF6N7. 509.18; m/z found. 510.5 IM+Hf. 1H NMR (MeOD): 8.69 (s. 1H). 8.47-8.42 (m. 1H). 8.41 (d. J = 8.8 Hz. 1H). 8.14 (dd. J = 8.9. 2.3 Hz. 1H). 8.02 (dd. J = 7.8. 1.7 Hz. 1H). 7.16-7.11 (m. 1H). 4.37-4.32 (m. 4H).; 3.63-3.58 (m. 2H). 3.55-3.51 (m. 2H). 3.29-3.24 (m. 2H). 3.15-3.10 (m. 2H). 2.57J-2.48 (m. 2H). The following Examples 198-201 were prepared using reduction methods analogous to those described in US Pat. Appl. Publ. 2000)006150343. Example 198: N-(2-n-MethylethylV7-[3-(trifluoromethyl]pyridin-2-yl]-6.7.8.9- tetrahvdro-5H-pyrimidor4.52d1azepin-4-vl}benzene-1.4-diamlne trifluoroacetic acid salt.j 1 The title compound was prepared from 2-(1-methylethyl)-N-(4-nitrophenyl)- 7-[3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4- I amine (Example 136). MS (ESI): mass calcd. for C23H25F3N6. 442.21; m/z found. 443.1 [M+H]". 1H NMR (CD3OD): 8.38-8.36 (m. 1H). 7.97-7.94 (m. 1H). 7.59-7.53 (m. 2H). 7.27-7.19 (m. 2H). 7.10-7.06 (m. 1H). 3.60-3.51 (m. 4H). 3.27-3.24 (m. 2H).;3.14-3.11 (m. 2H). 3.03-2.96 (m. 1H). 1.20 (d. J = 6.8 Hz. 6H). Example 199; 4-H.1-DimethylethylVN1-(2-(1-methylethylV7-[3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazeDin-4- vl)benzene-1.3-diamine. The title compound was prepared from N-[4-(1.1-dimethylethyl)-3- nitroiahenylJ22I-methylethylH-P-2rifluoromethyOpyridin2-yll-ej.S.g-tetrahydro- 5H-piyrimido[4.5-d]azepin-4-amine (Example 143).. MS (ESI): mass calcd. for C27H33F3N6. 498.27; m/z found. 499.2 [M+H]+. ""H NMR (CDCI3): 8.31-8.29 (m. 1H). 7.8027.78 (m. 1H). 7.21 (d. J = 2.3 Hz. 1H). 7.10 (d. J = 8.5 Hz. 1H). 6.87-6.84 (m. 1H).i6.82 (dd. J = 8.5. 2[3 Hz. 1H). 6.31 (s. 1H). 3.82-3.70 (br s. 2H). 3.59-3.51 (m. 4H).!3.16-3.10 (m. 2H). 3.02-2.91 (m. 1H). 2.87-2.82 (m. 2H). 1.35 (s. 9H). 1.26 (d. J = 6.9 Hz. 6H). Example 200: 4-( 1.1-Dlmethylethyl1-N1-r2-piperidin-1-yl-7-[3- (trifluorometriyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4- vl)benzene-1.3-diamine. I The title compound was prepared from N-[4-(1.1-dimethylethyl)-3- nitrophenyl]-2-piperidiri-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H- pyrirnido[4.5-d]azepin-4-amine (Example 159). MS (ESI): mass calcd. for C29H36F3N7. 539.30; m/z found. 540.3 [M+H]+. 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.87(dd. J = 7.8. 1.8 Hz. 1H). 7.16 (d. J = 8.5 Hz. 1H). 7.08 (d. J = 2.3 Hz. 1H). 6.95:6.91 (m. 1H). 6.85 (dd. J = 2.3. 8.5 Hz. 1H). 6.24 (s. 1H). 3.83-3.74 (m. 6H). 3.63T3.56 (m. 4H). 3.10-3.05 (m. 2H). 2.85-2.80 (m. 2H). 1.70-1.59 (m. 6H). 1.43 (s. 9H). Example 201: 7-(5-Amino-3-(trifluoromethyl)pyridin-2-yl]-N-(4-(1.1- dime|hvlethy[2phenyl]-2-(1-methylethyl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5- diazepln-4-amine. 1 : The title compound was prepared from N-[4-(1.1-dimethylethyl)phenyl]-2-(1- methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-amine (Example 290). MS (ESI): mass calcd. for C27H33F3N6. 498.27; m/z found. 499.5 [M+H]+. 1H NMR (CDCI3): 7.99-7.95 (m. 1H). 7.63-7f.56 (m. 2H). 7.38-7.32 (m. 2H). 7.26-7.24 (m. 1H). 6.48 (s. 1H). 3.75-3.68 (m. 2H0. 3.25-3.18 (m. 4H). 3.19-3.12 (m. 2H). 3.08-2.97 (m. 1H). 2.91-2.84 (m. 2H). 1L61-1.48 (m. 9H). 1.35-1.30 (m. 6H). The following Examples 202-206 were prepared using methods analogous to those described in Example 52. substituting the appropriate amidines in Step A and amines in Step C. Example 202: N44-(1.1-DlmBthylethyl2Dhenvl1-22methylsulfanyl].7-[3. (trifluoromethyl)ovr1d)n-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidot4.S-d1azepin-4.amine. MS (ESI): mass calcd. for C2H2NiS. 487.20; m/z found. 488.1 [M+HJ". 1H NMR (CDCb): 8.40-8.37 (m. 1H). 7.88-7.86 (m. 1H). 7.51-7.47 (m. 2H). 7.36- 7.34 (m. 2H). 6.97-6.93 (m. 1H). 6.48 (s. 1H). 3.65-3.62 (m. 2H). 3.60-3.57 (m. 2H). 3.18-3.14 (m. 2H). 2.94-2.90 (m. 2H). 2.52 (s. 3H). 1.33 (s. 9H). Example 203: N-r2-Chloro-4-)trifluoromethyl)Dhenyl]-2-(methyl3ulfanv1V-7-(3- (trifluoromethyl)pyridin-2-vll-6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1a2epln-4-amine. MS (ESI): mass calcd. for CjaHieCIFoNsS. 533.09; m/z found. 534.1 [M+H]". 1H NMR (DMSO): 9.48 (s. 1H). 9.16-9.14 (m. 1H). 8.74-8.71 (m. 1H). 8.60 (d. J = 2.0 Hz. 1H). 8.48 (d. J = 8.5 Hz. 1H)..8.41-8.39 (m. 1H). 7.81-7.78 (m. 1H).4.20- 4.17 (m. 4H). 3.78-3.72 (m. 4H). 2.91 (s. 3H). Example 204: 2-(Methyi8utfanvl)-N-r2-methyl-4-rtrifluoromethyltohenyl]-7-[3- (trifluoromethyl)pyrldin-2-vl1-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-amine. : MS (ESI): mass calcd. for C23H2iF6N5S. 513.14; mfe found. 514 [M+Hf. 1H NMR (CDCI3): 8.38 (dd. J =4.7. 1.5 Hz. 1H). 8.08 (d. J = 8.6 Hz. 1H). 7.88 (dd. J = 7.8. |i.8 Hz. 1H). 7.49-7.44 (m. 2H). 6.99-6.92 (m. 1H). 6.42 (bs. 1H). 3.68-3.62 (m. 2H).i3.62-3.54 (m. 2H). 3.21-3.15 (m. 2H). 2.98-2.92 (m. 2H). 2.45 (s. 3H). 2.36 (s. 3H).. Example 205: 2-MethylsulfanvlVN-( 1-methyl-1.2.3.4-tetfBhvdroouinolin-7-vl)-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimldor4t5-d1azepin-4-amine. ; MS (ESI): mass calcd. for C25H27F3N6S. 500.20; m/z found. 501 [M+H]+. 1H NMR(CDCI3): 8.38(dd. J = 4.7. 1.5 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 6.97- 6.91 (m. 1H). 6.89 (d. J = 7.9 Hz. 1H). 6.78 (d. J = 2.0 Hz. 1H). 6.74 (dd. J = 7.9. 2.1 Hz. 1H)t 6.41 (bs. 1H). 3.66-3.61 (m. 2H). 3.61-3.55 (m. 2H). 3.23 (t. J = 5.6 Hz. 2H). 3.19-3.11 (m. 2H). 2.93-2.83 (m. 2H). 2.89 (s. 3H). 2.73 (t. J = 6.4 Hz. 2H). 2.52 (s. 3H). 2.03-1.93 (m. 2H). Example 206: 2-(MethylsulfanvlV-7-(3-rtrifluoromethyl)pyridin-2-vl|-N-n .4.4- trimethyl-1.2.3.4-tetrahvdroauinolin-7-yl]-6.7.8.9-tetrahvdro-5H-pyrirnidor4.5- diazepin-4-amine. MS (ESI): mass calcd. for CzrHaiFaNaS. 528.23; m/z found. 529 [M+H]+. 1H NMR (CDCI3): 8.38 (dd. J = 4.7.1.5 Hz. 1H). 7.86 (dd. J == 7.8.1.8 Hz. 1H). 7.12 (d. J = 82 Hz. 1H). 6.93 (dd. J = 7.4. 4.7 Hz. 1H). 6.84-6.78 (m. 2H). 6.41 (bs. 1H). 3.66-3.61 (m. 2H). 3.61-3.55 (m. 2H). 3.27-3.21 (m. 2H). 3.17-3.11 (m. 2H). 2.93- 2.86! (m. 2H). 2.91 (s. 3H). 2.53 (s. 3H). 1.78-1.72 (m. 2H). 1.28 (s. 6H). Examples 207-211 syl]thesized in a manner similar to Example 53 substituting the appropriate amines in Step C o[ Example 52. Example 207: N-(4-(1.1-Dimethylethyltohenyl]-2-(methylsulfonyl]-7-F3- (trifluoromethyl)pyridin-2-vH-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazepin-4-amine. i The title compound was prepared starting with N-[4-(1.1 - dimethylethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahydrb-5H-pyrimido[4.5-d]azepin-4-amine (Example 202). MS (ESI): mass calcd.. for C25H28F3N5O2S. 519.19; m/z found. 520.2 [M+H]+. 1H NMR (CDCI3): 8.40- 8.38 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.49-7.45 (m. 2H). 7.41-7.38 (m. 2H). 7.00-6.96 (m. 1H). 6.77 (s. 1H). 3.72-3.67 (m. 2H). 3.64-3.59 (rri. 2H). 3.36-3.31 (m. 2\\). 3.25 (s. 3H). 3.07-3.02 (m. 2H). 1.33 (s. 9H). Example 208: 2-1 Methylsulfonvl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1.4.4- trimethyl-1.2.3.4-tetrahvdroquinolin-7-vl)-6.7.8.9-tetrahvdro-5H-pyrim?dor4.5- diazepin-4-amt'ne. i The title compound was prepared starting with 2-(methylsulfanyl)-7-[3- (triflupromethyl)pyridin-2-yl]-N-(1.4.4-trimethyl-1.2.3.4-tetrahydroquinolin-7-yl)- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amirie (Example 206). MS (ESI): mass calcd. for C27H31F3N6O2S. 560.22; m/z found. 561 [M+H]+. 1H NMR (CDCI3): 8.57 (d. J = 2.2 Hz. 0.6 H). 8.51 (d. J = 2.0 Hz. 0.4H). 8.43-8.37 (m. 1H). 8.07-7.94 (m. jlH). 7.91-7.85 (m. 1H). 7.30-7.20 (m. 1H). 7.02-6.95 (m. 1H). 5.75-5.40 (m. 1H)j 3.93-3.78 (m. 2H). 3.68-3.47 (m. 7H). 3.44-3.21 (m. 4H). 2.90 (s. 1.5 H). 2.87 (s. 1.5H). 2.05-1.90 (m. 2H). 1.39 (s. 3H). 1.37 (s. 1.5H). 1.35 (s. 1.5H). Example 209; 2-(Methy ; The title compound was prepared starting with 2-(methylsulfanyl)-N-[2- methyl-4-(trifiuoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6.7t8.9- tetrdhydro-5H-pyrimido[4.5-d]azepin-4-amine (Example 204). MS (ESI): mass calcd. for CzaHaiFeNsOaS. 545.13; m/z found. 546 [M+H]+. 1H NMR (CDCI3): 8.38 (dd. J = 4.6.1.4 Hz. 1H). 7.96 (d. J = 8.2 Hz. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.55-7.48 (m. 2H). 7.00 (dd. J = 7.4. 4.7 Hz. 1H). 6.71 (bs. 1H). 3.74-3.67 (m. 2H). 3.66-3.59 (m. 2H). 3.38-3.32 (m. 2H). 3.20 (s. 3H). 3.11-3.05 (m. 2H). 2.37 (s. 3H). Example 210: 2-n-Methylethyl)-N-r4-(methylsulfonyl]phenyll-7-[3- (trifluoromethyl]pyrldin-2-vll-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazepin-4-amine. . The title compound was prepared starting with 2-(1-methyIethyl)-N-[4- (mefhylsulfanyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6.7.8I9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-amine (Example 135). MS (ESI): mass calcd. for C24H26F3N5O2S. 505.18; m/z found. 506.4 [M+H]+. 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.92-7.86 (m. 5H). 6.99-6.94 (m. 1H). 6.77 (s. 1H). 3.69-3.57 (m. 4H). 3.28- 3.21 (m. 2H). 3.11-3.04 (m. 4H). 3.02-2.99 (m. 2H). 1.33 (d. J = 6.9 Hz. 6H). Example 211: Methyl 5-chloro-6-(2-(methyisutfonv2-4-24- (trifl2o[omethyl)phenyl]arnlnoV5.6.8.9-tetrahvdro-7H-DvrimkJo[4.g- The title compound was prepared starting from methyl 5-chloro-6-[2- (methylsulfanyl)-4-{[4-(trifluoromethyl)phenyllamino}-5.6.8.9-tetrahydro-7H- pyrimido[4.5-d]azepin-7-yl]pyridine-3-carboxy1ate (Example 303). MS (ESI): mass calcd. for C23H2.CIF3N5O4S. 555.10; m/z found. 556.1 [M+H]\ 1H NMR (CD3OD): 8.50 (d. J = 2.00 Hz. 1H). 7.96 (d. J = 2.00 Hz. 1H). 7.54 (d. J = 8.55 Hz. 2H). 7.44 (d. J = 8.64 Hz. 2H). 6.93 (s. 1H). 3.86-3.71 (m. 4H). 3.70 (s. 3H). 3.26-3.11 (m. 2H). 3.02-2.95 (m. 2H). The following Examples 212-277 wore prepared using methods analogous to those described in Example 55. substituting the appropriate amines. Example 212: 2-M .1-Dioxido-1.2-thlazinan-2-v trifluoroacetic acid salt. MS (ESI): mass calcd. for C2H2FeNsOzS. 586.16; mVz found. 587.5 [M+H)+. "H NMR (CDCI3): 9.89-9.69 (m. 1H). 8.49-8.34 (m. 1H). 7.92 (d. J + 7.0 Hz. 1H). 7.68-7.54 (m. 4H). 7.05 (dd. J = 7.6. 4.7 Hz. 1H). 4.15-4.08 (m. 2H). 3.68-3.52 (m. 4H). 3.43-3.34 (m. 2H). 3.28-3.08 (m. 4H). 2.39-2.23 (m. 2H). 1.82-1.65 (m. 2H). Example 213: N'2-dVlethyloxvlethyli-N2-arifluoromethyi2phenyl]-?2. (trtfl0orornethyl)pyridin-2-vf1-6.7.8.9-tetrahvdro-5H-Dvrirnidor4.5-d?a2epln2-2.4- diamine trifluoroacetlc acid salt. MS (ESI): mass calcd. for Cz2FgNsO. 526.19; m/z found. 527.5 [M+HJ". 1H NMR (CD3OD): 8.45 (dd. J = 4.7. 1.4 Hz. 1H). 8.02 (dd. J + 7.8. 1.8 Hz. 1H). 7.79 (d. J = 8.5 Hz. 2H). 7.69 (d. J = 8.6 Hz. 2H). 7.14 (dd. J = 7.7. 4.8 Hz. 1H). 3.65-3.59 (m. 2H). 3.58-3.47 (m. 6H). 3.33-3.31 (m. 3H). 3.20-3.15 (m. 2H). 3.11- 3.07 (m. 2H). Example 214: 2-(3-(Methyloxv)plperidin-1-v trifluoroacetic agicj salt. MS (ESI): mass calcd. for C27H28F6NBO. 566.22; m/z found. 567.6 [M+HJ". 1H NMR (CD3OD): 8.47-8.43 (m. 1H). 8.03 (dd. J •= 7.8. 1.7 Hz. 1H). 7.71 (s. 4H). 7.17-7.10 (m. 1H). 3.91-3.67 (m. 3H). 3.65-3.50 (m. 5H). 3.43-3.36 (m. 1H). 3.29- 3.26 (m. 2H). 3.20 (s. 3H). 3.12-3.07 (m. 2H). 1.95-1.73 (m. 3H). 1.61-1.50 (m. 1H). Example 215: 2-(f2S)-2-rfMethyloxv)methylipyrrolidin-1 -vll-N-(4- (triflUoromethyl]phenyl]-7-[3-(trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdrn-RH- Pvrirhidor4.5-dlazepin-4-amine trifluoroacetic acid salt. . MS (ESI): mass calcd. for C22sFeNeO. 566.22; m/z found. 567.6 tM+HJ+. 1H NMR (CD3OD): 8.46-8.43 (m. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.80 (d. J = 8.5 Hz. 2H). 7.69 (d. J = 8.6 Hz. 2H). 7.14 (dd. J = 7.8.4.8 Hz. 1H). 4.34-4.25 (m. 1H).j3.66-3.37 (m. 9H). 3.29-3.20 (m. 4H). 3.14-3.07 (m. 2H). 2.23-1.90 (m. 4H). Example 216: N2-(Furan-2-vlmethyl]-N2-methyl-N4-(4-(trifluoromethyl]phenyl]-7-[3- (trifliioromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin"e-2.4- diamins trifluoroacetic acid salt. : MS (ESI): mass calcd. for C27H24F6N6O. 562.19; m/z found. 563.5 [M+H1+. 1H NMR (CD3OD): 8.46-8.43 (m. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.74 (d. J = 8.6 Hz. 2H). 7.66 (d. J = 8.7 Hz. 2H). 7.50-7.46 (m. 1H). 7..14 (dd. J = 7.8.4.8 Hz. 1H). J6.37 (dd. J = 3.2. 1.9 Hz. 1H). 6.17 (d. J = 2.5 Hz. 1H). 4.76 (s. 2H). 3.65-3.58 (m. 2H). 3.58-3.53 (m. 2H). 3.34-3.30 (m. 2H). 3.21 (s. 3H). 3.14-3.09 (m. 2H). Example 217: 2-Azetidin-1-yl-7-[3-(trifluoromethyl]pyridin-2-yl]-N-r6- (trifluoromethyl]pyridin-3-yl]-6.7.8.9-tetrahvdro-5H-Pvrimidor4.5-d1azepin-4-amine. MS (ESI): mass calcd. for C2HaiFoNz. 509.18; m/z found. 510.1 [M+HJ". "H NMR 1H). 7.10 (dd. J = 7.6. 4.7 Hz. 1H). 3.97 (t. J = 7.4 Hz. 4H). 3.45-3.38 (m. 4H). 3.00-2.96 (m. 4H). 2.27-2.22 (m. 2H). Example 218: N2.N2-Dimethyl-7-(3-(trifluoromethyhDVridin-2-v11-)M4-)r6- (trifluoromethyl)pyridin-3-yl]methyH-6.7.8.9-t8trahvdro-5H-pyrimidor4.5-d1azeplne- 2.4-dlamine trifluoroacetic acid salt. MS (ESI): mass calcd. for C23H23F6N7. 511.19; m/z found. 512.4 [M+H]". 1H NMR (MeOD): 8.69 (d. J + 1.6 Hz. 1H). 8.40 (dd. J = 4.8. 1.5 Hz. 1H). 8.02-7.96 (m. 2H). 7.77 (d. J = 8.0 Hz. 1H). 7.10 (dd. J = 7.5. 4.7 Hz. 1H). 4.80 (s. 2H). 3.60- 3.55 (m. 2H). 3.54-3.49 (m. 2H). 3.24-3.20 (m. 2H). 3.13 (s. 6H). 2.96-2.93 (m. 2H). Example 219: N2-(2-2Dimethylamlno)ethyl1-N2-mettiv1-N4-r4-rtnfluoromethyl)ohenv11- 7-(3-(trffluo[omethyl)pyiidirv2-v11-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-d1azepine-2.4- diarpine trifluoroacetic acid salt. j MS (ESI): mass calcd. for C26H29F6N7. 553.24; m/z found. 554.2 [M+H]+. 1H NM(t (MeOD): 8.48-8.45 (m. 1H). 8.04 (dd. J = 7.9. 1.7 Hz. 1H). 7.78 (d. J = 8.6 Hz. 2H). 7.67 (d. J = 8.4 Hz. 2H). 7.19-7.12 (m. 1H). 3.93 (t. J = 6.1 Hz. 2H). 3.63- 3.53 (m. 2H). 3.58-3.53 (m. 2H). 3.36-3.31 (m. 2H). 3.29-3.24 (m. 2H). 3.23 (s. 3H). 3.12-3.08 (m. 2H). 2.57 (s. 6H). Example 220: 2-(4-MethylDiperazin-1-vl)-7-[3-(trifluoromethyhDvridin-2-v)]-N-(6- (trif)il)oromethylbvridin-3-yl]-6.7.8.9-tetrahvdro-5H-Dvrimidor4.5-d1azeDin-4-amine. I MS (ESI): mass calcd. for C25H26F6N8. 552.22; m/z found. 553.5 [M+HJ". 1H NMF2 (CDCI3): 8.86 (d. J = 2.4 Hz. 1H). 8.40-8.37 (m. 1H). 8.14 (dd. J = 8.4. 2.3 Hz. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.65 (d. J = 8.6 Hz. 1H). 6.98-6.93 (m. 1H). 6.55 (s. 1H). 3.82-3.75 (m. 4H). 3.63-3.53 (m. 4H). 3.14-3.05 (m. 2H). 2.95-2.87 (rh. 2H). 2.50-J2.43 (m. 4H). 2.34 (s. 3H). Example 221: N-(3-Chloro-4-(trifluoronnethyl]phenyl]-2-(r4-methylpiperazin-1-vl)-7- f3-(trifluoromethy0pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d]azepm-4- amine. MS (ESI): mass calcd. for C26H26CIF6N7. 585.18; m/z found. 586.5 [M+H]". "H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.5 Hz. 1H). 8.01 (d. J = 1.9 Hz. 1H). 7.87 (dd.- J = 7.8. 1.8 Hz. 1H). 7.59 (d. J = 8.7 Hz. 1H). 7.37-7.31 (m. 1H). 6.95 (dd. J = 7.5. 4.9 Hz. 1H). 6.53 (s. 1H). 3.84-3.77 (m. 4H). 3.62-3.52 (m. 4H). 3.13-3.03 (m. 2H). 2.90-2.83 (m. 2H). 2.51-2.46 (m. 4H). 2.35 (s. 3H). Example 222: 2-Azepan-1-yl-N-r4-(trifluoromethyl]Dhenyl]-7-[3- (trifluDromethyl)pyriclin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-amine. MS (ESI): mass calcd. for C27H26F6Ne. 550.23; m/z found. 551.5 [M+H]". 1H NMR (CDCI3): 8.39-8.36 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.72 (d. J = 8.5 Hz. 2H). 7.54 (d. J = 8.6 Hz. 2H). 6.93 (dd. J = 7.5. 4.9 Hz. 1H). 6.50 (s. 1H). 3.78-3.67 (m. 4;H). 3.63-3.53 (m. 4H). 3.12-3.01 (m. 2H). 2.89-2.83 (m. 2H). 1.83-1.74 (m. 4H).:i.65-1.47(m.4H). Example 223: 2-Azepan-1-yl-7-[3-(trifluoromethyl]pyridin-2-vll-N-(6- (trifluoromethyl)pyridin-3-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d]azeDin-4-amine. MS (ESI): mass calcd. for CzeHzyFeNy. 551.22; m/z found". 552.5 [M+H]+. 1H NMR (CDCI3): 8.78 (d. J = 2.5 Hz. 1H). 8.40-8.34 (m. 2H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.62 (d. J = 8.7 Hz. 1H). 6.97-6.91 (m. 1H). 6.54 (s. 1H). 3.76-3.68 (m. 4H). 3.6323.52 (m. 4H). 3.13-3.05 (m. 2H). 2.93-2.87 (m. 1H). 1.83-1.72 (m. 4H). 1.60- 1.49 [(m. 4H) coincidental with water peak]. Example 224: 2-Azepan-1 -yl-N-[3-chloro-4-(trifluqromethyr)phenyl]-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazepin-4-amine. MS (ESI): mass calcd. for C27H27CIFBN6. 584.19; m/z found. 585.5 [M+H]". 1H NMR (CDCI3): 8.39-8.36 (m. 1H). 8.25 (d. J = 1.9 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.56 (d. J = 8.7 Hz. 1H). 7.32-7.28 (m. 1H). 6.96-6.91 (m. 1H). 6.52 (s. 1H). 3(80-3.68 (m. 4H). 3.62-3.52 (m. 4H). 3.12-3.03 (m. 2H). 2.89-2.83 (m. 2H). 1.86-1176 (m. 4H). 1.61-1.50 [(m. 4H) coincidental with water peak]. Example 225: N2-r2-(Dimethylamino)ethyll-N2-methyl-7-[3-(trifluoromethyl)Dvridin-2- vlVN4-r6-(trifluoromethyl)pyridin-3-vl]-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepine- 2.4-di4mine. MS (ESI): mass calcd. for Czs2aFeNs. 554.23; m/z found. 555.5 [M+HJ". 1H NMR:(CDCI3): 8.77 (s. 1H). 8.40-8.37 (m. 1H). 8.36-8.32 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.61 (d. J = 8.6 Hz. 1H). 6.98-6.92 (m. 1H). 6.54 (s. 1H). 3.78-3.67 (m. 2H). 3.63-3.52 (m. 4H). 3.15 (s. 3H). 3.12-3.06 (m. 2H). 2.94-2.87 (m. 2H). 2.54- 2.46 (m. 2H). 2.28 (s. 6H). Example 226: N4-[3-Chloro-4-(trifluoroinethy[2phenyl]-N2-r2-(dimethylaminotethyl]- N2-methyl-7-(3-(trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5- d1azepine-2.4-diamine. '=. MS (ESI): mass calcd. for CzeHaaCIFeNr. 587.20; m/z found. 588.5 [M+H]+. 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.4 Hz. 1H). 8.02 (s. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. -JH). 7.57 (d. J = 8.7 Hz. 1H). 7.43 (d. J = 8.6 Hz. 1H). 6.94 (dd. J = 7.4. 4.9 Hz. 1H). 6.53 Example 227: N4-r(3.4-Dichtorophenyl)methyl]-N2-(2-(dimethylamino)ethyl]- N2- methyl-7-[3-(trlfluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-Pvrinnido[4.5- dlazepine-2.4-diam?ne trifluoroacetlc acid salt. : MS (ESI): mass calcd. for C26H30CI2F3N7. 567.19; m/z found. 568.5 [M+H]+. 1H NMR (MeOD): 8.42 (dd. J = 4.7. 1.4 Hz. 1H). 8.01 (dd. J = 7.8. 1.8 Hz. 1H). 7.51 (d. J =f 8.3 Hz. 1H). 7.47-7.44 (m. 1H). 7.22 (dd. J = 8.3. 2.1 Hz. 1H). 7.14-7.08 (m. 1H). 42.73 (s. 2H). 4.00-3.93 (m. 2H). 3.62-3.58 (m. 2H). 3.57-3.52 (m. 2H). 3.29- 3.22 (m. 2H). 3.21 (s. 3H). 3.01-2.96 (m. 2H). 2.78 (s. 6H). Example 228: N2-Methyl-N2-r2-(methyloxv)ethyl]-7-|'3-(trlfluoromethyl)pyridin-2-yl]- N4-r6-(trifluoromethyl]pyridin-3-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azeplne- 2.4-diamine trifluoroacetic acid salt. MS (ESI): mass calcd. for CatHfesFeNrO. 641.20; m/z found. 542.5 [M+Hf. 1H UMR (MeOD): 8.47-8.44 (m. 1H). 8.26 (dd. J = 8.5. 2.2 Hz. 1H). 8.03 (dd. J = 7.8. |1.7 Hz. 1H). 7.86 (d. J = 8.6 Hz. 1H). 7.18-7.12 (m. 1H). 3.79 (t. J = 5.1 Hz. 2H). 3.65-3.53 (m. 6H). 3.32 (s. 3H). 3.32-3.29 (m. 2H). 3.23 (s. 3H). 3.15-3.11 (m. 2H). Example 229: N4-[3-Chloro-4-(trifluoromethyl)phenyll-N2-methyl-N2-(2- (meth vloxv)ethyl]-7-(3-(trifluorometh vl )pyrid in-2-vfl-6.7.8.9-tetrah vd ro-5H- pyrimidor4.5-d1azepine-2.4-diamine trifluoroacetic acid salt. MS (ESI): mass calcd. for CasHasCIFeNeO. 574.17; m/z found. 575.5 [M+H]". 1H NMR (MeOD): 8.45 3.86-3.79 (m. 2H). 3.65-3.58 (m. 4H). 3.56-3.51 (m. 2H). 3.34 (s. 3H). 3.33-3.30 (m. 2|H). 3.25 (s. 3H). 3.12-3.07 (m. 2H). Example 230: N4-rf3.4-Dichlorophenyl)rnethyl1-N2-rnethyl-N2-r2-2methyloxv)ethyl]-7- [3-rtrifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dTazepine-2.4- diamine trifluoroacetic acid salt. MS (ESI): mass calcd. for Cjjs2TCbFsNeO. 554.16; m/z found. 554.2 [M+H]\ 1H NMR (MeOD): 8.42-8.39 (m. 1H). 8.00 (dd. J = 7.8. 1.7 Hz. 1H). 7.46 (d. J = 8.3 Hz. 1H). 7.44-7.42 (m. 1H). 7.21 (dd. J = 8.3. 2.0 Hz. 1H). 7.12-7.07 (m. 1H). 4.62 (3. 2H). 3.70 (t. J = 5.1 Hz. 2H). 3.61-3.57 (m. 2H). 3.56-3.50 (m. 2H). 3.38-3.32 (m. 2H). 3.25 (s. 3H). 3.24-3.19 (m. 2H). 3.15 (s. 3H). 2.98-2.93 (m. 2H). Example 231: 2-Azetidin-1-v1-N-(3-chloro-4-(trifkiOPomethyl)phenvfl-7-(3- (trffluoromethyl)Dvr MS (ESI): mass calcd. for C2iCIFM. 542.14; m/z found. 543.5 {M+H]1H NMR (MeOD): 8.46-8.43 (m. 1H). 8.16-8.13 (m. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.76-7.73 (m. 2H). 7.16-7.11 (m. 1H). 4.30 (t. J = 7.7 Hz. 4H). 3.62-3.58 (m. 2H). 3.55-3.49 (m. 2H). 3.27-3.21 (m. 2H). 3.12-3.07 (m. 2H). 2.55-2.45 (m. 2H). Example 232: 2-Azetidin-1-vt-N-(f3.4-dichtorophenv1)methyl]-7-(3- (trtfluoronTe2hvi)pypdin-2-v MS (ESI): mass calcd. for Ca2CfeFaNe. 522.13; m/z found. 523.5 [M+Hf. 1H NMR (MeOD): 8.43-8.35 (m. 1H). 7.98 (dd. J = 7.8. 1.7 Hz. 1H). 7.50-7.42 (m. 2H).i 7.27-7.20 (m. 1H). 7.11-7.05 (m. 1H). 4.62-4.55 (m. 2H). 4.23-4.13 (m. 4H). 3.61|-3.53 (m. 2H). 3.51-3.46 (m. 2H). 3.16-3.09 (m. 2H). 2.94-2.86 (m. 2H). 2.49- 2.37J (m. 2H). Example 233: N-[3-Chloro-4-(trifluoromethyQphenyl]-2-piperidin-1 -yl-7-[3- (trifluoromethyl)pyridin-2-vl|-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-amihe trifluoroacetic acid salt. i MS (ESI): mass calcd. for C26H25CIF6N6. 570.17; m/z found. 571.5 [M+H]"". 1H NMR (MeOD): 8.47-8.44 (m. 1H). 8.06-7.98 (m. 2H). 7.79 (d. J = 8.7 Hz. 1H).. 7.62 (dd. J = 8.6. 1.3 Hz. 1H). 7.18-7.12 (m. 1H). 3.79-3.71 (m. 4H). 3.63-3.56 (m. 2H). 3.56-3.51 (m. 2H). 3.32-3.25 (m. 2H). 3.12-3.07 (m. 2H). 1.81-1.66 (m. 6H). I Example 234: 2-Plper!din-1 -yl-7-[3-(trlfluoromethyl)pyridin"2-yl]-N-r6- rtrifluoromethyl)pyridin-3-yl]-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-dTazepin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C2SH25F6N7. 537.21; m/z found. 538.5 [M+H]". 1H NMR (MeOD): 8.94 (d. J = 2.4 Hz. 1H). 8.46 (dd. J = 4.7. 1.3 Hz. 1H). 8.20 (dd. J = 8.3. 2.2 Hz. 1H). 8.04 (dd. J = 7.9. 1.7 Hz. 1H). 7.87 (d. J = 8.6 Hz. 1H). 7.18-7.13 (m. 1H). 3.74-3.68 (m. 4H). 3.64-3.58 (m. 2H). 3.58-3.52 (m. 2H). 3.32-3.27 (m. 2H). 3.14-3.09 (m. 2H). 1.78-1.62 (m. 6H). Example 235: 2-(2.6-Dlmethylmorpholin-4-yl]-N-(4-(trifluoromethyl)phenyl]-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahydro-5H-Pyrimldo[4.5-d]azepin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C27H28F6N6O. 566.22; m/z found. 566.2 [M+H]". 1H NMR (MeOD): 8.45 (d. J = 4.7 Hz. 1H). 8.03 (dd. J = 7.8. 1.6 Hz. 1H). 7.74-7.67 (m. 4H). 7.18-7.12 (m. 1H). 4.19 (d. J = 13.1 Hz. 2H). 3.69-3.58 (m. 4H). 3.58-3.52 (m. 2H). 3.30-3.25 (m. 2H). 3.14-3.08 (m. 2H). 2.80-2.69 (m. 2H). 1.19 (d. J = 6.2 Hz. 6H). j Example 236: 2-[(2R.6SV2.6-Dimethylmorpholin-4-yl]-N-(4-(tifluoromethyl]phenyl] 7-(3-(trifluoromethyl]pyridin-2-yl]-6.7.8.9-teirahydro-5H-pyrimidor4.5-d]azepin-4- amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C27H28F6N6O. 566.22; m/z found. 567.5 [M+H]+ 1H NMR (MeOD): 8.47-8.44 (m. 1H). 8.03 (dd. J - 7.8. 1.7 Hz. 1H). 7.74-7.68 (m. 4H). 7.17-7.12 (m. 1H). 4.20 (d. J = 13.0 Hz. 2H). 3.71-3.58 (m. 4H). 3.58-3.52 (m. 2H).!3.30-3.26 (m. 2H). 3.14-3.08 (m. 2H). 2.80-2.68 (m. 2H). 1.19 (d. J = 6.2 Hz. 6m.! Example 237: 2-(1.4-Oxazepan-4-yl]-N-(4-rtrifluoromethyl]phenyl]-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C26H26F6N6O. 552.20; m/z found. 553.2 [M+H]+. 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.66 (d. J = 8.4 Hz. 2H). 7.54 (d. J = 8.6 Hz. 1H). 6.97-6.89 (m. 1H). 6.52 (s. 1H). 3.94-3.85 (m. 4H). 3.84-3.78 (m. 2H). 3.74-3.70 (m. 2H). 3.63-3.54 (m. 4H). 3.11-3.04 (m. 2H). 2.91-2.85 (m. 2H). 2.04-1.95 (m. 2H). Example 238: 2-(3.3-Difluoropiperidin-1 -yl)-N-(4-(trifluoromettivl)phenylV7-(3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimidor4.5-d]azepin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C26H24F8N6. 572.19; m/z found. 573.1 [M+H]+. 1H NMR (MeOD): 8.46-8.43 (m. 1H). 8.02 (dd. J = 7.8. 1.7 Hz. 1H). 7.73-7.67 (m. 4H). 7.16r7.11 (m..1H). 4.02 (t. J = 11.4 Hz. 2H). 3.79-3.74 (m. 2H). 3.64-3.59 (m. 2H). 3.5743.53 (m. 2H). 3.30-3.27 (m. 2H). 3.13-3.08 (m. 2H). 2.21-2.09 (m. 2H). 1.91- 1.80 (m.2H). Example 239: 2-(4-Methylpiperidin-1 -yl]-N-2-(trifluoromethyl]phenyll2-rS- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C27H28F6N6. 550.2; m/z found. 551.5 [M+H]+. 1H NMR (MeOD): 8.47-8.43 (m. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.75-7.67 (m. 4H). 7.18-7.10 (m. 1H). 4.34 (d. J = 13.5 Hz. 2H). 3.66-3.57 (m. 2H). 3.57-3.51 (m. 2H). 3.30-3.24 (m. 2H). 3.15-3.02 (m. 4H). 1.85-1.67 (m. 3H). 1.29-1.09 (m. 2H). 0.99 (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-amlne trifluoroacetic acid salt. MS (ESI): mass calcd. for C27H2aFeN6. 550.2; m/z found. 551.6 [M+H]+. 1H NMR (MeOD): 8.47-8.43 (m. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.75-7.67 (m. 4H). 7.19-7.10 (m. 1H). 4.32-4.15 (m. 2H). 3.63-3.57 (m. 2H). 3.57-3.51 (m. 2H). 3.30- 3.24 (m. 2H). 3.13-3.01 (m. 3H). 2.82-2.66 (m. 1H). 1.93-1.73 (m. 2H). 1.73-1.45 (m. 2H). 1.34-1.17 (m. 1H). 0.94 (d. J = 6.6 Hz. 3H). Example 241: 2-(3.3-Difluoroazetidin-1-vlVN-r4-rtrifluorom9thyl]phenyl1-7-(3- (trifluoromethyl)pyridin-2-vll-6.7.8.9-tetrahvdro-5H-Pyrimido[4.5-d]azepin-4-amine. MS (ESI): mass calcd. for C24H20F8N6. 544.16; m/z found. 545.5 [M+H]+. 1H NMR (MeOD): 8.45 (dd. J = 4.8. 1.4 Hz. 1H). 8.03 (dd. J = 7.8. 1.8 Hz. 1H). 7.80 (d. J = 8.5 Hz. 2H). 7.71 (d. J = 8.6 Hz. 2H). 7.18-7.11 (m. 1H). 4.64-4.59 (m. 4H). 3.6523.59 (m. 2H). 3.58-3.53 (m. 2H). 3.29-3.23 (m. 2H). 3.16-3.10 (m. 2H). Example 242: 2-(4.4-Difluoropiperidin-1-yl]-N-(4-(trifluoromethyl]phenyl1-7-[3- (trifluoromethyhpyridin-2-vr|-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-amine. ; MS (ESI): mass calcd. for C26H24F8N6. 572.19; m/z found. 573.1 [M+H]. 1H NMR (CDCI3): 8.39 (dd. J = 4.7. 1.6 Hz. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.63- 7.55; (m. 4H). 6.98-6.91 (m. 1H). 6.53 (s. 1H). 3.95-3.88 (m. 4H). 3.62-3.58 (m. 2H). 3.58-3.54 (m. 2H). 3.11-3.06 (m. 2H). 2.91-2.86 (m. 2H).. 2.04-1.93 (m. 4H). Example 243: 2-(3.3-Difluoropyrrolidin-1-yl]-N-r4-(trifluoromethyl)phenyl]-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azeDin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C25H22F8N6. 558.18 m/z found. 559.5 [M+H]+. 1H NMR;(MeOD): 8.45 (dd. J = 4.4. 1.4 Hz. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.81 (d. J = 8-6 Hz. 2H). 7.71 (d. J = 8.661 Hz. 2H). 7.16-7.11 (m. 1H). 3.99-3.92 (m. 2H). 3.84 (t. J = 7.4 Hz. 2H). 3.64-3.58 (m. 2H). 3.57-3.52 (m. 2H). 3.31-3.27 (m. 2H). 3.15-8.10 (m. 2H). 2.62-2.50 (m. 2H). Example 244: 2-(2-Methylpyrrolldin-1 -yl]-N-(4-2trifluoromethyl)phenyll-7-(3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimidor4.5-d]azepin-4-amine. MS (ESI): mass calcd. for C26H26F6N6. 536.21; m/z found. 537.6 [M+H]+. 1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.6 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.77 (d. J = 8.6 Hz. 2H). 7.55 (d. J = 8.6 Hz. 2H). 6.95-6.91 (m. 1H). 6.52 (s. 1H). 4.33-4.24 (m. 1H). 3.68-3.49 (m. 6H). 3.13-3.05 (m. 2H). 2.90-2.85 (m. 2H). 2.13-2.00 (m. 2H). :1.97-1.88 (m. 1H). 1.74-1.65 (m. 1H). 1.26 (d. J = 6.3 Hz. 3H). Example 245: N-[3-Chloro-4-(trifluoromethyl]phenviy2-( 1.4-oxazepan-4-vi)-7-[3- (trifluoromethyl)pyridin-2-Yl1-6.7.8.9-tetrahydro-5H-pyrimidor4.5-dlazepin-4-amine trifluoroacetic acid salt. MS (ESI): mass calcd. for C26H25CIF6N6O. 586.17; m/z found. 587.5 [M+H]+. 1H NMR (MeOD): 8.46-8.44 (m. 1H). 8.04-8.00 (m. 2H). 7.79 (d. J = 8.7 Hz. 1H). 7.64-7.59 (m. 1H). 7.17-7.11 (m. 1H). 3.92-3.81 (m. 6H). 3.80-3.76 (m. 2H). 3.64- 3.59l(m. 2H). 3.57-3.52 (m. 2H). 3.36-3.32 (m. 2H). 3.13-3.09 (m. 2H). Exarnple 246: 2-(2-Methylpjperldin-1-vlVN-(4-2trifluoromethyl]phenyl].7-(3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-Dvrimidor4.5-d]azepin-4-amine hvdrochloride salt. MS (ESI): mass calcd. for C27H28F8N6. 550.23; m/z found. 551.6 [M+H]". 1H NMR (MeOD): 8.45 (dd. J = 4.7. 1.4 Hz. 1H). 8.03 (dd. J = 7.8. 1.8 Hz. 1H). 7.74- 7.68 (m.4H). 7.17-7.11 (m. 1H). 4.70-4.63 (m. 1H). 4.19-4.11 (m. 1H). 3.64-3.58 (m. 2H). 3.56-3.52 (m. 2H). 3.30-3.26 (m. 2H). 3.24-3.15 (m. 1H). 3.12-3.07 (m. 2H). 1.85-1.62 (m. 5H). 1.58-1.46 (m. 1H). 1.27 (d. J = 6.9 Hz. 3H). Example 247: 2-(1.1-Dioxidothiomorpholin-4-v1)-N-(4-(trtfluoromothyl)phenyl]-7-(3- (tfifluo[ornethyl)pyridin-2-v11-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepin-4-amine trlfluoroacetic acid salt. MS (ESI): mass calcd. for C25H24F6N8O2S. 586.16; m/z found. 587.1 [M+H]+ 1H NMR ((CD3)2CO): 8.46-8.44 (m. 1H). 8.02-8.00 (m. 1H). 7.88-7.84 (m. 2H). 7.64-7.62 (m. 2H). 7.13-7.08 (m. 1H). 4.31-4.25 (m. 4H). 3.56-3.48 (m. 4H). 3.14- 3.04 (m. 6H). 2.07-2.04 (m. 2H). Example 248: N-(4-21.1-Pimethyletrivlk)henyl]-2-PVrro MS (ESI): mass calcd. for C28H33F3N6. 510.27; m/z found. 511.2 [M+H]+ 1H NMR (CDCI3): 8.38-8.36 (m. 1H). 7.85 (dd. J = 7.8. 1.8 Hz. 1H). 7.62-7.58 (m. 2H). 7.34-7.31 (m. 2H). 6.94-6.90 (m. 1H). 6.35 (s. 1H). 3.61-3.56 (m. 8H). 3.09-3.06 (m. 2H). 2.86-2.82 (m. 2H). 1.99-1.92 (m. 4H). 1.32 (s. 9H). Example 249: 2-Azetidin-1-yl-N-(4-M .1-dimethylethyl]Dhenvll-7-(3- (trifluoromethyl)pyridin-2-yl1-6.7.8.9-tetrahvdro-5H-pyrimidor4.5-d1azepin-4-amlne. MS (ESI): mass calcd. for C27H31F3N6. 496.26; m/z found. 497.2 [M+H]+. 1H NMR (CDCI3): 8.38-8.37 (m. 1H). 7.85 (dd. J = 7.7.1.9 Hz. 1H). 7.58-7.54 (m. 2H). 7.33J-7.30 (m. 2H). 6.94-6.90 (m. 1H). 6.37 (s. 1H). 4.15-4.10 (m. 4H). 3.62-3.54 (m. 4H). 3.10-3.05 (m. 2H). 2.86-2.81 (m. 2H). 2.35-2.28 (m. 2H). 1.31 (s. 9H). ! Example 250: 2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5- (trifluoromethyl)pyridin-2-yl-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d]azepin-4-amine. i MS (ESI): mass calcd. for C25H25F6N7, 537.21; m/z found. 538.2 [M+H]+. 1H NMR (CDCI3): 8.49-8.47 (m. 1H). 8.43 (d. J = 8.9 Hz. 1H). 8.40-8.39 (m. 1H). 7.89- 7.85 (m. 2H). 7.42 (s. 1H). 6.97-6.92 (m. 1H). 3.79-3.74 (m. 4H). 3.58-3.52 (m. 4H). 3.12-3.06 (m. 2H). 2.95-2.88 (m. 2H). 1.73-1.59 (m. 6H). i I Example 251: N-r(3.4-Dichlorophenyl)methyl]-2-piperidin-1-yl-7-(3- (trifluoromethyl')pyridin-2-vll-6.7.8.9-tetrahvclro-5H-pyrimicloF4.5-cnazepin-4-amine. MS (ESI): mass calcd. for C26H27CI2F3N6, 551.16; m/z found. 551.1 [M+H]+. 1H NMR (CDCI3): 8.36-8.35 1H). 4.59 (d. J = 5.7 Hz. 2H). 3.69-3.65 (m. 4H). 3.57-3.52 (m. 4H). 3.03-2.99 (m. 2H), 2.72-2.69 (m. 2H). 1.64-1.59 (m. 2H). 1.56-1.50 (m. 4H): Example 252: N-[4-(1,1-Dimethylethyl)henyl]-2-(4-methyliperazin-1-yl)-7-[3- (trifluoromethyl]pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine. MS (ESI): mass calcd. for C29H36F3N7. 539.30; m/z found. 540.2 [M+H]+. 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.7 Hz. 1H). 7.48-7.45 (m, 2H), 7.36-7.32 (m. 2H). 6.94-6.90 (m. 1H), 6.34 (s. 1H). 3.84-3.76 (m. 4H). 3.64-3.55 (m. 4H). 3.09-3.04 (m. 2H). 2.87-2.81 (m. 2H). 2.51-2.42 (m. 4H). 2.34 (s. 3H). 1.33 (s. OH). Example 253: 2-Azepan-1-yl-N-r4-(1,1-dimethylethy0phenyl]-7-[3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimidor4.5-d]azepin-4-amine. MS (ESI): mass calcd. for C30H37F3N6. 538.30; m/z found. 539.2 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m. 1H). 7.85 (dd, J = 7.8.1.7 Hz. 1H). 7.56-7.53 (m. 2H). 7.33-7.30 (m. 2H). 6.93-6.90 (m. 1H). 6.31 (s. 1H). 3.76-3.70 (m. 4H). 3.63-3.56 (m. 4H). 3.08-3.04 (m. 2H). 2.86-2.82 (m. 2H). 1.83-1.74 (m. 4H). 1.58-1.52 (m. 4H). 1.32 (s. 9H). Example 254: N2-(2-(Dimethylamino2ethyl]-N4-(4-(1.1-dimethyleth|v+Dhenyl]-N2- methyl-7-(3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-t9trahvdro-5H-Dvrimidor4.5- dlazepine-2.4-diaming. | MS (ESI): mass calcd. for C29H38F3N7. 541.31; m/z found. 542.3 [M+H]+. 1H NMR (CDCI3): 8.38-8.37 (m. 1H). 7.86-7.85 (m. 1H). 7.50-7.46 (m. 2H). 7.33-7.30 (m. 2H). 6.94-6.90 (m. 1H). 6.29 (s. 1H). 3.72-3.70. (m. 2H). 3.63-3.55 (m. 4H). 3.15 i(s. 3H). 3.08-3.04 (m. 2H). 2.86-2.82 (m. 2H). 2.52-2.46 (m. 2H). 2.26 (s. 6H). 1.31 (s.9H). Example 255: 2-Azepan-1-yl-N-[(3.4-dichlorophenyl]methyl]-7-[3- (triflubromethyl)pyridin-2-vlT-6.7.8.9-tetrahydro-5H-pyrimidor4.5-dla2epin-4-amine. MS (ESI): mass calcd. for C27H28Cl2F3N8. 564.18; m/z found. 565.1 [M+H]+. 1H NMR (CDCI3): 8.37-8.35 (m. 1H). 7.86-7.83 (m. 1H). 7.43-7.42 (m. 1H). 7.36 (d. J = 8.2Hz. 1H). 7.17-7.15 (m. 1H). 6.91-6.89 (m. 1H). 4.83-4.79 (m. 1H). 4.59 (d. J = 5.7 Hz. 2H). 3.69-3.52 (m. 8H). 3.03-3.00 (m. 2H). 2.72-2.69 (m. 2H). 1.72-1.61 (m.4H). 1.52-1.47 (m.4H). Example 256; N-[(3.4-Dlchlorophenyl)methy (trifluoromethyl)PVridin-2-vll-6.7.8.9-tetrahvdro-5H-pyrimidor4.5- MS (ESI): mass calcd. for C26H28CI2F3N7. 565.17; m/z found. 566.1 [M+H]". 1H NMR (CDCI3): 8.37-8.35 (m. 1H). 7.86-7.84 (m. 1H). 7.44-7.43 (m. 1H). 7.38 (d. J = 8!2 Hz. 1H). 7.17-7.15 (m. 1H). 6.93-6.90 (m. 1H). 4.86-4.82 (m. 1H). 4.60 (d. J = 5.7 Hz. 2H). 3.77-3.69 (m. 4H). 3.57-3.52 (m. 4H). 3.04-3.00 (m. 2H). 2.73-2.69 (m. 2H). 2.43-2.39 (m. 4H). 2.32 (s. 3H). Example 257: N4-\4-(1.1-Dlmethy MS (ESI): mass calcd. for CaHaaFjNaO. 528.28; m/z found. 529.2 [M+H]". 1H NMR (CDCI3): 8.38-8.37 (m. 1H). 7.86 (dd. J = 7.8. 1.9 Hz. 1H). 7.52-7.49 (m. 2H). 7.34-7.30 (m. 2H). 6.94-6.90 (m. 1H). 8.32 (s. 1H). 3.77 (t. J = 6.1 Hz. 2H). 3.62-3.56 (m. 6H). 3.34 (s. 3H). 3.19 (s. 3H). 3.07-3.05 (m. 2H). 2.86-2.82 (m. 2H). 1.32(s. 9H). Example 258: N-(3-Chloro-4-(trifluoromet2yl]Dhenyl]-2-Dvrrolidin-1-yl-7-{3- (trifluoromethyl)Dvrldin-2-yl]-6.7.8.9-tetrahvdro-5H-Dvi1mldo[4.5-d1azeDln-4-amin9. MS (ESI): mass calcd. for CasHaaCIFeNe. 556.16; m/z found. 557.4 {M+Hf. 1H NMR (CDCI3): 8.39-8.38 (m. 1H). 8.23 (d. J = 1.9 Hz. 1H). 7.87 (dd. J = 7.8.1.8 Hz. 1H). 7.58 (d. J = 8.7 Hz. 1H). 7.46-7.42 (m. 1H). 6.97-6.93 (m. 1H). 6.54 (s. 1H). 3.65-3.53 (m. 8H). 3.14-3.06 (m. 2H). 2.90-2.84 (m. 2H). 2.02-1.94 (m. 4H). Example 259: n-(4-{f4-(Ti1fluoromethyl)prienv)1amirK))-7-(3-(trif1uoromethyl)pyr1din- 2-vf|-6.7.8.9-tetrahvdro-5H-pyrimldo[4.5- MS (ESI): mass calcd. for C27H28F8N6O. 566.22; m/z found. 567.5 [M+HJ". 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.65-7.61 (m. 2H). 7.59-7.56 (m. 2H). 6.97-6.92 (m. 1H). 6.52 (8. 1H). 4.94-4.87 (m. 1H). 4.58- 4.51 (m. 1H). 4.05-4.00 (m. 1H). 3.74-3.65 (m. 2H). 3.61-3.53 (m. 4H). 3.15-3.04 (m. 3H). 2.89-2.84 (m. 2H). 1.78-1.57 (m. 5H). Example 260; f(2S)-W4-2f4-n"rifluoromethy (trtfli|ioromethy0Dvi1din-2-vtl-6.7.8.9-tetrahvdro-5H-ovrinriido[4.5-dlazeDin-2- vQpyrrolldin-2-vlimethanol hvdrochloride salt. MS (ESI): mass calcd. for CajHajFeNsO. 552.21; m/z found. 553.1 [M+HJ". 1H NMR (CD3OD): 8.48-8.45 (m. 1H). 8.06-8.01 (m. 1H). 7.86-7.81 (m. 2H). 7.72- 7.67 (m. 2H). 7.19-7.12 (m. 1H). 4.26-4.14 (m. 1H). 3.87-3.49 (m. 8H). 3.30-3.19 (m. 2H). 3.15-3.08 (m. 2H). 2.23-1.85 (m. 4H). Example 261: F(2R)-1-(4-ir4-(rrifluoromethyl)phenyl1amlno)-7-(3- (trifluoromethyl)pyridin-2-vH-6.7.8.9-letrahvdro-5H-pyrim{do[4.5-d|azepln-2- yltovrrolldin-2-yllmethanol hvdrochloride salt. MS (ESI): mass calcd. for CaeH2FeNeO. 552.21; m/z found. 553.1 [M+H]+ 1H NMR (CD3OD): 8.47-8.44 (m. 1H). 8.04-8.01 (m. 1H). 7.84-7.81 (m. 2H). 7.71- 7.69 (m. 2H). 7.16-7.12 (m. 1H). 4.24-4.16 (m. 1H). 3.84-3.52 (m. 8H). 3.28-3.20 (m. 2H). 3.13-3.10 (m. 2H). 2.22-1.85 (m. 4H). Example 262: K2S)-1-(7-[3-rrrifluoromethy (trifluoromethy vDpyrrolidlri-2-v MS (ESI): mass calcd. for C25H25F+NrO. 553.20; m/z found. 554.1 [M+H]". 1H NMR (CDCI3): 8.66-8.62 (m. 1H). 8.50-8.40 (m. 2H). 8.07-8.01 (m. 1H). 7.94- 7.89 (m. 1H). 7.07-7.02 (m. 1H). 5.15-5.03 (m. 1H). 3.91-3.56 (m. 10H). 3.09-2.98 (m. 2H).2.16-1.99(m.4H). Example 263: N2-R3R)-Tetrahvdro[uran-3-vH-7-[3-(trifluoromethyl)PVrldin-2-yl]-N4- f5-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-Pvrlmido[4.5-d1a2epine-2.4- diamine. MS (ESI): mass calcd. for CwH2FeNrO. 539.19; m/z found. 540.2 [M+H]". 1H NMR (CD3OD): 8.56-8.54 (m. 1H). 8.46-8.43 (m. 2H). 8.04-7.99 (m. 2H). 7.14- 7.10 (m. 1H). 4.55-4.49 (m. 1H). 4.01-3.95 (m. 2H). 3.90-3.83 (m. 1H). 3.73-3.69 (m. 1.H). 3.51-3.44 (m. 4H). 3.10-3.01 (m. 4H). 2.36-2.26 (m. 1H). 2.01-1.92 (m. 1H). Example 264; N4-(4-(1.1-Dimethylethyl)phenvf1-N2-K3R)-tetrahvdro[uran-3-v1)-7-(3- (trifluoromethyl]pyridin-2-vH-6.7.8.9-tetrahvdro-5H-Pvrimldor4.5-dlazeplne-2.4- diamine. MS (ESI): mass calcd. for C2aH3oF3NeO. 526.27; m/z found. 527.3 [M+H]". 1H NMR (CD3OD): 8.33-8.32 (m. 1H). 7.90 (dd. J = 7.8. 1.8 Hz. 1H). 7.41-7.37 (m. 2H)r 7.25-7.22 (m. 2H). 7.02-6.99 (m. 1H). 4.32-4.27 (m. 1H). 3.85-3.76 (m. 2H). 3.73-3.68 (m. 1H). 3.52 (dd. J = 9.0. 3.9 Hz. 1H). 3.37-3.34 (m. 4H). 2.92-2.84 (m. 4H). 2.17-2.09 (m. 1H). 1.81-1.74 (m. 1H). 1.22 (s. 9H). Example 265: N)2-n"etrahvdro-(uran-3-vl)-N4-(4-trtfluoromethyl-Dhenvl)-7-(3- trifluoromethyl-Dvridin-2-yl]-6.7.8.9-tetrahydro-5H-Pvrimidor4.5-cnazepine-2.4- diamine trifluoroacetic add salt. MS (ESI): mass calcd. for C2sH24F6NeO. 538.19; m/z found. 539.2 [M+H)". 1H NMR (CD3OD): 8.49-8.46 (m. 1H). 8.04 (dd. J = 7.8. 1.7 Hz. 1H). 7.78 (d. J = 8.6 Hz. 2H). 7.73 (d. J = 8.7 Hz. 2H). 7.19-7.15 (m. 1H). 4.42-4.38 (m. 1H). 3.98- 3.92 (m. 1H). 3.84-3.78 (m. 2H). 3.71 (dd. J = 9.5. 3.2 Hz. 1H). 3.65-3.62 (m. 2H)f 3.57-3.55 (m. 2H). 3.23-3.18 (m. 2H). 3.14-3.10 (m. 2H). 2.31-2.22 (m. 1H). 1.98- 1.92 (m.1H). Example 266: N2-Methyl-N2-(1-methyletrivl)-7-(3-(tfffluoromethy diamlne. MS (ESI): mass calcd. for C24H25F6N7. 525.21; m/z found. 526.2 fM+HT. Example 267: N2-Cvclohexvt-N2-methyl-N4-(2-methy f32trifluoromethyi)pyridin-2-vfl-6.7.8.9-tetrahvdro-5H-pyt1midor4.5-d1azepine-2.4- diamlne. MS (ESI): mass calcd. for C2H2Ne. 578.26; m/z found. 579.3 (M+HJ". Example 268: 2-r7-Azabtovdor2.2.nhept-7-v (tfifluoromethyl)pyridin-2-v1I-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-dlazeDln-4-amin8. MS (ESI): mass calcd. for C27H2eF6N6. 548.521 m/z found. 549.2 [M+H]". 1H NMR(CDCI3): 8.40-8.38 (m. 1H). 7.89-7.87 (m. 1H). 7.71 (d. J = 8.5 Hz. 2H). 7.59 (d. J " 8.5 Hz. 2H). 6.97-6.94 (m. 1H). 6.55 (s. 1H). 4.63 (s. 2H). 3.62-3.56 (m. 4H). 3.12-3.10 (m. 2H). 2.91-2.89 (m. 2H). 1.84-1.80 (m. 4H). 1.51-1.46 (m. 4H). Example 269: 2-(2-(1-M9thylethy 2trifluoromethyl)Dhenv11-7-(32triflUQit)methyl)pyridin-2-v MS (ESI): mass calcd. for CaHnFeNe. 578.26; m/z found. 579.3 [M+HJ". 1H NMR (CDCI3): 8.40-8.37 (m. 2H). 7.88-7.85 (m. 1H). 7.45-7.42 (m. 2H). 6.95-6.91 (m. 1H). 6.33 (s. 1H). 4.04-4.02 (m. 1H). 3.76-3.69 (m. 1H). 3.65-3.56 (m. 4H). 3.54-3.48 (m. 1H). 3.11-3.08 (m. 2H). 2.89-2.86 (m. 2H). 2.42-2.37 (m. 1H). 2.35 (s. 3H). 1.96-1.87 (m. 1H). 1.86-1.80 (m. 3H). 0.86 (d. J = 9.0 Hz. 3H). 0.77 (d. J = 9.0 Hz. 3H). Example 270: N2fCvdohexvlmethyl2-(S-(tiifluoromethyDpyridin2-yl]-2-(e- (trifluoromethyl)pyridin-3-v11-6.7.8.9-tetrahvdrc)-5H-Dvrimidor4.5-d1azeplne-2.4- dlamlne. MS (ESI): mass calcd. for Ca)HjoFeN). 565.24; m/z found. 566.3 [M+H]\ 1H NMR (CDCI3): 8.75 (s. 1H). 8.40-8.38 (m. 2H). 7.88-7.86 (m. 1H). 7.62 (d. J = 8.5 Hz. 1H). 6.97-6.94 (m. 1H). 6.60 (s. 1H). 3.60-3.55 (m. 4H). 3.22 (t. J = 6.0 Hz. 2H). 3.08-3.05 (m. 2H). 2.91-2.89 (m. 2H). 1.80-1.72 (m. 3H). 1.68-1.64 (m. 1H). 1.83- 1.5t(m. 3H). 1.27-1.22 (m. 3H). 1.02-0.94 (m. 2H). Example 271: f4-(4-(f4-(Trifluoromethylk3henvflamlno)-7-[3-Ctr1fluoromethyl)pyridin- 2-yl]-6.7.8.9-tetrahydro-5H-ovrimido[4.5-d1azepin-2-yl)morpholin-2-yl]methanol. MS (ESI): mass calcd. for C26H26F6N6O2. 568.20; m/z found. 569.3 [M+H]1H NMR (CDCI3): 8.39-8.38 (m,1H). 7.88-7.86 (m. 1H). 7.62 (d. J " 11.0 Hz. 2H). 7.56 (d. J = 11.0 Hz. 2H). 6.97-6.93 (m. 1H). 6.54 (s. 1H). 4.48-4.38 (m. 2H). 4.04- 4.01 (m,1H). 3.76-3.72 (m, 1H). 3.70-3.62 (m. 3H). 3.61-3.52 (nfi. 4H). 3.10-3.06 (m. 3H). 2.89-2.86 (m. 3H). 2.03-1.95 (m. 1H). Example 272: N2-Methyl-N2-(1-methyfethylVN4-(4-(trifluoromethyt)phenyl]-7-[3- (trifluoromethyl)Dvridin-2-vll-6.7.8.9-tetrahvdro-5H-Pvrimldo[4.5 MS (ESI): mass calcd. for CahfeeFeNe. 524.21; m/z found. 525.3 [M+H]\ 1H NMR (CDCb): 8.39-8.37 (m. 1H). 7.88-7.85 (m. 1H). 7.70 (d. J = 8.5 Hz. 2H). 7.55 (d. J = 8.5 Hz. 2H). 6.95-6.92 (m. 1H). 6.50 (s. 1H). 5.05-5.00 (m. 1H). 3.61-3.56 (m. 4H). 3.11-3.07 (m. 2H). 2.98 (s. 3H). 2.90-2.84 (m. 2H). 1.18 (d. J = 6.5 Hz. 6H). Example 273: f4-T4-lf2-Metfiyl-4-(trifluoromethyl)phenyl1amino)-7-(3- (trlfluoromethyl)Pvridin-2-v11-6.7.8.9-tetrahvdro-5H-ovrimido[4.5-d1azepin-2- vJlmorprconn-2-yl]roethanol. MS (ESI): mass calcd. for C27H28F6N6O2. 582.22; m/z found. 583.3 [M+H]". 1H NMR (CDCI3): 8.39-6.37 (m. 1H). 8.04 (d. J = 11.5 Hz. 1H). 7.88-7.86 (m. 1H). 7.45 (d. J = 9.0 Hz. 2H). 6.96-6.93 (m. 1H). 6.31 (s. 1H). 4.43-4.34 (m. 2H). 4.02- 3.98 (m. 1H). 3.74-3.71 (m. 1H). 3.66-3.55 (m. 7H). 3.11-3.08 (m. 2H). 3.07-2.99 (m. 1H). 2.89-2.80 (m. 3H). 2.34 (s. 3H). 1.99 (br s. 1H). Example 274: 2-(2-n-Methylethyl)pyrrolidin-1-yl]-7-(3-(trifluoromethyl)Dvrldin-2-vfl- N-[6-)trifluoromethyl)pyridin-3-vl1-6.7.8.9-tetrahydro-5H-pyrirnido[4.5-dlazepin-4- amine. MS (ESI): mass calcd. for C27H28F6N6O2. 565.24; m/z found. 566.3 [M+HJ". 1H NMR (CDCI3): 8.86 (d. J = 2.5 Hz. 1H). 8.41-8.40 (m. 1H). 8.14-8.11 (m. 1H). 7.90- 7.88 (m. 1H). 7.66 (d. J = 9.0 Hz. 1H). 6.99-6.96 (m. 1H). 6.60 (s. 1H). 4.47 (d. J = 13.0 Hz. 1H). 4.39 (d. J = 13.0 Hz. 1H). 4.06-4.03 (m. 1H). 3.79-3.75 (m. 1H). 3.71- 3.56 (m. 7H). 3.13-3.05 (m. 3H). 2.95-2.85 (m. 3H). 2.07 (2.04 (m. 1H). Example 275: N2-Cvck)hexyl-N2-methyl-7-[3-(tri(tuoromethyl2pyridin-2-yl]-N"-r6- (trifluoromethyl)pyridin-3-yl]-6.7.8.9-tetrahvdro-5H-Pyrimido[4.5-dIazeplne-2.4- diamine. MS (ESI): mass calcd. for C27H29F6N7, 565.24; m/z found. 566.3 [M+H]+. 1H NMR (CDCI3): 8.70 (8. 1H). 8.42 (d. J = 10.0 Hz. 1H). 8.39-8.38 (m. 1H). 7.88-7.86 (m. 1H). 7.61 (d. J = 10.0 Hz. 1H). 7.00-6.93 (m. 1H). 6.55 (s. 1H). 4.49 (brs. 1H). 3.61-3.55 (m. 4H). 3.11-3.08 (m. 2H). 3.01 (s. 3H). 2.91-2.88 (m. 2H). 1.87-1.84 (m. 2H). 1.75-1.71 (m. 3H). 1.52-1.12 (m. 5H). Example 276: 2-(2S or 2R)-2-Methylpiperidin-1-yl]-N-(4-(trifluoromethyl)ohenyl]-7- [3-)trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimidor4,5-d1azepln-4- amine. MS (ESI): mass calcd. for C27H28F6N6O2. 550.23; m/z found. 551.3 [M+H]. 1H NMR (CD3OD): 8.53-8.35 (m. 1H). 8.08-7.97 (m. 1H). 7.80 (d. J = 8.8 Hz. 2H). 7.55 (d. J = 8.4 Hz. 2H). 7.18-7.07 (m. 1H). 3.59-2.87 (m. 12H). 2.02-1.52 (m. 4H). 1.20 (d. J = 6.8 Hz. 3H). [] 20 = +58.2 (c = 0.005. MeOH). Example 277: 2-[(2R or 2S)-2-Methylpiperidin-1-yl]-N-(4-(trifluoromethyl)phenyl]-7- [3-(trifluoromethyl)pyridin--2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4,5-dlazepin-4- amine. MS (ESI): mass calcd. for C27H28F6N6O2, 550.23; m/z found. 551.3 [M+H]+ 1H NMR (CD3OD): 8.54-8.33 (m. 1H). 8.02 (dd. J = 7.9. 1.8 Hz. 1H). 7.80 (d. J = 8.5 Hz. 2H). 7.54 (d. J = 8.6 Hz. 2H). 7.17-7.07 (m. 1H). 3.60-3.37 (m. 2H). 3.36-3.31 (m. 2H). 3.11-2.97 (m. 4H). 1.80-1.68 (m. 4H). 1.66-1.60 (m. 4H). 1.20 (d. J = 6.89 Hz. 3H). [a]0 20 = -53.8 (c = 0.005. MeOH). The following Examples 278-280 were prepared using methods analogous to those described in Example 54. substituting the appropriate amines. Example 278: N2-(2-Methylphenyl)-N4-(4-(trifluoromethyl]phenyl]-7-[3- (trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-dlazepine-2,4- diamine trifluoroacetic acid salt MS (ESI): mass calcd. for C27H28F6N6O2 ,558.19; m/z found. 559.4 [M+H]+. 1H NMR (MeOD): 8.45 (dd. J = 4.7.1.5 Hz. 1H). 8.02 (dd. J = 7.8.1.8 Hz. 1H). 7.58 (d. J = 8:5 Hz. 2H). 7.41 (d. J = 8.6 Hz. 2H). 7.33-7.28 (m. 3H). 7.28-7.22 (m. 1H). 7.14 (dd. J = 7.7. 4.8 Hz. 1H). 3.66-3.62 (m. 2H). 3.57-3.54 (m. 2H). 3.27-3.23 (m. 2H). 3.14-3.09 (m. 2H). 2.21 (s. 3H). Example 279: N2-(3-Methylphenyl)-N4-[4-(trifluoromethyl)phenyl]-7-(3- (trlfluoromethy)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-dlazeplne-2.4- diamine trifluoroacetic acid salt. MS (ESI): mass calcd. for C28H28F6N6, 558.20; m/z found. 559.1 [M+-H]+. 1H NMR (MeOD): 8.45 (dd. J =4.7. 1.4 Hz. 1H). 8.02 (dd. J = 7.8. 1.8 Hz. 1H). 7.67 (d. J = 8.5 Hz. 2H). 7.61 (d. J + 8.7 Hz. 2H). 7.17-7.11 (m. 3H). 7.01-6.96 (m. 1H). 3.67-3.59 (m. 2H). 3.59-3.55 (m. 2H). 3.35 (s. 1H). 3.26-3.23 (m. 2H). 3.14-3.09 (m. 2H). 2.20 (s. 3H). Example 280. N2-(4-Methylphenyl)-N4-(4-(trifluoromethyl)phenyl]-7-(3- (trifluoromethyl) pyridin-2- yl]-6,7,8,9-tetrahydro-5H-pyrimido[4.5-d1azeDlne-2.4- diamine trifluoroacetic acid salt MS (ESI): mass calcd. for C27H28F6N6 558.20; m/z found. 559.5 [M+H]+. 1H NMR (MeOD): 8.46 (dd. J =4.7.1.3 Hz. 1H). 8.03 (dd. J " 7.8. 1.7 Hz. 1H). 7.65 (d. J = 8.6 Hz. 2H). 7.58 (d. J = 8.6 Hz. 2H). 7.21 (d. J = 8.4 Hz. 2H). 7.18-7.12 (m. 1H). 7.10 (d. J = 8.2 Hz. 2H). 3.66-3.60 (m. 2H). 3.59-3.53 (m. 2H). 3.25-3.19 (m. 2H). 3-14-3.08 (m. 2H). 2.33 (s. 3H). The following Examples 281-295 were prepared using methods analogous to those described in Example 26. substituting the appropriate 2-chloro pyridines in Step C and and anilines in Step E: Example 281: N-(2-(2-21-Methylethyl)-4-([4-(trifluoromethyl)prienyl]amino)-5.6.8.9- tetrahydro-7H-pyrimido[4.5-dlazepin-)-yl)pyridin-3-yl)metrianesulfonamide. The title compound was prepared using methods analogous to those described by Richardson. T.I. et al. J. Med. Chem. 2004. 47. 744) starting from [7- (2-amlno-phenyl)-2-isopropyl-6.7.8.9-tetrahydro-5H-pyrimldo[4.5-d]azepin-4-yl)(4- trifluoromethyl-phenyl)-amine (Example 84). MS (ESI): mass calcd. for C24H27F3N8OeS. 520.20; m/z found. 521.1 [M+H]+. 1H NMR (CDCI3): 8.11 (dd. J = 4.8. 1.6 Hz. 1H). 7.82-7.76 (m. 3H), 7,61-7.58 (m, 2H). 7.09 (dd. J =8.1. 4.8 Hz. 1H). 6.81-6.51 (m, 1H). 3.36-3.30 (m, 4H). 3.28-3.20 (m, 2H). 3.15-3.13 (m. 3H). 3.11-3.03 (m. 1H). 3.03-2.96 (m. 2H). 1.34 (d. J = 6.9 Hz. 6H). Example 282: 2-(1-Methylethyl)-7-(3-2methylsulfonyl)pyridin-2-yl]-N)-r6- (trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahvdro-5H-pyrimido[4.5-dlazepin-4-amine. The title compound was prepared analogously to the methods described in. Example 26. substituting 2-chloro-3-methanesulfonyl-pyrtdine (J. Org. Chem. 1979. 44(17). 3080-3082) in Step C. MS (ESI): mass calcd. for C23H25F3N6O2S. 506.17; m/z found. 507.1 (M+H]+. 1H NMR (CDCI3): 8.78 (dd. J = 4.8. 1.9 Hz. 1H). 8.48 (dd. J = 7.9. 1.9 Hz. 1H). 8.09-8.07 (m. 1H). 7.53 (dd. J = 7.9. 4.8 Hz. 1H). 7.45 (d. J = 8.6 Hz. 1H). 6.90 (dd. J = 8.5. 2.7 Hz. 1H). 5.96-5.78 (m. 1H). 4.25-4.00 (m. 2H). 3.58-3.52 (m. 2H). 3.24 (s. 3H). 3.20-3.13 (m. 2H). 2.95-2.91 (m. 2H). 2.91-2.81 (m. 1H). 1.18 (d. J = 6.9 Hz. 6H). Example 283: 7-(3-(Methylsulfonyl]pyridin-2-vl]-N-(4-2trifluoromethyl2Dhenyl]- 6.7.8.9-tetrahvdro-5H-pyrimidor4.5-dlazepin-4-amlne. The title compound was prepared analogously to the methods described in Example 26. substituting 2-chloro-3-methanesulfony1-pyridine (J. Org. Chem. 1979. 44(17). 3080-3082) in Step C. MS (ESI): mass calcd. for C21H20F3N5O2S. 463.13; m/z found. 464 [M+H]+. 1H NMR (CDCI3):.866-8.60 (m. 1H). 8.55 (dd. J = 4.8. 1.9 Hz. 1H). 8.38 (dd. J = 7.8.1.9 Hz. 1H). 7.73 (d. J = 8.6 Hz. 2H). 7.65 (d. J " 8.6 Hz. 2H). 7.28-7.24 (m. 1H). 3.67-3.59 (m. 2H). 3.59-3.54 (m. 2H). 3.39-3.28 (m. 2H). 3.14-3.05 (m. 2H). 2.99 (3. 3H). Example 284: 7-(3-Aminopyridin-2-yl)-N-[4-(1,1-dimethethyl]phenyl]-2-(1- methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-dlazepin-4-amine. MS (ESI): mass calcd. for C28N34N6, 430.28; m/z found. 431.2 [M+H]+. 1H NMR (CDCI3): 7.78 (dd. J = 4.8. 1.6 Hz. 1H). 7.63-7.56 (m. 2H). 7.39-7.32 (m. 2H). 7.01-6.95 (m. 1H). 6.88-6.83 (m. 1H). 6.51-6.47 (m. 1H). 3.87-3.75 (m. 2H). 3.44- 3.30 (m. 4H). 3.23-3.15 (m. 2H). 3.08-2.99 (m. 1H). 2.94-2.88 (m. 2H). 1.37-1.30 (m. 1H). Example 285: 7-[3-Chloro-5-rtrifluoromethyl)pyrid)r)-2-yl]-N-(4-(1.1- dimethylethy+phenyl]-2-n-methy MS (ESI): mas3 calcd. for C27H3iCIF3N5. 517.22; m/z found. 518.2 [M+HJ". 1H NMR (CDCI3): 8.41-8.26 (m. 1H). 7.64-7.55 (m. 2H). 7.40-7.33 (m. 2H). 7.28- 7.23 (m. 1H). 3.99-3.78 (m. 4H). 3.28-3.17 (m. 2H). 3.08-2.94 (m. 3H). 1.43-1.26 (m. 6H). Example 286: 7-(5-Bromo-3-chloropyridin-2-v1)-N-(4-(1.1-dimethy = MS (ESI): mass calcd. for CwHstBrCINs. 527.15; m/z found. 530.1 [M+H]". 1H NMR (CDCI3): 8.21-8.08 (m. 1H). 7.73-7.68 (m. 1H). 7.63-7.57 (m. 2H). 7.40- 7.31 (m. 2H). 6.46 (s. 1H). 3.79-3.58 (m. 4H). 3.26-3.15 (m. 2H). 3.06-2.98 (m. 1H). 2.96-2.91 (m. 2H). 1.37-1.30 (m. 6H). Example 287: 7-p-Chloro-5- MS (ESI): mass catcd. for C24H22CIF6N5. 529.15; m/z found. 530.1 [M+H]". 1H NMR (CDCI3): 8.40-8.28 (m. 1H). 7.83-7.77 (m. 2H). 7.77-7.74 (m. 1H). 7.62- 7.57:(m. 2H). 3.99-3.81 (m. 4H). 3.33-3.18 (m. 2H). 3.11-2.98 (m. 3H). 1.32 (d. J = 6.9 Hz. 6H). Example 288: 5-Chloro-6-r2-(1-methylethylM-(f4-)trifluoromethyl)phenvf|amlno)- 5.6.8.9-tetrahydro-7H-Pvrlmldor4.5-d]azepin-7-yl]pyridine-3-cart)oxylic acid trifluoroacetic acid salt. MS (ESI): mass calcd. for C24H23CIF3N5O2. 505.15; m/z found. 506.1 [M+H]". 1H NMR (CD3OD): 8.75-8.57 (m. 1H). 8.18-8.10 (m. 1H). 7.87-7.78 (m. 2H). 7.72-7.67 (m. 2H). 4.08-3.82 (m. 4H). 3.43-3.34 (m. 2H). 3.28-3.22 (m. 2H). 3.10-3.02 (m. 1H). 1.29 (d. J = 6.8 Hz. 6H). Example 289: N-(4-n.1-Dlmethylethyl]Dhenyl]-2-)1-methylethylV7-C3-methyt-5- nltropyridin-2-yl)-6.7.8.9-tetrahvdro-5H-pyrimidor[4,5-d]azepin-4-amine. 1 MS (ESI). mass calcd. for C27H34N6O2. 474.27; m/z found. 475.5 [M+H]+ 1H NMR (CDCI3): 8.97-8.85 (m. 1H). 8.16-8.02 (m. 1H). 7.63-7.54 (m. 2H). 7.39-7.33 (m. 2H). 6.45 (3. 1H). 3.99-3.88 (m. 2H). 3.86-3.81 (m. 2H). 3.27-3.16 (m. 2H). 3.05-2.94 (m. 3H). 2.39 (3. 3H). 1.34-1.33 (m. 9H). 1.31 (d. J = 6.9 Hz. 6H). Example 290: N-r4-M.1-Dimethytethyl)phenyl)-2-n-methylethyl)-7-(5-nrtro-3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H-pyr1mldor4.5-dlazepin-4-amine. : MS (ESI): mass calcd. for C27H31F3N6O2. 528.25; m/z found. 529.5 [M+H]+ 1H NMR (CDCI3): 9.12-9.01 (m. 1H). 8.63-8.57 (m. 1H). 7.67-7.50 (m. 2H). 7.40- 7.32 (m. 2H). 6.38 (s. 1H). 4.22-4.14 (m. 2H). 4.00-3.95 (m. 2H). 3.32-3.22 (m. 2H). 3.06-3.02 (m. 2H). 3.02-2.95 (m. 1H). 1.34-1.32 (m. 9H). 1.29 (d. J = 6.9 Hz. 6H). Example 291: 2-(1-Methytethyl)-7-(5-n}tro-3-)trinuoromethyt)pyridin-2-vfl-N-(4- (triflyioromethy MS (ESI): mass calcd. for C24H22F6N6O2. 540.17; m/z found. 541.5 [M+H]+. 1H NMR (CDCI3): 9.14-9.04 (m. 1H). 8.64-8.56 (m. 1H). 7.86-7.74 (m. 2H). 7.63- 7.58 (m. 2H). 6.57 (s. 1H). 4.23-4.15 (m. 2H). 4.02-3.94 (m. 2H). 3.35-3.24 (m. 2H). 3.12-3.06 (m. 2H). 3.07-2.97 (m. 1H). 1.30 (d. J = 6.9 Hz. 6H). Example 292: N-(4-M .1-Dlmethylethyl]phenyl]-7-l5-(luoro-3-methylDvridin-2-yl]-2- M-methylethy . The title compound was prepared from N-[4- metriylethyl)-7-(3-methyl-5-nltropyridin-2-yl)-6.7)8.9-tetrahydro-5H-pyrimWo(4.5- d]azepln-4-amine (Example 289) using procedures analogous to those reported in US 2000)006150343 and Marsais. F. et al. J. Heterocycl. Chem. 1988. 25(1). 81. MS (ESI): mass calcd. for C27H34FN5. 447.28; m/z found. 448.5 [M+H]". 1H NMR (CDCI3): 8.03-7.92 (m. 1H). 7.66-7.55 (m. 2H). 7.40-7.31 (m. 2H). 7.24-7.17 (m. 1H). 6.54-6.43 (m. 1H). 3.45-3.36 (m. 2H). 3.36-3.31 (m. 2H). 3.21-3.14 (m. 2H). 3.07-2.98 (m. 1H). 2.93-2.88 (m. 2H). 2.33 (s. 3H). 1.60-1.53 (m. 9H). 1.37-1.31 (m. 6H). Example 293: 2-(4-([4-rrrifluoromethyl]phenyl]amino)-5.6.8.9-tetrahydro.7H. Dvrimidor4.5-dlazepin-7-yl)pyridine-3-carbonitrile. MS (ESI): mass calcd. for C21H17F3N6. 410.15; m/z found. 411.1 [M+H]+ 1H NMR (CDCI3): 8.60 (s. 1H). 8.34 (dd. J + 4.7. 1.9 Hz. 1H). 7.78 (dd. J = 7.6. 1.9 Hz. 1H). 7.73 (d. J = 8.7 Hz. 2H). 7.64 (d. J = 8.4 Hz. 2H). 6.78-6.66 (m. 1H). 4.25-4.14 (m. 2H). 4.112.07 (m. 2H). 3.47-3.30 (m. 2H). 3.20-3.13 (m. 2H). Example 294: 2-(4-{f4-n)ifluoromethy pyrimido[4.5-d]azep MS (ESI): mass calcd. for C2iH19F3N«O. 428.16; m/z found. 429.1 [M+H]". 1H NMR (CD3OD): 8.62 (s. 1H). 8.22 (dd. J = 5.0. 1.9 Hz. 1H). 7.83 (dd. J = 7.5. 1.9 Hz. 1H). 7.78 (d. J = 8.7 Hz. 2H). 7.73 (d. J = 8.7 Hz. 2H). 6.89 (dd. J = 7.5. 5.0 Hz. 1H). 3.94-3.80 (m. 4H). 3.51-3.38 (m. 2H). 3.31-3.26 (m. 2H). Example 295: 7-[3-Fluoropyridin-2-vlVN-(4-)trifluorometfivltori9nyl]-6.7.8.9- tetrahvdro-5H-pyrimido[4.5-d1azepln-4-arnlne. MS (ESI): mass calcd. for C20H17F4N5. 403.14; m/z found. 404.2 [M+H]+. 1H NMR (CDCl3): 8.62 (s. 1H). 8.11-7.79 (m. 2H). 7.77-7.62 (m. 4H). 7.34-7.22 (m. 1H). 6.86-6.60 (m. 1H). 4.15-3.90 (m. 4H). 3.26-2.96 (m. 4H). Example 296: N-(4-(1.1-Dimethylethyl)phenyl]-7-(3-(ethylsulfonyl)pyridin-2-yl-2-(1- methylethyl)-6.7.8.9-tetrahvdro-5H-pyrimldo[4,5-d]azepin-4-amine. The title compound was prepared analogously to the methods described in Example 26. substituting 2-chloro-3-ethanesulfonyl-pyridine (prepared using methods analogous to those reported in J. Org. Cham. 1979. 44(17). 3080-3082) In Step C. MS (ESI): mass calcd. for C28H37N5O2S. 507.27; m/z found. 508.2 [M+H]+. 1H NMR (CDCI3): 8.44 (dd. J =4.7. 1.9 Hz. 1H). 8.27 (dd. J = 7.8. 1.9 Hz. 1H). 7.61-7.47 (m. 2H). 7.32-7.24 (m. 2H). 7.14 (dd. J + 7.8. 4.8 Hz. 1H). 6.56 (s. 1H). 3.53-3.43 (m. 2H). 3.45-3.41 (m. 2H). 3.22 (q. J « 7.4 Hz. 2H). 3.15-3.08 (m. 2H). 3.01-2.92 (m. 1H). 2.91-2.86 (m. 2H). 1.29-1.22 (m. 15H). Example 297: 7-[3-TEthylsulfonyl)pyridin-2-yl]-2-piperidin-1-yl-N-(4- (trifluoromethyl)phenyl]-6.7.8.9-tetrahvdro-5H-pyrimldo[4.5-dlazepln-4-amine. The title compound was prepared analogously to the methods described in Example 26. substituting 2-chloro-3-ethanesulfonyl-pyridine (prepared using methods analogous to those reported in J. Org. Chem. 1979.44(17). 3080-3082) in Step C. MS (ESI): mass calcd. for C27H31F3N6O2S. 560.22; m/z found. 561.1 [M+HJ". 1H NMR (CDCb): 8.44 (dd. J = 4.7. 1.9 Hz. 1H). 8.27 (dd. J = 7.8. 1.9 Hz. 1H). 7.58 (d. J = 8.5 Hz. 2H). 7.49 (d. J = 8.7 Hz. 2H). 7.13 (dd. J = 7.8. 4.8 Hz. 1H). 6.60 (s. 1H). 3.76-3.58 (m. 4H). 3.49-3.42 (m. 2H). 3.41-3.37 (m. 2H). 3.28 (q. J = 7.4 Hz. 2H). 3.03-2.96 (m. 2H). 2.85-2.78 (m. 2H). 1.65-1.49 (m. 4H). 1.02 (t. J = 7.5 Hz. 3H). The following Examples 298-302 were prepared using methods analogous to those described In Example 26. substituting the appropriate 2-chloro pyridines (see Cordl. A.A. et al. )) Farmaco. 2002. 57. 787) In Step C and and anilines in Step E. Example 288: 2-(2-PiDeridin-1-yl-4-)r4-2trifluoromethyl)phenyl]amino)-5.6.8.9- tetrahydro-7H-Pyrimldor4.5-dlazep|n-7-yl)pyridine-3-sulfonamide. MS (ESI): mass calcd. for C25H28F3N7O2S. 547.20; m/z found. 54S.1 [M+H]+. 1H NMR (CDCI3): 8.45 (dd. J = 4.8. 1.9 Hz. 1H). 8.23 (dd. J = 7.8. 1.9 Hz. 1H). 7.57 (d. J'= 8.6 Hz. 2H). 7.49 (d. J = 8.6 Hz. 2H). 7.15 (dd. J = 7.8. 4.8 Hz. 1H). 6.60 (s. 1H). 3.72-3.61 (m. 4H). 3.46-3.38 (m. 2H). 3.36-3.31 (m. 2H). 3.05-2.95 (m. 2H). 2.85-2.80 (m. 2H). 1.66-1.51 (m. 4H). Example 299: N-Cvclopropyl-2-22-piperidin-1-yl-4-(r4- (trifluoromethyt)phenyl]amino)-5.6.8.9-t8trahvdro-7H-py|1midor4.5-cflazepin-7- v1k)VTidine-3-sulfonarn{de. MS (ESI): mass calcd. for C25H28F3N7O2S. 587.23; m/z found. 588.1 [M+H]". 1H NMR (CDCI3): 8.44 (dd. J = 4.8. 1.9 Hz. 1H). 8.26 (dd. J =7.8. 1.9 Hz. 1H). 7.56 (d. J f= 8.6 Hz. 2H). 7.49 (d. J = 8.8 Hz. 2H). 7.13 (dd. J « 7.8.4.8 Hz. 1H). 6.62 (s. 1H). 6.68-5.41 (m. 1H). 3.72-3.64 (m. 3H). 3.46-3.39 (m. 2H). 3.36-3.32 (m. 2H). 3.03-2.93 (m. 2H). 2.84-2.78 (m. 2H). 1.68-1.50 (m. 4H). 0.41-0.16 (m. 4H). Example 300: N-(1-Methylethyl)-2-(2-piperidin-1-yl-4-[4- rtrifliloromethyODhenvllaminol-S.e.S.a-tetrahvdro)H-BvrimidorA.S-cnazenin.?- vOpyridine-3-sulfonamide. MS (ESI): mass calcd. for C25H28F3N7O2S. 589.24; m/z found. 590.2 [M+Hf. 1H NMR (CDCI3): 8.41 (dd. J =4.8. 1.9 Hz. 1H). 8.21 (dd. J = 7.7. 1.9 Hz. 1H). 7.58 (d. J = 8.5 Hz. 2H). 7.49 (d. J = 8.6 Hz. 2H). 7.10 (dd. J = 7.7. 4.8 Hz. 1H). 6.72 (s. 1H). 3.72-3.63 (m. 4H). 3.45-3.38 (m. 2H). 3.36-3.31 (m. 2H). 3.11-3.02 (m. 1H). 3.00-2.95 (m. 2H). 2.86-2.79 (m. 2H). 1.67-1.48 (m. 4H). 0.70 (d. J = 6.5 Hz. 6H). Example 301: 7-[3-)Ethylsulfonv1)Dvridin-2-vl1-N-r4-(triflucromethyl)phenv MS (ESI): mass calcd. for C25H28F3N7O2S. 477.14; m/z found. 478.1 [M+H]". 1H NMR (CDCI3): 8.63 (s. 1H). 8.55 (dd. J = 4.7. 1.9 Hz. 1H). 8.35 (dd. J = 7.8. 1.8 Hz. 1H). 7.72 (d. J = 8.6 Hz. 2H). 7.65 (d. J = 8.5 Hz. 2H). 7.27-7.24 (m. 1H). 3.66- 3.58 (m. 2H). 3.58-3.54 (m. 2H). 3.41-3.30 (m. 2H). 3.17-3.06 (m. 4H). 1.04 (t. J = 7.4 Hz. 3H). Example 302: 2-(4-24-rrrifluoromethyOphenv MS (ESI): mass calcd. forCsoH2FaNeC2S. 464.12; m/z found. 465.1 [M+HJ". 1H NMR (MeOD): 8.45-8.34 (m. 2H). 8.23 (dd. J = 7.8. 1.8 Hz. 1H). 7.63 (d. J = 8.5 Hz. 2H). 7.52 (d. J = 8.6 Hz. 2H). 7.15 (dd. J = 7.8. 4.8 Hz. 1H). 3.49-3.39 (m. 2H). 3.39-3.34 (m. 2H). 3.23-3.17 (m. 2H). 3.07-3.02 (m. 2H). Example 303: Methyl 5-chloro-6-r2-(methylsulfanvO-4-{f4- (trifluoromethyl)phenyl]am 1 Step A. 4-Hvdroxv-2-methyl3ulfanyl-5.6.8.9-tetrahvdro-ovrimidor4.5- dlazeplne-7-carboxvllc add tert-butyl ester. To solution o[ 5-oxo-azepane-1.4- dicarboxylic acid 1-tert-butyl ester 4-othyl ester (10.5 g. 0.04 mol) in EtOH (168 mL) was added NaOEt (8.1 g. 0.12 mol) and thiourea (4.2 g. 0.06 mol). The mixture was heated at reflux for 12 h. The mixture was cooled. treated With Mel (3.0 mL. 0.05 mol) drop-wise. and stirred at rt for 1 h. The mixture was concentrated and the residue was dissolved in water and acidified to pH = 7 with HOAc (a precipitate formed). The solid was filtered to give the title compound (8.4 g. 73%). which was used in the next step without further purification. 1 Step B: 2-Methytsulfanyl-4-trifluoromethane8ulfonvtoxv-5.6.8.9-tetrahvdro- pyrimido[4.5-cnazepine-7-carboxvlic acid tert-butvt ester. To a solution o[ 4- hydroxy-2-methyl3ulfanyl-5.6.8.9-tetrahydro-pyrimido[4.5-d]azepine-7-carboxylic acid tert-butyl ester (1.2g. 3.86 mmol) In THF (129 mL) was added KOtBu (518 mg. 4.63 mmol) at rt A(ter 20 min. N-phenyl-bis(trtfluoromethanesulfonimide) (1.9 g. 5.40 mmol) was added. The reaction mixture was stirred for an additional 24 h at rt and then concentrated. The residue was purified (FCC) to afford the title compound (1.4 g. 82%) Steo C: 22-Methylutfanv1-6.7.8.9-tetrahvdro-5H-Dvrimldo[4.5-d1a2eDin2-vl)- (4-trifluoromethyJ-Phenvll-amine. A solution containing mothylsulfanyM- trifluoromethanesulfonytoxy-5.6.8.9-tetrahydix)-pyrirnkk)[4.5-d]a2epine-7-cart)oxy1lc acid tert-butyl ester (950 mg. 2.15 mmol). 4-trifluoromethylaniline (0.6 mL. 4.74 mmol) and DMSO (8 mL) was heated at 100 °C for 24 h. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified (FCC; MeOH)CH2CI2) to give the title compound (422 mg. 55%). Step P. A solution o[ (2-methyisulfanyl-6.7.8.9-tetrahydro-5H-pyrimick)[4.5- d]azepin-4-yl)- nicotinic acid methyl ester (129 mg. 0.58 mmol). and EtaN (0.2 mL. 1.58 mmol) in i DMF (1.2 mL) was heated at 120 °C for 2 h. The mixture was cooled to rt. diluted with water. and extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified (FCC) to give the title compound (203 mg. 74%). MS (ESI): mass calcd. for C23H21CIF3N5O2S. 523.11; m/z found. 524.1 [M+H]". 1H NMR (CDCI3): 8.57 (d. J = 2.0 Hz. 1H). 8.00 (d. J = 2.0 Hz. 1H). 7.59 (d. J = 8.6 Hz. 2H). 7.48 (d. J + 8.6 Hz. 2H). 6.73-6.59 (m. 1H). 3.89-3.65 (m. 7H). 3.19-3.07 (m. 2H). 2.95-2.87 (m. 2H). 2.40 (s. 3H). The following Examples 304-306 were prepared using methods analogous to those described in Example 303. substituting the appropriate anilines in Step C and 2-chloro pyridines in Step D. Example 304: 2-(Methylsulfanvl)-7-[3-(methytsulfonvl)Dvridin-2-vll-N-r4- (trifluo[omethyt)DhenN41-6.7.8.9-tetrahvdro-5H-pyr)midor4.5-d]azepin-4-arnine. MS (ESI): mass calcd. for C25H28F3N7O2S. 509.11; m/z found. 510.1 [M+H]". 1H NMR (CDCI3): 8.62-8.49 (m. 1H). 8.40-8.35 (m. 1H). 7.73 (d. J = 8.5 Hz. 2H). 7.62 (d. J + 8.5 Hz. 2H). 7.25 (dd. J = 7.8. 4.7 Hz. 1H). 7.05-6.94 (m. 1H). 3.61-3.54 (m. 2H). 3.55-3.50 (m. 2H). 3.28-3.17 (m. 2H). 3.06 (s. 3H). 3.04-2.99 (m. 2H). 2.55 (s. 3H). Example 305: r7-(3-Ethanesulfonyl-Pvrtdin-2-viy-2-rnethyteulfanv tetrahvdro-5H-pyrimidor4.5-d1azepin-4-vfl-(4-trifluoromethyl-phenv1 famine. MS (ESI): mass calcd. for C25H28F3N7O2S. 523.13; m/z found. 524.1 [M+Hf. 1H NMR (CDCI3): 8.62-8.46 (m. 1H). 8.38-8.31 (m. 1H). 7.72 (d. J « 8.5 Hz. 2H). 7.62 (d. J = 8.5 Hz. 2H). 7.26-7.22 (m. 1H). 3.63-3.42 (m. 4H). 3.30-3.17 (m. 4H). 3.05-2.96 (m. 2H). 2.54 (a. 3H). 1.10-1.05 (m. 3H). i Example 306: (5-Chloro-6-(2-(methylsutfanv1)-4-{r4-(trifluoronnethyl]phenvflaminoV- 5.6.8.9-tetrahvdro-7H-pyrimidor4.5- The title compound was prepared analogously to that reported starting methyl 5-chloro-6-[2-(methylsulfanyl)-4-{I4-(trlfluorornethyi)-phenyl]amino}-5.6.8.9- tetrahydro-7H-pyrimido[4.5-d]azepin-7-yrjpyridine-3-cart)oxyIate (Example 303) (Boechat. N. et al. Tetrahedron Lett. 2004.45. 6021). MS (ESI): mass calcd. for C22H2iCIF3NsOS. 495.11; m/z found. 496.1 [M+H]+. 1H NMR (MeOD): 8.38-8.26 (m. 1H). 8.03 (d. J = 8.6 Hz. 2H). 7.96-7.92 (m. 1H). 7.80 (d. J = 8.6 Hz. 2H). 4.79-4.69 (m. 2H). 3.86-3.69 (m. 4H). 3.41-3.27 (m. 4H). 2.68 (s. 3H). EfflfpnlB 307: 2-aff4SV2-2-Dimeth pyrimido[4,5-d]azepin-4-amino A dispersion o[ NaH in mineral oil (12.0 mg. 0.28 mmol) was added to a flask containing (2.2-dimethyl-[1.3]dioxotan-4-yl)-mettianol (116nL. 0.94 mmol) and DMF (1.0 mL). A(ter 30 min. the mixture was transferred to a flask containing [2- rnetnanesuIfonyt-7-(3-trifluoromethykpyridin-2-y1)-6.7.8.9-tetrahydro-5H- pyrimido[4.5-dlazepln-4-yI]-(4-trffluoromethyl-phenyl)-amine (Example 53; 50 mg. 0.094 mmol). The resulting mixture was then heated at 70 °C for 24 h. The mixture was cooled. diluted with MeOH (1.0 mL) and purified by reverse phase HPLC. yielding 39 mg (70%) o[ the title compound. MS (ESI): mass calcd. for C27H27F6N5O3. 583.20; m/z found. 584.2 [M+H]". 1H NMR (CDCI3): 8.39-8.37 (rh. 1H). 7.89-7.86 (m. 1H). 7.69 (d. J = 11.0 Hz. 2H). 7.59 (d. J = 11.0 Hz. 2H). 6.98- 6.94 (m. 1H). 6.68 (s. 1H). 4.52-4.56 (m. 1H). 4.42-4.38 (m. 1H). 4.28-4.24 (m. 1H). 4.16-4.12 (m. 1H). 3.94-3.90 (m. 1H). 3.63-3.56 (m. 4H). 3.18-3.15 (m. 2H). 2.96- 2.93 (m. 2H). 1.46 (s. 3H). 1.38 (s. 3H). The following Examples 308-340 were prepared using methods analogous to those described in Example 307. substituting the appropriate alcohols. Example 308: 2-2CvcJohexvioxv)-7-[3-(trifluoromethyOpyrldin-2-v [(trifluoromethyl2sulfonvliDhenvll-6.7.8.9-tetrahvdro-5H-Dvrimidor4.5-cnazepln-4- amlrie. MS (ESI): mass calcd. for C27H27F6N5O3S. 615.17; m/z found. 616.2 [M+H]". 1H NMR (CDa3): 8.40-8.38 (d. J = 5.0 Hz. 1H). 7.98 (d. J = 9.0 Hz. 2H). 7.93-7.87 (m. 3H). 7.00-6.97 (m. 1H). 6.96 (s. 1H). 4.92-4.87 (m. 1H). 3.64-3.57 (m. 4H). 3.22-3.18 (m. 2H). 3.00-2.95 (m. 2H). 2.11-2.08 (m. 2H). 1.89-1.86 (m. 2H). 1.69- 1.63(m. 2H). 1.46-1.25 (m. 4H). Example 309: 2-r(1-Cvdohexvlethyl)oxv1-N-(2-methyM-(1r amine. MS (ESI): mass calcd. for C2H2NsC). 593.26; m/z found. 594.3 [M+H]1H NMR (CDCb): 8.39-8.37 (m. 1H). 8.08 (d. J - 11.0 Hz. 1H). 7.89-7.86 (m. 1H). 7.46 (s. 2H). 6.97-6.94 (m. 1H). 6.42 (s. 1H). 4.84-4.78 (m. 1H). 3.66-3.53 (m. 4H). 3.19-3.16 (m.2H). 2.94-2.91 (m. 2H). 2.36 (s. 3H). 1.80-1.72 (m. 4H). 1.68-1.57 (m. 2H). 1.24 (d. J = 8.0 Hz. 3H). 1.21-0.97 (m. 5H). Example 310: 2-(CvdopentvloxvVfS-(2-methy (triflijiorometliv1)pyridin-2-yl]-€.7.8.9-tetrahvdro-5H-pyrimkior4.5-d1azepin-4-annine. MS (ESI): mass calcd. for C2I2FeNsO. 551.21; m/z found. 552.3 [M+H]". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 8.17 (d. J + 11.0 Hz. 1H). 7.89-7.87 (m. 1H). 7.46 (s. 2H). 6.97-6.94 (m. 1H). 6.44 (s. 1H). 5.25-5.20 (m. 1H). 3.66-3.57 (m. 4H). 3.18-3.15 (m. 2H). 2.95-2.92 (m. 2H). 2.36 (s. 3H). 1.88-1.76 (m. 6H). 1.63-1.54 (m. 2H). Example 311: 2-rM-Methylpiperidin-4-vlk)xv1-N-(4-(trifluoromethyl)Dhenyl]-7-[3- (trifluorometh22pyrkJin-2-v11-6T.8.9-tetrahvdro-5H-Dvrimidor4.5-d1azeDin-4-amine. MS (ESI): mass calcd. for CwHttFeNeO. 566.22; m/z found. 567.3 [M+H]1H NMR (CDCI3): 8.40-8.37 (m. 2H). 7.88-7.86 (m. 1H). 7.60 (s. 3H). 7.00-6.97 (m. 1H). 5.24 (br s. 1H). 3.57-3.52 (m. 4H). 3.46-3.05 (m. 6H). 3.05-3.02 (m. 2H). 2.79 (s. 3H). 2.65 (8. 1H). 2.37-2.30 (m. 2H). 2.18-2.13 (m. 2H). Example 312: N-(2-Methyl-4-(trifluoromethyi)Dhenyl]-2-(tetrahvdro-2H-pyran-4- vloxv)-7-(3-(trifluoromethyl)Pwidin-2-yll-6.7.8.9-tetrahvdro-5H-Dvr1mldo[4.5- dlazepin-4-amlne. MS (ESI): mass calcd. for C25H28F3N7O2S. 567.21; m/z found. 568.2 [M+HJ". 1H NMR (CDCb): 8.39-8.38 (m. 1H). 8.01 (d. J = 10.5 Hz. 1H). 7.89-7.86 (m. 1H). 7.48-7.46 (m. 2H). 6.98-6.95 (m. 1H). 6.43 (3. 1H). 4.99-4.92 (m. 1H). 4.02-3.96 (m. 2H). 3.90 Example 313: N-(2-Methyl-4-)trifluoromettivl2nhenyl]-2-)tetrahvdro[uran-3-v amine. MS (ESI): mass calcd. for CasHaFeNsOa. 553.19; m/z found. 554.2 [M+H]". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.97 (d. J = 11.0 Hz. 1H). 7.89-7.86 (m. 1H). 7.49 (s. 2H). 6.98-6.95 (m. 1H). 6.42 (s. 1H). 5.33-5.28 (m. 1H). 3.97-3.85 (m. 4H). 3.66-3.57 (m. 4H). 3.19-3.16 (m. 2H). 2.96-2.93 (m. 2H). 2.35 (s. 3H). 2.20-2.08 (m. 2H). Example 314: N-r4-(Pvrrolidirv1-vlsulfonyl]phenyl]-2-2tetrahvdro[uran-3-v1oxv)-743- (trif1uoromethyl]pyridin-2-vll-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-cnazep{n-4-amine. MS (ESI): mass calcd. forC2aH3iF3N604S. 604.21; m/z found. 605.2 [M+H]". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.89-7.87 (m. 1H). 7.79 (d. J =11.0 Hz. 2H). 7.72;(d. J = 11.0 Hz. 2H). 6.99-6.96 (m. 1H). 6.81 (s. 1H). 5.46-5.42 (m. 1H). 4.70- 3.90 (m. 4H). 3.63-3.56 (m. 4H). 3.27-3.24 (m. 4H). 3.19-3.16 (m. 2H). 2.98-2.95 (m. 2H). 2.25-2.20 (m. 2H). 1.80-1.76 (m. 4H). Example 315: 2-{f1-(1-Methylethyl)pyrrolidin-3-v MS (ESI): mass calcd. for C28H30FeNflO. 580.24; m/z found. 581.3 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.88 (m. 1H). 7.70 (d. J = 9.0 Hz. 2H). 7.61 (d. J = 9.0 Hz. 2H). 8.99-6.96 (m. 1H). 6.67 (s. 1H). 5.37-5.33 (m. 1H). 3.65- 3.58 (m. 4H). 3.31-3.28 (m. 1H). 3.20-3.17 (m. 2H). 2.97-2.94 (m. 2H). 2.83-2.79 (m. 1H). 2.69-2.62 (m. 2H). 2.47-2.42 (m. 1H). 2.34-2.27 (m. 1H). 2.08-2.02 (m. 1H). 1.12-1.10 (m.6H). Example 316: 2-(n-Cyglohexytethy0oxv)-N-(1-methyH .2.3.4-tetrahvdrPQuinolin-7- vlW7-(?-rtrifluorom6thy+ovrid(n-2-vf1-6.7.8.9-tetrahvdro-5H-DVrimtdo[4.5-d1azepfn-4- amine. MS (ESI): mass calcd. for CuHaFaNeO. 580.31; m/z found. 581.4 [M+H]Example 317: 2-(n-CvcloDroDv MS (ESI): mass calcd. for CaeHajFeNsOaS. 601.16; m/z found. 602.2 [M+HJ". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.97 (d. J = 9.0 Hz. 2H). 7.90-7.88 (m. 1H). 7.88 (d. J = 9.0 Hz. 2H). 7.00-6.97 (m. 1H). 6.95 (s. 1H). 4.64-4.58 (m. 1H). 3.63- 3.57 (m. 4H). 3.21-3.19 (m. 2H). 3.00-2.98 (m. 2H). 1.45 (d. J = 1.5 Hz. 3H). 1.24- 1.17 (m. 1H). 0.61-0.51 (m. 2H). 0.47-0.42 (m. 1H). 0.34-0.29 (m. 1H). Example 318; 2-t(1-Cvctohexvlethyl)oxv]-743-(trifluorom9thyl)pyridin-2-yl]+N-{4- f(trifluoromethyl)sulfonyl]phenv1)-6.7.8.9-tetrahvdro-5H-Dvrimido[4.5-dlazepin-4- amlr)e. MS (ESI): mass calcd. for C2HaiFeNeOaS. 643.21; m/z found. 644.2 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.98 (d. J = 9.0 Hz. 2H). 7.92-7.88 (m. 1H). 7.90 (d. J = 9.0 Hz. 2H). 7.00-6.98 (m. 1H). 6.95 (s. 1H). 4.95-4.90 (m. 1H). 3.63- 3.58 (m. 4H). 3.22-3.20 (m. 2H). 3.00-2.97 (m. 2H). 1.91-1.88 (m. 1H). 1.83-1.76 (m. 3H). 1.72-1.66 (m. 2H). 1.33 (d. J = 1.5 Hz. 3H). 1.30-1.08 (m. 5H). Example 319; 2-(Cvdopentv1oxv)-7-[3-(trifluoromethy f(trifluoromettivl)3ulfonyl]phenyl)-6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1azepin-4- amine. MS (ESI): mass calcd. for C25H28F3N7O2S. 601.16; m/z found. 602.2 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.99 (d. J = 9.0 Hz. 2H). 7.94 (d. J = 9.0 Hz. 2H). 7.90-7.88 (m. 1H). 7.00-6.97 (m. 1H). 6.97 (s. 1H). 5.37-5.33 (m. 1H). 3.63- 3.57 (m. 4H). 3.22-3.19 (m. 2H). 3.00-2.98 (m. 2H). 2.00-1.91 (m. 4H). 1.91-1.85 (m. 2H). 1.69-1.63 (m.2H). Example 320: 2-rM-Cvdohexvlethy0oxv]-N-(4-(PViTol)din-1-v1sutfonv1)ohenvf1-7-(3- (trifluo[omethyl)pyr MS (ESI): mass calcd. for C25H28F3N7O2S. 644.28; m/z found. 645.5 [M+H]". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.89-7.86 (m. 1H). 7.80 (d. J = 9.0 Hz. 2H). 7.74 (d. J = 9.0 Hz. 2H). 6.96 (m. 1H). 6.75 (s. 1H). 4.932.87 (m. 1H). 3.62-3.54 (m. 4H). 3.27-3.23 (m. 4H). 3.19-3.16 (m. 2H). 2.95-2.93 (m. 2H). 1.89-1.85 (m. 1H). 1.82-1.71 (m. 7H). 1.68-1.62 (m. 2H). 1.29 (d. J = 1.5 Hz. 3H). 1.27-1.04 (m. 5H). Example 321: 2-K1-Cvdopropy1ethyttoxyl-N-( 1-methyl-1.2.3.4-tetrahvdrooulnotin- 7-vlV7-[3-(trifluoromethyl)pyi1din-2-yl]-6.7.8.9-tetrahvdro-5H-pyrimldor4.5-dlazeDln- 4-amine. 1 IMS (ESI): mass calcd. for C2H2NaC 580.7; m/z found. 581.4 [M+Hf. Example 322: 2-rretrahvdro-2H-DvrBn-4-viQxvV7-[3-(trifluoromethVl)ovridin-2-vfl-N- 24-22rif2uo2omethy2)s2lfonvflphenyl)-6.7.B=9-tet2ahvdfx)-5H-Pvrim2do24.5-C1-6azeo222-4- flmine. MS (ESI): mass calod. for CzeH2sFeNsC2S. 617.15; mJz found. 618.2 [M+H]". 1H NMR (COCI3): 8.41-8.40 (m. 1H). 7.99 (d. J = 9.0 Hz. 2H). 7.91-7.87 (m. 3H). 7.01-6.98 (m. 1H). 6.95 (s. 1H). 5.16-5.11 (m. 1H). 4.07-4.03 (m. 2H). 3.64-3.58 (m. 6H). 3.23-3.21 (m. 2H). 3.01-2.99 (m. 2H). 2.13-2.08 (m. 2H). 1.94-1.87 (m. 2H). Example 323: N-(1-MethyH 2.3.4-tetrahvdroQuinolin-7-v vloxvV7-[3-rtrifluoromethyl)pyrtdirt-2-vH-6.7.8.9-tetrahvdro-5H-PVrimklo[4.5- dlazepin-4-amine. == MS (ESI): mass calcd. for C28H31F3N6O2. 540.24; m/z found. 541.3 [M+Hf. 1H NMR (CDCb): 8.41-8.39 (m. 1H). 7.89-7.87 (m. 1H). 6.97-6.94 (m. 1H). 6.92 (d. J = 8.0 Hz. 1H). 6.81-6.79 (m. 1H). 6.60 (d. J = 2.0 Hz. 1H). 6.44 (s. 1H). 5.45-5.42 (m. 1H). 4.10-4.06 (m. 1H). 4.00-3.95 (m. 1H). 3.93-3.88 (m. 2H). 3.65-3.58 (m. 4H). 3.26-3.23 (m. 2H). 3.16-3.14 (m. 2H). 2.92-2.89 (m. 4H). 2.76 (t. J = 6.0 Hz. 2H). £23-2.13 (m. 3H). 2.02-1.97 (m. 2H). Example 324: 2-(Cvdopentyloxv)-N-n-ro6thyl-1.2.3.4-tetrahvdroauinoHn-7-v1V7-(3- (tr1fluo[omethy))Dvridin-2-vlI-6.7.8.9-tetrahvdro-5H-Dvrimldor4.5-dlazeD MS (ESI): mass calcd. for C29H33F3N6O. 538.27; m/z found. 539.3 [M+H]Example 325: Z-(d-Cvclopropylethyitoxvi-N-(Z-methyl-2(trifluoromettivOphenvil-?- f32triflLKifornethyl)pyridin-2-yl]-6.7.8.9-tetrahvdro-5H2pyrirnidor4.5-d)a2eoin-4- amlne. MS (ESI): mass calcd. for C27H27F8N5O. 551.21; m/z found. 552.3 [M+H]". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 8.03 (d. J = 11.5 Hz. 1H). 7.89-7.86 (m. 1H). 7.47 (s. 1H). 7.45 (s. 1H). 6.97-6.94 (m. 1H). 6.39 (s. 1H). 4.52-4.45 (m. 1H). 3.65- 3.57 (m. 4H). 3.18-3.15 (m. 2H). 2.93-2.90 (m. 2H). 2.35 (s. 3H). 1.37 (d. J = 8.0 Hz. 3H). 1.18-1.09 (m. 1H). 0.55-0.43 (m. 2H). 0.40-0.33 (m. 1H). 0.25-0.19 (m. 1H). Example 326; 2-2Cvclohexv1oxv)-N-(2-methy (trifluoromethyl')pyridin-2-vfl-6.7.8.9-tetfahvdro-5H-pyrimldo[4.5-d]azepln-4-amina. MS (ESI). mass calcd. for C2eH2sFsN3O. 565.23; m/z found. 566.3 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 8.16 (d. J = 9.0 Hz. 1H). 7.90-7.88 (m. 1H). 7.49-7.48 (m. 2H). 6.99-6.96 (m. 1H). 6.46 (s. 1H). 4.81-4.76 (m. 1H). 3.67-3.66 (m. 2H). 3.61-3.59 (m. 2H). 3.20-3.17 (m. 2H). 2.96-2.94 (m. 2H). 2.38 (s. 3H). 2.05-2.01 (m. 2H). 1.85-1.80 (m. 2H). 1.63-1.51 (m. 1H). 1.38-1.27 (m. 5H). Example 327: 2-TButv1O)cv)-7-(3-rtiTfluoromethyHDvridin-2-v11-N-r6- (trifluoromethy MS (ESI): mass calcd. for C25H28F3N7O2S. 526.19; m/z found. 527.2 [M+H]". 1H NhiR (CDCI3): 8.82 (d. J + 2.5 Hz. 1H). 8.39-8.34 (m. 2H). 7.89-7.87 (m. 1H). 7.67 (d. J = 8.5 Hz. 1H). 6.98-6.95 (m. 1H). 6.83 (brs. 1H). 4.29 (t. J " 6.5 Hz. 2H). 3.64-3.61 (m. 2H). 3.59-3.56 (m. 2H). 3.21-3.19 (m. 2H). 3.01-2.98 (m. 2H). 1.80- 1.74 (m. 2H). 1.55-1.47 (m. 2H). 0.96 (t. J = 7.0 Hz. 3H). Example 328: 2-(Cvclohexvloxv)-N-( 1-methyl-1.2.3.4-tetrahvdroQulnoHn-7-vt)-7-[3- (trifluorornethyl)pwidin-2-v MS (ESI): mass calcd. for C25H28F3N7O2S. 552.28; m/z found. 553.3 [M+HJ". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.87-7.84 (m. 1H). 6.94-6.88 (m. 3H). 6.56 (d. J = 2.5 Hz. 1H). 6.41 (s. 1H). 4.93-4.86 (m. 1H). 3.63-3.58 (m. 4H). 3.23 (t. J = 7.0 Hz. 2H). 3.14-3.11 (m. 2H). 2.89 (s. 3H). 2.88-2.86 (m. 2H). 2.74 (t. J = 8.0 Hz. 2H). 2.0 -1.94 (m. 4H). 1.81 -1.78 (m. 2H). 1.59-1.53 (m. 3H). 1.37-1.26 (m. 3H). Example 329: N-n-Methyl-1.2.3.4-tetrahvdroQuino tflazepln-4-amine. MS (ESI): mass calcd. for C29H33F3N0O2. 554.26; m/z found. 555.3 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.89-7.87 (m. 1H). 6.97-6.94 (m. 1H). 6.91 (d. J + 8.0 Hz. 1H). 6.86-6.83 (m. 1H). 6.59 (d. J = 2.0 Hz. 1H). 6.43 (3.1H). 5.13-5.08 (m. 1H). 4.03-3.99 (m. 2H). 3.65-3.53 (m. 6H). 3.26-3.24 (m. 2H). 3.17-3.14 (m. 2H). 2.92-2.89 (m. 5H). 2.76 (t. J = 6.5 Hz. 2H). 2.08-1.97 (m. 4H). 1.89-1.81 (m. 2H). Example 330: 2-((f(4RV2.2-Dlmethyl-1.3-dloxotan-4-vllmethylk)xvVN-(4- (trifluonomethyl)phenyl]-7-(3-(trifluoromethyl)pyridin-2-vll-6.7.8.9-tetrahvdro-5H- pyrimido[4.5-dlazepirt-4-amine. MS (ESI): mass calcd. for C25H28F3N7O2S. 583.20; m/z found. 584.2 [M+H]". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.89-7.86 (m. 1H). 7.69 (d. J " 11.0 Hz. 2H). 7.59:(d. J = 11.0 Hz. 2H). 6.98-6.94 (m. 1H). 6.68 (s. 1H). 4.52-4.56 (m. 1H). 4.42- 4.38 (m. 1H). 4.28-4.24 (m. 1H). 4.16-4.12 (m. 1H). 3.94-3.90 (m. 1H). 3.63-3.56 (m. 4H). 3.18-3.15 (m. 2H). 2.96-2.93 (m. 2H). 1.46 (s. 3H). 1.38 (s. 3H). Example 331: 2-rretrahvdro[uran-3-vtoxvV7-[3-(trifluorom9thyl)pyridin-2-vfT-N44- fnrifluoromethy))sutfonvrfiphenvf)-6.7.8.9-tetrahvclro-5H-PVrimtdo[4.5- amlne. MS (ESI): mass calcd. for CasHzaFeNsC2S. 603.14; m/z found. 604.2 [M+H]1H NMR (CDCI3): 8.40-8.39 (m. 1H). 7.99 (d. J = 9.0 Hz. 2H). 7.91-7.87 (m. 3H). 7.01-6.98 (m. 2H). 5.50-5.46 (m. 1H). 4.12-4.08 (m. 1H). 4.06-3.93 (m. 3H). 3.64- 3.58 (m. 4H). 3.23-3.20 (m. 2H). 3.02-2.99 (m. 2H). 2.28-2.24 (m. 2H). Example 332: 2-rn-Cvclohexvlethyl)oxv1-N-(4-(trifluoromethyl2Dhenv1V7-[3- (trifluprome MS (ESI.): mass calcd. for C25H28F3N7O2S. 579.24; m/z fourxl. 580.2 (M+H)". 1H NMR (CDCI3): 8.41-6.39 (m. 1H). 7.90-7.88 (m. 1H). 7.70 (d. J = 8.5 Hz. 2H). 7.59 (d. J = 8.5 Hz. 2H). 6.99-6.96 (m. 1H). 6.67 (s. 1H). 4.94-4.88 (m. 1H). 3.65- 3.58 (m. 4H). 3.20-3.17 (m. 2H). 2.96-2.94 (m. 2H). 1.90-1.87 (m. 1H). 1.83-1.75 (m. 3H). 1.72-1.65 (m. 2H). 1.31 (d. J = 6.5 Hz. 3H). 1.28-1.07 (m. 5H). Example 333: 2-(Cvctopenty1oxv)-N-(4-Ypyrrolidin-1-v1sutfonyl]ph8nvil-7-(3- (trffluoromethyl)Pvridin-2-vl]-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azephi-4-amine. MS (ESI): mass calcd. for C25H28F3N7O2S. 602.23; m/z found. 603.3 [M+H]". 1H NMR (CDCI3): 8.39-6.37 (m. 1H). 7.89-7.86 (m. 1H). 7.79 (s. 4H). 6.98-6.94 (m. 1H). 6.77 (s. 1H). 5.33-5.30 (m. 1H). 3.62-3.55 (m. 4H). 3.27-3.23 (m. 4H). 3.18- 3.16 (m. 2H). 2.96-2.93 (m. 2H). 1.96-1.75 (m. 9H). 1.66-1.58 (m. 3H). Example 334: 2-((1-CvdoDropyl8thyt)oxv1-N-r4-2pyrrolidin-1-vtsulfonvt)phenyll-7-(3- rtrlfluoromethyl)pyridin-2-vlT-6.7.8.9-tetrahvdro-5H-pyTimido[4.5-cllazepin-4-amlne. MS (ESI): mass calcd. for C25H28F3N7O2S. 602.23; m/z found. 603.3 [M+H]". 1H NMR (CDCI3): 8.39-8.37 (m. 1H). 7.89-7.86 (m. 1H). 7.78 (d. J = 11.0 Hz. 2H). 7.71 (d. J = 11.0 Hz. 2H). 6.98-6.94 (m. 1H). 6.74 (s. 1H). 4.61-4.54 (m. 1H). 3.62- 3.55 (m. 4H). 3.27-3.23 (m. 4H). 3.18-3.15 (m. 2H). 2.95-2.93 (m. 2H). 1.79-1.75 (m. 4H). 1.42 (d. J = 8.0 Hz. 3H). 1.21-1.15 (m. 1H). 0.58-0.39 (m. 3H). 0.30-0.24 (m. 1H). Example 335: N-r4-2PvrroHdin-1-vtsulfonv2Dhenvl)-2-(tetrahvdro-2H-ovran-4-vtoxvV 7-(3-2trifluoromethyHpyrldin-2-vll-6.7.8.9-tetrahvdro-5H-pyrimldo[4.5-d1azepln-4- pmine. MS (ESI): mass calcd. for C29H33F3N8O4S. 618.22;m/z found. 619.3 [M+H]". 1H NMR (CDCI3): 8.40.8.38 (m. 1H). 7.89-7.86 (m. 1H). 7.79 (d. J = 11.0 Hz. 2H). 7.72 (d. J = 11.0 Hz. 2H). 6.99-6.95 (m. 1H). 6.80 (s. 1H). 5.13-5.06 (m. 1H). 4.06- 4.00 (m. 2H). 3.62-3.54 (m. 6H). 3.27-3.24 (m. 4H). 3.19-3.16 (m. 2H). 2.97-2.94 (m. 2H). 2.11-2.06 (m. 2H). 1.92-1.83 (m. 2H). 1.80-1.75 (m. 4H). Example 336: 2-2CvdoheDtv MS (ESI): mass calcd. for C25H28F3N7O2S. 565.23; m/z found. 566.2 [M+H]1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.88 (m. 1H). 7 71 (d. J = 9.0 Hz. 2H). 7.60 (d. J = 9.0 Hz. 2H). 6.99-6.96 (m. 1H). 6.68 (s. 1H). 5.08-5.03 (m. 1H). 3.65- 3.58 (m. 4H). 3.19-3.17 (m. 2H). 2.96-2.94 (m. 2H). 2.13-2.07 (m. 2H). 1.88-1.74 (m. 4H). 1.64-1.58 (m. 4H). 1.51-1.44 (m. 2H). Example 337: 2-CCvdODentvloxy)-N-(4-(trifluoromethyl)Dhenvl]-7-(3- (trinuoromethyl)ovrldin-2-v1V6.7.8.9-tetrahvdro-5H-pyrlrnldo[4.5-d1azepln-4-amlne. MS (ESI): mass calcd. for Ca2FsNsO. 537.20; m/z found. 538.2 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.87(m. 1H). 7.74 (d. J = 8.5 Hz. 2H). 7.60 (d. J = 8.5 Hz. 2H). 6.99-8.96 (m. 1H). 6.70 (3. 1H). 5.34-5.30 (m. 1H). 3.64- 3.57 (m. 4H). 3.19-3.17 (m. 2H). 2.97-2.94 (m. 2H). 1.97-1.92 (m. 4H). 1.88-1.83 (2H). 1.65-1.62 (m.2H). Example 338: 2- MS (ESI): mas3 calcd. for C27H27F6N5O. 551.21; m/z found. 552.2 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 7.90-7.87 (m. 1H). 7.72 (d. J = 8.5 Hz. 2H). 7.59 (d. J = 8.5 Hz. 2H). 6.98-6.96 (m. 1H). 6.71 (s. 1H). 4.90-4.84 (m. 1H). 3.64- 3.57 (m. 4H). 3.19-3.17 (m. 2H). 2.96-2.94 (m. 2H). 2.10-2.07 (m. 2H). 1.88-1.84 (m. 2H). 1.65-1.55 (m. 3H). 1.44-1.27 (m. 3H). i Example 339; 2-(Tetrahvdro-2H-pyran-4-vtoxv)-N-(4-(trifluoromethyl)DhenvlV743- (trifluoromathyl)Pvridin-2-vll-6.7.8.9-tetrahvdrQ-5H-Pvrimidor4.5-dlazepin-4-amifie. 1 MS (ESI): mass calcd. for C25H28F3N7O2S. 553.19; m/z found. 554.2 [M+HJ". 1H NM.R (CDCI3): 8.41-8.40 (m. 1H). 7.91-7.88 (m. 1H). 7.68 (d. J = 8.5 Hz. 2H). 7.60 (d. J = 8.5 Hz. 2H). 6.99-6.96 (m. 1H). 6.69 (s. 1H). 5.12-5.06 (m. 1H). 4.06- 4.02 (m. 2H). 3.97 (s. 1H). 3.65-3.56 (m. 5H). 3.20-3.18 (m. 2H). 2.97-2.95 (m. 2H). 2.11-2.04 (m. 2H). 1.93-1.85 (m. 2H). Example 340: 2-(retrahvdro[urart-3-v MS (ESI): mass calcd. for CMHzjFeNoOz. 539.18; m/z found. 540.2 [M+H]". 1H NMR (CDCI3): 8.40-8.38 (m. 1H). 7.89-7.86 (m. 1H). 7.65 (d. J = 11.0 Hz. 2H). 7.60 (d. J = 11.0 Hz. 2H). 6.98-6.95 (m. 1H). 6.67 (s. 1H). 5.43-5.39 (m. 1H). 4.09- 4.05 (m. 1H). 4.00-3.89 (m. 3H). 3.64-3.56 (m. 4H). 3.19-3.15 (m. 2H). 2.96-2.93 (m.2H). 2.24-2.17 (m.2H). The following Examples 341-343 were prepared using methods analogous to those described in Example 307. substituting the appropriate alcohols and using the appropriate alcohol as the solvent. Example 341: 2-rC1-Methylethy (trtfluoromethyl)pyl]\jln-2-yl]-6.7.8.94etrahvdrc-5H-pyrimldo[4.5-d1a.29Pln-4-am)ne trifluoroacetic acid salt. MS (ESI): mass calcd. for C25H28F3N7O2S. 511.18; m/z found. 512.5 [M+H]". 1H NMR (MeOD): 8.46-8.44 (m. 1H). 8.03 (dd. J = 7.8. 1.7 Hz. 1H). 7.74 (s. 4H). 7.17-7f12 (m. 1H). 5.22-5.16 (m. 1H). 3.65-3.61 (m. 2H). 3.60-3.58 (m. 2H). 3.26- 3.21 (m. 2H). 3.19-3.14 (m. 2H). 1.37 (d. J = 6.2 Hz. 6H). Example 342: 2-(Phenvloxv)-N-(4-(trlf1uQfomethyl)ohenyl]-7-[3- (trifluoromethyl]Dvridin-2-vfl-6.7.8.9-tetrahvdro-5H-Pvrimklor4.5-d1azepln-4-amine trifluoroacetic acid satt. MS (ESI): mass calcd. for C27H21F8N9O. 545.17; m/z found. 546.5 [M+H]". 1H NMR (MeOD): 8.48-8.46 (m. 1H). 8.04 (dd. J = 7.8. 1.7 Hz. 1H). 7.51-7.46 (m. 2H). 7.44 (d. J = 8.6 Hz. 2H). 7.40-7.34 (m. 3H). 7.24 (d. J = 7.7 Hz. 2H). 7.16 (dd. J = 7.7. 4.8 Hz. 1H). 3.69-3.64 (m. 2H). 3.61-3.55 (m. 2H). 3.35-3.31 (m. 2H). 3.21- 3.16 (m.2H). Example 343: 2-(Butyloxv)-N-(4-)trifluorom9thy nrifluoromethyl)Dvr1din-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine. MS (ESI): mass calcd. for C25H28F3N7O2S. 525.20; m/z found. 526.1 [M+H]". 1H NMR (CDCI3): 8.40-8.37 (m. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.72-7.69 (m. 2H). 7.61-7.57 (m. 2H). 6.98-6.94 (m. 1H). 6.66 (a. 1H). 4.29 (t. J = 6.6 Hz. 2H). 3.64-3.56 (m. 4H). 3.20-3.15 (m. 2H). 2.97-2.94 (m. 2H). 1.81-1.75 (m. 2H). 1.54- 1.47 (m. 2H). 0.96 (t. J = 7.4 Hz. 3H). Example 344: 4-(f4-(Trifluoromethy yl]-6.7.8.9-tefrahvdro-5H-pyrimidor4.5-dlazepiri-2-ol triflubroacetic arid salt. A solution o[ IZ-methanesulfonyt-Z-(S-trifluoronriethyf-pyridin2-yiVej.a.g- tetrahydro-5H-pyrirnido[4(5- H2O)dioxane (4 mL) was heated at 60 °C for 1 h. The mixture was cooled. acidified with TFA (3 drops). and directJy purified using Preparative HPLC (conditions as in Example 54) to give the title compound (60 mg. 98%). MS (ESI): mass calcd. for C25H28F3N7O2S. 469.13; m/z found. 470.5 [M+H]". 1H NMR (CDCI3): 8.46-8.41 (m. 1H). 7.97 (dd. J = 7.8. 1.5 Hz. 1H). 7.64 (s.4H). 7.09 (dd. J = 7.7. 4.9 Hz. 1H). 3.63-3.58 (m. 2H). 3.58-3.53 (m. 2H). 3.18-3.12 (m. 2H). 2.89-2.84 (m. 2H). Example 345: 2-(EthyloxvVN-(42trifluoromethylk)henvH-7-[3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrarivdro-5H-pyiimido[4.5-d]azepin-4-amine trifluproacetic ado" salt. The title compound was prepared using methods analogous to ttiose described in Example 62. MS (ESI): mass calcd. for C23H21F6N5O. 497.17; m/z found. 498.4 [M+H]". 1H NMR (MeOD): 8.45 (dd. J =4.7. 1.5 Hz. 1H). 8.03 (dd. J = 7.8. 1.8 Hz. 1H). 7.75 (q. J = 8.9 Hz. 4H). 7.15 (dd. J = 7.5. 4.8 Hz. 1H). 4.45 (q. J « 7.1 Hz. 2H). 3.64-3.61 (m. 2H). 3.59-3.56 (rn. 2H). 3.25-3.22 (m. 2H). 3.17-3.15 (m. 2H). 1.38 (t. J = 7.1 Hz. 3H). Example 346: 2-r(Methyloxv)methyl]-7-[3-{trifluororn«thyl)Dvridin-2-vll-N-(6- (trifluoromethyl]pyrldin-3-yll-6.7.8.9-tetrahvdro-5H-oyrimido[4f5-d1azeplr)-4-Bmine trifluoroacetic acid salt. The title compound was prepared using methods analogous to those described for Example 39 with modifications to Step A as follows: Step A. 2-Hvdroxvmethy)-7-(3-trffluoromethyl-Dvridin-2-v1)-6.7.8.9- tetraLhvdro-5H-pyr1midor4.5-dla2epin-4-ol. To solution o[ NaOMe (1.9 mL) in MeOH (0.5 mL) was added 5-oxo-1-(3-trifluoromethyl-pyridin-2-y1)-a2epane-4-carboxy1ic add ethyl ester (Intermediate B; 285 mg. 0.96 mmol). followed by 2-chloro- acetamidine (149 mg. 1.16 mmol). A(ter heating at 100 CC in a microwave for 15 min. the mixture was cooled and concentrated. The residue was dissolved in water and extracted with CH2C2. The combined organic layers were dried. concentrated. and directly purified using Preparative HPLC (conditions as in Example 54) to give the title compound (86 mg. 26%). MS (ESI): mass calcd. for CaHMFeNeO. 498.16; m/z found. 499.3 [M+H]". 1H NMR (MeOD): 8.95 (d. J = 2.3 Hz. 1H). 8.47-8.45 (m. 1H). 8.29 (dd. J = 8.5. 2.2 Hz. 1H). 8.04 (dd. J = 7.8. 1.7 Hz. 1H). 7.88 (d. J = 8.6 Hz. 1H). 7.16 (dd. J = 7.7.4.9 Hz. 1H). 4.61 (s. 2H). 3.68-3.61 (m. 4H). 3.53 (s. 3H). 3.49-3.45 (m. 2H). 3.30-3.28 (m. 2H). Example 347: 2-Methyl-2-(4-(f2-(rmethyloxv)methyfl-7-(3-(trifluoromethyl)pyridin-2- yl]-6.7.8.9-tetrahvdro-5H-ovr)mklo[4.5-d1azepln-4-vl)amino)phenvf)propanenitrile trifluo'roacetic acid salt. The title compound was prepared using methods analogous to those described in Example 346. substituting the appropriate anilines in Step E. MS (ESI).' mass calcd. for C26H27F3N6O.496.22; m/z found. 497.5 [M+H]". 1H NMR (MeOD): 8.45 (dd. J = 4.7. 1.4 Hz. 1H). 8.03 (dd. J = 7.8. 1.8 Hz. 1H). 7.58 (s. 4H). 7.14 (dd. J = 7.4. 4.8 Hz. 1H). 4.54 (s. 2H). 3.68-3.60 (m. 4H). 3.51 (s. 3H). 3.44- 3.40 (m. 2H). 3.25-3.21 (m. 2H). 1.75 (s. 6H). Example 34fr ?-2M«thylsulfonvlV7-[3-arifluoromethy+PVridin-2.yl]-N-(5- rtrifluoromethYl)PVridin-2-vl1-e.7.8.9-tetrahvdro-5H-PVrimldo[4.5- The title compound was syl]thesized in a manner similar to Example 53 wtth modifications to Step C in Example 52 as follows: Step C. To a solution o[ 4-chloro-2-rnethyteu{fanyl-7-(3-trifluoromethyl- pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine (400 mg. 1.07 mmol). 4- trifluoromethyt-amino-pyridine (208 mg. 1.28 mmol). and NaOtBu (144 mg. 1.5 mmol) in toluene (4 mL) in a microwave vial was added a solution o[ Pd(OAc)2 (3.7 mg. 0.016 mmol) and 2- microwave at 200 °C for 2 h. The mixture was cooled. filtered through a plug o[ diatomaceous earth. and concentrated. The residue was purified (FCC) to afford the title compound (230 mg. 48%). MS (ESI): mass calcd. for C2iHuFoNeOaS. 532.11; m/z found. 533.1 [M+H]\ 1H NMR (CDCI3): 8.67 (d. J = 8.9 Hz. 1H). 8.56- 8.54 (m. 1H). 8.42-8.40 (m. 1H). 8.03-8.00 (m. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.85 (s. 1H). 7.03-6.98 (m. 1H). 3.70-3.65 (m. 2H). 3.63-3.59 (m. 2H). 3.39-3.36 (m. 2H). 3.32 (s. 3H). 3.10-3.15 (m. 2H). Example 349: 2-(Phenv)sulfanvl)-N-r4-2trifluoromethyl)Dhenyl]-7-[3- rtrifluoromethyl)Pvridin-2-vfl-6.7.8.9-tetrahvdro-5H-pyrimido[4.5-d1azepln-4-amine. To a microwave reaction viaJ were added [2-methanesulfonyl-7-(3- trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5-dJazepin-4-ylH4- trjfluoromethyl-phenyl)-amine (53 mg. 0.1 mmol). thiophenol (16 mg. 0.15 mmol). p-toluenesulfonlc acid monohydrate (10 mg. 0.05 mmol). and DMF (0.4 mL). The vial was capped. and the mixture was heated via microwave irradiation at 100 °C for 10 min. filtered through a 0.45 nm filter. and the filtrate was purified by reversed phase HPLC (Phenomenex Gemini 30 mm x 100 mm column. gradient o[ acetonitrile in 20 mM aqueous NH4OH). The titJe compound was obtained as a white solid (27 mg. 48%). MS (ESI): mass calcd. for C2TH2IF«N5S. 561.14; m/z found. 562 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.7.1.5 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.68-7.62 (m. 2H). 7.56-7.50 (m. 1H). 7.50-7.42 (m. 2H). 7.23 (d. J = 8.7 Hz. 2H). 7.16 (d. J = 8.7 Hz. 2H). 6.96 (dd. J = 7.4. 4.6 Hz. 1H). 6.58 (bs. 1H). 3.66-3.55 (m. 4H). 3.23-3.17 (m. 2H). 2.96-2.90 (m. 2H). Examples 350-352 were syl]thesized in a manner similar to Example 349 substituting the appropriate thiols. Example 350: 2-(Phenylsulfanyl)-7-(3- amine. MS (ESI). mass calcd. for C27H2iF6NsO2S2. 625.10; m/z found. 626 [M+HJ". 1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.4 Hz. 1H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.70-7.64 (m. 2H). 7.63-7.53 (m. 3H). 7.50-7.44 (m. 2H). 6.98 (dd. J = 7.9. 5.0 Hz. 1H). 6.81 (bs. 1H). 3.65-3.53 (m. 4H). 3.25-3.18 (m. 2H). 3.00-2.92 (m. 2H). Example 351; N-(2-Methyt-4-(trif1uoromethylk?henyl]-2-CPhenvl3UlfanylV7-(3- (trifluoromethyl)DVridin-2-vH-6.7.8.9-tetrahvdro-5H-pyrimkJor4.5-d1azepln-4-amlne. MS (ESI): mass calcd. for Cj-aHnFeNsS. 575.16; m/z found. 576 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.4 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.61- 7.56 (m. 2H). 7.48-7.42 (m. 2H). 7.42-7.33 (m. 2H). 7.32-7.28 (m. 1H). 7.02-6.93 (m. 2H). 6.43 (bs. 1H). 3.70-3.62 (m. 2H). 3.62-3.56 (m. 2H). 3.23-3.16 (m. 2H). 2.97-2.91 (m. 2H). 2.22 (s. 3H). Example 352: 2-(Pheny1surfgnvi)-7-(3-ltrifluoromethyl)pyridlp-2-yl]-N-( 1.4.4- trimethyt-1.2.3.4-tetrahvdroqu|no|in-7-v0-6.7.8.9-tetrahydro-5H-pyrimido[4.5- dlazeDln-4-amlne. MS (ESI): mass calcd. for C32H33F3N6S. 590.24; m/z found. 591 [M+H]". 1H NMR (CDCI3): 8.37 (dd. J = 4.7. 1.6 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1 H). 7.66- 7.60 (m. 2H). 7.43-7.33 (m. 3H). 6.94 (dd. J = 7.7. 4.8 Hz. 1H). 6.77 (d. J = 8.3 Hz. 1H). 6.53 (dd. J = 8.3. 2.2 Hz. 1H). 6.35 (bs. 1H). 6.23 (d. J = 2.2 Hz. 1H). 3.65- 3.54 (m. 4H). 3.22-3.10 (m. 4H). 2.91-2.83 (m. 2H). 2.77 (s. 3H). 1.76-1.70 (m. 2H). 1.25 (s.6H). Examples 353-375 were syl]thesized in a manner similar to Example 349 substituting the appropriate thiols and substituting CS2CO3 (4 molar equivalents) for p-toluenesulfonic acid. Example 353: 2-((Phenv1methy (trifluoromethylk)vridin-2-vfl-6.7.8.9-tetrarivdro-5H-Dvrlmldor4.5-dTazepirt-4-amlne. MS (ESI): mass calcd. for CasHaFgNsS. 575.16; m/z found. 576 [M+HJ". 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.4 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.59 (d. J = 8.6 Hz. 2H). 7.52 (d. J = 8.7 Hz. 2H). 7.37-7.32 (m. 2H). 7.30-7.20 (m. 3H). 6.96 (dd. J = 7.4. 4.8 Hz. 1H). 6.62 (bs. 1H). 4.36 (s. 2H). 3.67-3.60 (m. 2H). 3.60- 3.54 (m. 2H). 3.21-3.15 (m. 2H). 2.98-2.91 (m. 2H). Example 354: 2-(CvctohexvtsutfanvlVN-(4-(trifluoromethy))phenyl]-7-[3- (trifluQromethyi)Dvridin-2-v MS (ESI): mass calcd. for C2rH27F6N9S. 567.19; m/z found. 568 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.4 Hz. 1H). 7.87 (dd. J " 7.8. 1.8 Hz. 1H). 7.67 (d. J = 8.6 Hz. 2H). 7.58 (d. J = 8.6 Hz. 2H). 6.96 (dd. J = 7.5. 4.6 Hz. 1H). 6.63 (be. 1H). 3.73-3.61 (m. 1H). 3.68-3.60 (m. 2H). 3.60-3.53 (m. 2H). 3.19-3.12 (m. 2H). 2.98-2.92 (m. 2H). 2.14-2.05 (m. 2H). 1.82-1.73 (m. 2H). 1.68-1.60 (m. 1H). 1.56- 1.43 (m. 2H). 1.43-1.23 (m. 3H). Example 355: 2-(n-Methylethylteulfanyl]-N-(4-(trtfluoromethyt)Dhanv MS (ESI): mass calcd. for C25H28F3N7O2S. 527.16; m/z found. 528 [M+H]". 1H NMR (C0CI3): 8.36 (dd. J = 4.6. 1.4 Hz. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.68 (d. J = 8.6 Hz. 2H). 7.58 (d. J = 8.6 Hz. 2H). 6.96 (dd. J = 7.8. 5.1 Hz. 1H). 6.63 (bs. 1H). 3.87 (sept. J = 6.8 Hz. 1H). 3.67-3.61 (m. 2H). 3.61-3.54 (m. 2H). 3.20-3.14 (m. 2H}. 2.98-2.92 (m. 2H). 1.41 (d. J = 6.8 Hz. 6H). Example 356: 1-rf4-)r4-rrrifluoromethy+Dhenv 2-vf1-6.7.8.9-tetrahvdro-5H-pyrimldo[4.5-d]azep(n-2-v1)sulfanvflprQDan-2-p<.> . MS (ESI): mass calcd. for C24H23F6N5OS. 543.15; m/z found. 544 [M+H]". 1H NMR(CDd3): 8.39 (dd. J = 4.7. 1.5 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.65 (d. J = 8.8 Hz. 2H). 7.60 (d. J = 8.8 Hz. 2H). 6.97 (dd. J = 7.5.4.7 Hz. 1H). 6.67 (bs. 1H). 4.24 (bs. 1H). 4.15-4.05 (m. 1H). 3.65-3.60 (m. 2H). 3.60-3.53 (m. 2H). 3.29 (dd. J = 14.6. 3.0 Hz. 1H). 3.19-3.12 (m. 2H). 3.08 (dd. J = 14.6. 7.4 Hz. 1H). 2.99- 2.92 (m. 2H). 1.26 (d. J =6.2 Hz. 3H). Example 357: f2-(2-MethyMotrahvdno-(uran-3-vlsulfanvlV7-(3-trifluoromethyt- pyl]din-2-v The title compound was isolated as a mixture o[ isomers. MS (ESI): mass calcd.for C25H28F3N7O2S. 569.17; m/z found. 570 [M+H]\ 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.3 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.65 (d. J = 8.6 Hz. 2H). 7.54 (d. J = 8.7 Hz. 2H). 6.97 (dd. J = 7.4. 4.8 Hz. 1H). 6.63 (bs. 1H). 4.35-4.23 (m. 2H). 4.06-3.98 (m. 1H). 3.82-3.74 (m. 1H). 3.68-3.61 (m. 2H). 3.61-3.54 (m. 2H). 3.20-3.14 (m. 2H). 2.98-2.92 (m. 2H). 2.55-2.43 (m.iH). 2.11-2.02 (m. 1H). 1.27 (d. J = 6.1 Hz. 3H). Example 358; f2- Pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimldo[4,5-d]azepin-4-yl]-(4-trifluoromethyl- Phenyl)-amine. The title compound was isolated as a mixture o[ isomers. MS (ESI). mass caicd. for CajHzsFgNsOS. 569.17; m/z found. 570 [M+HJ\ 1H NMR (CDCI3). 8.39 (dd. J = 4.6. 1.4 Hz. 1H). 7.88 (dd. J " 7.8. 1.8 Hz. 1H). 7.64 (d. J = 8.7 Hz. 2H). 7.59 (d. J = 8.7 Hz. 2H). 6.97 (dd. J = 7.2. 4.8 Hz. 1H). 6.63 (bs. 1H). 4.00-3.92 (m. 1H). 3.90-3.81 (m. 2H). 3.81-3.74 (m. 1H). 3.67-3.60 (m. 2H). 3.60-3.53 (m. 2H). 3.31-3!25 (m. 2H). 2.99-2.92 (m. 2H). 2.59-2.46 (m. 1H). 2.04-1.93 (m. 1H). 1.30 (d. J = 6.0 Hz. 3H). Example 359: 2-((Phenv1m8thy f(trifluoromethyl)sulfQnvflphenylV6.7.8.9-(etrahvdrp-5H-Dvrfmldo[4.5-d]azeDln-4- amlne. MS (ESI): mass calcd. for C25H28F3N7O2S. 639.12; m/z found. 640 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J + 4.7. 1.5 Hz. 1H). 7.91-7.85 (m. 3H). 7.79-7.74 (m. 2H). 7.42-7.37 (m. 2H). 7.33-7.26 (m. 2H). 7.26-7.22 (m. 1H). 6.98 (dd. J = 8.2. 5.2 Hz. 1H). 6.86 (bs. 1H). 4.40 (s. 2H). 3.65-3.55 (m. 4H). 3.25-3.20 (m. 2H). 3.01- 2.96 (m. 2H). Example 360. 2-2Cvclohexv amine MS (ESI): mass calcd. for C25H28F3N7O2S. .631.15; m/z found. 632 [M+HJ". 1H NMR (CDCI3): 8.38 (dd. J = 4.8. 1.6 Hz. 1H). 7.97 (d. J = 8.9 Hz. 2H). 7.90-7.84 (m. 3H). 6.98 (dd. J = 7.6. 4.7 Hz. 1H). 6.88 (bs. 1H). 3.75-3.67 (m. 1H). 3.64-3.60 (m. 2H). 3.60-3.54 (m. 2H). 3.21-3.15 (m. 2H). 3.02-2.95 (m. 2H). 2.16-2.07 (m. 2H). 1.85-1.74 (m. 2H). 1.69-1.61 (m. 1H). 1.57-1.45 (m. 2H). 1.45-1.25 (m. 3H). Exampl? 361: 2-[n-Methytethyl)sulfanvl]-7-(3-rtrifluoromethy0pyridin-2-yl]-N-{4- f(trffluoromethylteulfonv1lDhenvi)-6.7.8.9-tetrahvdro-5H-pyrlmido[4.5-d1azepin-4- aminq. . MS (ESI): mass calcd. for C25H28F3N7O2S. 591.12; m/z found. 592 [M+Hf. 1H NMR (CDCI3); 8.38 (dd. J = 4.7. 1.5 Hz. 1H). 7.96 (d. J = 8.9 Hz. 2H). 7.90-7.84 (m. 3H). 6.98 (dd. J = 7.4. 4.8 Hz. 1H). 6.90 (bs. 1H). 3.90 (sept. J = 6.8 Hz. 1H). 3.66-3.60 (m. 2H). 3.60-3.54 (m. 2H). 3.23-3.18 (m. 2H). 3.03-2.95 (m. 2H). 1.43 (d. J-6.8HZ. 3H). Example 362:1-2(7-(3-rrri(tuo[omethyl)pyridin-2-vfl-4-((4- farifluQromethyhsulfonyl]phenvt)amlnoV6.7.8.9-tetrahvdro-5H-pyrimidor4.5- d1azep)p-2-vl)sulfanvODropan-2-ol. MS (ESI): mass calcd. for C24H23F8N9O3S2. 607.11; m/z found. 608 [M+H]1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.6 Hz. 1H). 8.01-7.95 (m. 2H). 7.91-7.84 (m. 3H). 7.02-6.94 (m. 2H). 4.19 (bs. 1H). 4.19-4.10 (m. 1H). 3.65-3.58 (m. 2H). 3.58- 3.52 (m. 2H). 3.33 (dd. J = 14.6. 3.1 Hz. 1 H). 3.21-3.13 (m. 2H). 3.15 (dd. J = 14.6. 7.2 Hz. 1H). 3.03. 2.95 (m. 2H). 1.30 (d. J = 6.2 Hz. 3 H). Example 363: f2-)2-Methyt-tetfahvdro-(uran~3-v1sulfanv1V7-23-trtfluoromethyl- pyridin-2-v1)-6.7.8.9-tetrahvdro-5H-Pvrimido[4.5-d1azepin-4-yl]-l4- trifluoromethanesutfonyl-Dhenvi famine. The title compound was prepared using 2-methyltetrahydro[uran-3-thiol. obtained as a mixture o[ isomers from Acros Organlcs (cat. #33270 0010). Upon purification by reverse phase HPLC (Phenomenex Gemini 5 2m Ci8 column. 30 x 100 mm. gradient o[ acetonitrile in 20 mM aqueous NH4OH). the title compound was isplated as a single diastereomer o[ unknown stereochemistry. Analytical HPLC:: Waters Xterra MS Cie 5 \nn column. 4.6 x 100 mm. gradient over 7 min from 1 to 99% acetonitrile In water modified with 0.05% TFA. 1.0 mL)min; to = 8.07 min. MS (ESI): mass calcd. for CwHzsFeNsC2. 633.13; m/z found. 634 [M+H]". 1H NMR (CDCIj): 8.38 (dd. J = 4.6. 1.5 Hz. 1H). 7.97 (d. J = 8.9 Hz. 2H). 7.89 (dd. J = 7.8. 1.8 Hz. 1H). 7.85 (d. J = 9.0 Hz. 2H). 6.98 (dd. J = 8.1. 5.4 Hz. 1H). 6.89 (bs. 1HJ. 4.03-3.96 (m. 1H). 3.93-3.84 (m. 2H). 3.84-3.78 (m. 1H). 3.66-3.61 (m. 2H). 3.23-3.18 (m. 2H). 3.03-2.95 (m. 2H). 2.61-2.50 (m. 1H). 2.06-1.95 (m. 1H). 1.33(d.J = 6.0Hz.3H). Example 364: N-r2-Methy [3-(trif)uoromethyl)pyrldin-2-vH-6.7.8.9-tetrahvdro-SH-pyrimidor4.S-d1?zep|p2- amlqe. MS (ESI): mass calcd. for CMHW2NSS. 589.17; m/z found. 590 [M+H]\ 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.4 Hz. 1H). 7.88 (dd. J « 7.8. 1.8 Hz. 1H). 7.86 (d. J = 8.3 Hz. 1H). 7.48-7.45 (m. 1H). 7.42-7.37 (m. 1H). 7.26-7.16 (m. 5H). 6.96 (dd. J = 7.7. 4.8 Hz. 1H). 6.35 (bs. 1H). 4.25 (s. 2H). 3.68-3.61 (m. 2H). 3.61-3.54 (m. 2H). 3.21-3.15 (m. 2H). 2.97-2.91 (m. 2H). 2.31 (s. 3H). Example 365: 2-(Cvclohexvlsulfanvl)-N-r2-methyl-4-(tt1fluoromethy (trifluororriethyl2Pvrldin-2-v i MS (ESI): mass calcd. for CajH2FoNsS. 581.20; m/z found. 582 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.8. 1.6 Hz. 1H). 7.98 (d. J = 9.0 Hz. 1H). 7.87 (dd. J = 7.8. 1.8 Hz. 1H). 7.49-7.44 (m. 2H). 6.96 (dd. J = 7.6. 4.7 Hz. 1H). 6.37 (bs. 1H). 3.68-3.61 (m. 2H). 3.61-3.45 (m. 3H). 3.19-3.12 (m. 2H). 2.98-2.92 (m. 2H). 2.34 (s. 3H). 2.05-1.95 (m. 2H). 1.77-1.65 (m. 2H). 1.65-1.53 (m. 1H). 1.48-1.34 (m. 2H). 1.33-1.17 (m.3H). Example 366: 2-[(1-Methylethy f3-(tr|fluorc2ethyl2pyridin-2-vil-6.7.819-tetrahvdro-5H-Pvrimidor4.5- MS (ESI): mass calcd. for C25H28F3N7O2S. 541.17; m/zfound. 542 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.5 Hz. 1H). 8.03 (d. J = 9.0 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.49-7.43 (m. 2H). 6.96 (dd. J = 7.8. 5.1 Hz. 1H). 6.38 (bs. 1H). 3.74 (sept. J = 6.8 Hz. 1H). 3.69-3.62 (m. 2H). 3.62-3.55 (m. 2H). 3.21-3.14 (m. 2H). 2.98-2.91 (m. 2H). 2.35 (s. 3H). 1.34 (d. J = 6.8 Hz. 6H). Example 367: 1-((4-H2-Methyl-4-2rifluoromethyf)phenyl1am)no)-7-[3- rtrifluoromethyl)DV(1din-2-v11-6.7.8.9-tetrahvdrc)-5H-pyrimldo[4.5-dlazepir)-2- y)teu)fanv11propao-2-ol. MS (ESI): mass calcd. for C25H28F3N7O2S. 557.17; m/z found. 558 [M+HJ". 1H NMR (CDCI3): 8.39 (dd. J = 4.7.1.5 Hz. 1H). 7.88 (dd. J = 7.7. 1.8 Hz. 1H). 7.86 (d. J = 8.6 Hz. 1H). 7.53-7.47 (m. 2H). 6.97 (dd. J = 7.6. 4.8 Hz. 1H). 6.39 (bs. 1H). 4.02-3.93 (m. 1H). 3.67-3.61 (m. 2H). 3.61-3.53 (m. 2H). 3.22-3.13 (m. 3H). 2.33 (s. 3H). 1.17(d.J = 6.2Hz. 3H). Example 368: 2.5-Anhvdro-1.4-dideoyv-3-S-(4-lf2-methy|-4- (trifluoromethyl]prianvl1aminol-7-(3-(trif1uoromethyi)pyridin-2-vll-6.7.8.9-tetrahvdrQ- 5H-o vrim)do[4.5-d1azepln-2-vt V 3-th iopentitol. The title compound was isolated as a mixture o[ isomers. MS (ESI): mass calcd. for C25H28F3N7O2S. 583.18; m/z found. 584 [M+H]". 1H NMR (CDCI3): 8.41- 8.37 (m. 1H). 7.91-7.85 (m. 2H). 7.48 (s. 2H). 6.97 (dd. J = 7.8. 4.8 Hz. 1H). 6.37 (bs. 1H). 4.20-4.15 (m. 1H). 3.92-3.83 (m. 1H). 3.83-3.76 (m. 2H). 3.68-3.55 (m. 4H). 3.20-3.14 (m. 2H). 2.99-2.92 (m. 2H). 2.42-2.32 (m. 1H). 2.34 (s. 3H). 1.96- 1.88 (m. 1H). 1.23 (d. J = 6.1 Hz. 3H). Example 369: 2.5-Anhvdro-1.4-dideoxv-3-S-(4-(f2-methyl-4- (trtfluororT)ethyl]phenyl]amirK?W-(3-(tnfluoromethyttovridin-2-vll-6.7.8.9-tetrahvdro- 5H-pyrirnido[4.5-dlazepin-2-vt)-3-thiopentitol. The title compound was isolated as a mixture o[ isomers.. MS (ESI): mass calcd. for C25H28F3N7O2S. 583.18; m/z found. 584 [M+H]". 1H NMR (CDCI3): 8.39 (dd. J = 4.8. 1.5 Hz. 1H). 7.92-7.85 (m. 2H). 7.50-7.45 (m. 2H). 6.97 (dd. J = 7.4. 4.8 Hz. 1H). 6.37 (bs. 1H). 3.92-3.83 (m. 1H). 3.85-3.76 (m. 2H). 3.68-3.55 (m. 5H). 3.21-3.15 (m. 2H). 3.00-2.93 (m. 2H). 2.42-2.32 (m. 1H). 2.34 (s. 3H). 1.96-1.87 (m. 1H). 1.23 (d.J = 6.1 Hz. 3H). Example 370: 2-((Phen\dm8thy0sulfanyl)-7-(3-(trifluoromethyltovrldin-2-vr|-N-n .4.4- trirneth\2-1.2.3.4-tetrahvdrDQulnolin-7-v1)-6.7.8.8-tetrahvdro-5H-pyrimklo[4.6- dlazepln-4-amine. MS (ESI): mass calcd. for C25H28F3N7O2S 604.26; m/z found. 605 [M+Hf. 1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.5 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.29- 7.14 (m. 5H). 7.11 (d. J = 8.0 hz. 1H). 6.94 (dd. J = 7.4. 4.5 Hz. 1H). 6.77-6.71 (m. 2H). 6.37 (bs. 1H). 4.33 (s. 2H). 3.68-3.54 (m. 4H). 3.27-3.19 (m. 2H). 3.19-3.11 (m. 2H). 2.93-2.84 (m. 2H). 2.89 (s. 3H). 1.78-1.71 (m. 2H). 1.26 (s. 6 H). Example 371: 2-(Cydohexvl9ulfanv1)-7-[3-)trifluo[Dmethy+pyridirv2-vfl-N-21.4.4- trimethyl-1.2.3.4-tetrahvdroQUlno MS (ESI): mass calcd. for C25H28F3N7O2S. 596.29; m/z found. 597 [M+H}\ 1H NMR (CDCI3): 8.38 (dd. J = 4.7. 1.5 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.13 (d. J = 8.2 Hz. 1H). 6.93 (dd. J = 7.6. 4.6 Hz. 1H). 6.88 (dd. J - 8.2. 2.0 Hz. 1H). 6.51 (d. J = 2.0 Hz. 1H). 6.33 (bs. 1H). 3.69-3.59 (m. 3H). 3.59-3.53 (m. 2H). 3.26- 3.21 (m. 2H). 3.17-3.10 (m. 2H). 2.92-2.84 (m. 2H). 2.90 (s. 3H). 2.09-2.01 (m. 2H). 1.79-1 £5 (m. 4H). 1.62-1.53 (m. 1H). 1.48-1.37 (m. 2H). 1.37-1.15 (m. 3H). 1.28 (s. 6H). Example 372: 2-(M-Methy MS (ESI): mass calcd. for C25H28F3N7O2S. 556.26; m/z found. 557 (M+H]\ 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.4 Hz. 1H). 7.86 (dd. J = 7.8. 1.9 Hz. 1H). 7.11 (d. J = 8.2 Hz. 1H). 6.96-6.90 (m. 1H). 6.87-6.82 (m. 1H). 6.69-6.65 (m. 1H). 6.37 (bs. 1H). 3.95-3.85 (m. 1H). 3.65-3.60 (m. 2H). 3.60-3.54 (m. 2H). 3.26-3.20 (m. 2H). 3.17-3.10 (m. 2H). 2.93-2.85 (m. 5H). 1.79-1.74 (m. 2H). 1.37 (d. J = 6.8 Hz. 6H). 1.28 (s.6H). Example 373: 1-(27-(3-TrrtfluorQmethyl)Dvrkiin-2-vfl-4-((1.4.4-trimethyl-1.2.3.4- tetrahvdroquinolin-7-v0amino]-6.7.8.9-tetrahydro-5H-pyrimldor4.5-d1azepin-2- yt}sulfanvl)propan-2-ol. MS (ESI): mass calcd. for C25H28F3N7O2S. 572.25; m/z found. 573 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.6. 1.4 Hz. 1H). 7.86 (dd. J = 7.8. 1.8 Hz. 1H). 7.14 (d. J = 8.2 Hz. 1H). 6.95 (dd. J = 7.7. 4.8 Hz. 1H). 6.75 (d. J = 2.1 Hz. 1H). 6.68 (dd. J = 8.2. 2.2 Hz. 1H). 6.40 (bs. 1H). 4.33 (bs. 1H). 4.07-3.99 (m. 1H). 3.66-3.60 (m. 2H). 3I60-3.52 (m. 2H). 3.27-3.21 (m. 2H). 3.20-3.10 (m. 3H). 3.05 (dd. J = 14.5. 7.0 Hzi. 1H). 2.92 (s. 3H). 2.91-2.84 (m. 2H). 1.78-1.71 (m. 2H). 1.27 (s. 6H). 1.20 (d. J = 6.2 Hz. 3H). Example 374: 2.5-Anhvdro-1.4-dideoxv-3-thlo-3-S-(7-[3-rtrtfluoromethyl)Pvr1din-2- vl]2MM.4.4«trimethy Pvrimldo[4.5-d)azepin-2-vDpentitol. The title compound was Isolated as a mixture o[ isomers. MS (ESI): mass calcd. for C25H28F3N7O2S. 598.27; m/z found. 599 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J = 4.6.1.7 Hz. 12H). 7.86 (dd. J = 7.7. 1.8 Hz. 1H). 7 12 (d. J = 8.2 Hz. 1H). 6.94 (dd. J = 7.8. 4.2 Hz. 1H). 6.75 (dd. J = 8.2. 2.2 Hz. 1H). 6.64 (d. J + 2.1 Hz. 1H). 6.36 (bs. 1H). 3.93-3.80 (m. 3H). 3.78-3.71 (m. 1H). 3.66-3.61 (m. 2H). 3.61- 3.54 (m. 2H). 3.24 (t. J = 5.9 Hz. 2H). 3.17-3.11 (m. 2H). 2.93-2.87 (m. 2H). 2.91 (s. 3H). 2.52-2.42 (m. 1H). 2.00-1.90 (m. 1H). 1.76 (t. J = 5.9 Hz. 2H). 1.27 (8. 6H). 1.24 (d. J = 6.1 Hz. 3H). Example 375: 2-(Propy1sulfanvl)-N-(4-(trifluoromethyl)Dhenvi1-7-T3- (trifluoromethy MS (ESI): mass calcd. for C24H23F(tN9S. 527.16; m/z found. 528 [M+H]". 1H NMR (CDCI3): 8.38 (dd. J =4.7. 1.4 Hz. 1H). 7.88 (dd. J = 7.8. 1.8 Hz. 1H). 7.67 (d. J = 8.6 Hz. 2H). 7.58 (d. J = 8.6 Hz. 2H). 6.96 (dd. J = 7.2. 4.8 Hz. 1H). 6.62 (bs. 1H). 3.66-3.61 (m. 2H). 3.61-3.54 (m. 2H). 3.20-3.13 (m. 2H). 3.08-3.02 (m. 2H). 2.98-2.91 (m. 2H). 1.73 (sextet. J = 7.4 Hz. 2H). 1.00 (t. J « 7.3 Hz. 3H). The compounds In Examples 376-394 were prepared using methods analogous to those described in the preceding examples. Example 376: 2-Methyl-2-l4-(2-morpholin-4-v1-7-(3-trifluoromethyl-Dvridin-2-vlW 6.7.8.9-tetrahvdro-5H-pyrlmldo[4.5-d1azepin-4-v1amino1-Phenv methyl ester. MS: mass calcd. for C25H28F3N7O2S. 570.2587; m/z found. 571.3 [M+H]". 1H NMR (CDCI3): 8.41-8.38 (m. 1H). 7.88 (dd. J = 1.8. 7.8 Hz. 1H). 7.53-7.48 (m. 2H). 7.33-7.29 (m. 2H). 6.98-6.92 (m. 1H). 6.40 (s. 1H). 3.80-3.72 (m. 8H). 3.67 (s. 3H). 3.64-3.56 (m. 4H). 3.11-3.06 (m. 2H). 2.89-2.85 (m. 2H). 1.60 (s. 6H). Example 377: 2-(1-Methylethy))-N-(4-pyrrolkiin-1-viDhenv1V7-(3- (trifluoromethyl)PYridin-2-yl]-6.7.8.9-tetrahvdro-5H-DVrimido[4.5-cl1azeDin-4-amine. MS: mass calcd. for C25H28F3N7O2S. 496.2562; m/z found. 497.3 [M+H]\ 1H NMR (CDCI3): 8.41-8.38 (m. 1H). 7.88 (dd. J = 1.8. 7.8 Hz. 1H). 7.47-7.43 (m. 2H). 6.97-6.92 (m. 1H). 6.60-6.55 (m. 2H). 6.31 (s. 1H). 3.69-3.59 (m. 4H). 3.34-3.28 (m. 4H). 3.22-3.17 (m. 2H). 3.02-2.94 (m. 1H). 2.93-2.87 (m. 2H). 2.07-1.98 (m. 4H). 1.30 (d. J = 6.9Hz.6H). Example 378: 2-Piperidin-1-yl-7-(3-(trifluoromethyl)pyridin-2-vfT-N-l4- Ktrifluoromethyl)sulfonvliPhenv(t-6.7.8.9-tetrahvdn)5H-PVrimidor4.5-dlazepin-4- amine. MS: mass calcd. for C25H28F3N7O2S. 600.1742; m/z found. 601.2 [M+H]". 1H NMR (CDCI3): 8.42-8.38 (m. 1H). 7.97-7.93 (m. 2H). 7.89 (dd. J = 1.8. 7.8 Hz. 1H). 7.86-7.82 (m. 2H). 6.99-6.95 (m. 1H). 6.78 (s. 1H). 3.81-3.72 (m. 4H). 3.63-3.52 (m. 4H). 3.14-3.09 (m. 2H). 2.94-2.88 (m. 2H). 1.74-1.60 (m. 6H). Example 379; N.N-Dlmethyt-4-(f2-moroholln-4-yl-7-(3-(trifluoromethyt2Dvrtdin-2-yl]- 6.7.8.9-tetfahvdro-5H-pyrimido[4.5-d1azepin"4-y|)amlno2benzenesulfonamlde. MS: mass calcd. for C25H28F3N7O2S. 577.2083; m/z found. 578.2 [M+H]". 1H NMR (CDCI3): 8.42-8.39 (m. 1H). 7.89 (dd. J = 1.8. 7.8 Hz. 1H). 7.79-7.67 (m. 4H). 7.00-6.95 (m. 1H). 6.64 (s. 1H). 3.82-3.73 (m. 8H). 3.64-3.55 (m. 4H). 3.15-3.09 (m. 2H). 2.95-2.88 (m. 2H). 2.73 (s. 6H). Example 380:1-r4- tetrahvdro-5H-Pvrimido[4.5-dlazepin-4-yl}amino)prienvHethanone. MS: mass calcd. for C25H28F3N7O2S. 512.2148; m/z found. 513.2 [M+H]". 1H NMR (CDCI3): 8.42-8.39 (m. 1H). 7.99-7.94 (m. 2H). 7.89 (dd. J « 1.8. 7.8 Hz. 1H). 7.66-7.60 (m. 2H). 6.99-6.94 (m. 1H). 6.63 (s. 1H). 3.82-3.74 (m. 8H). 3.64-3.55 (m. 4H). 3.14-3.09 (m. 2H). 2.93-2.89 (m. 2H). 2.60 (s. 3H). Example 381: (3-Chlo[D-4-t(tfluoromethy trffluoromethyl-Pvridin-2-vlV-6.7.8.9-tetrahvdro-5H-Pvrim)dor4.5-dlazepln-4-v MS: mass calcd. for C25H28F3N7O2S. 572.1526; m/z found. 573.2 [M1H)+. 1H NMR (CDCIj): 8.42-8.39 (m. 1H). 8.00 (d. J = 2.0 Hz. 1H). 7.89 (dd. J = 1.8. 7.8 Hz. 1H). 761 (d. J = 8.6 Hz. 1H). 7.38-7.35 (m. 1H). 7.00-6.95 (m. 1H). 6.55 (s. 1H). 3.83-3.74 (m. 8H). 3.63-3.55 (m. 4H). 3.14-3.08 (m. 2H). 2.92-2.87 (m. 2H). Example 382: 2-Methyl-2-(4-(2-(TK)rpho MS: mass calcd. for C25H28F3N7O2S. 537.2464; m/z found. 538.2 [M+H]". 1H NMR (CDCI3): 8.40-8.36 (m. 1H). 7.87 (dd. J = 1.8. 7.8 Hz. 1H). 7.58-7.52 (m. 2H). 7.44-7.39 (m. 2H). 6.97-6.90 (m. 1H). 6.42 (s. 1H). 3.81-3.69 (m. 8H). 3.64-3.53 (m. 4H). 3.11-3.05 (m. 2H). 2.90-2.84 (m. 2H). 1.73 (s. 6H). Example 383: 2-Methy 6.7.8.9-tetrahvdro-5H-pyr MS: mass calcd. for C25H28F3N7O2S. 540.2825; m/z found. 541.3 [M+H]". 1H NMR (CDCI3): 8.43-8.36 (m. 1H). 7.87 (dd. J = 1.8. 7.8 Hz. 1H). 7.58-7.53 (m. 2H). 7.36-7.32 (m. 2H). 6.96-6.91 (m. 1H). 6.35 (s. 1H). 3.78-3.72 (m. 4H). 3.65-3.56 (rn. 6H). 3.11-3.05 (m. 2H). 2.89-2.83 (m. 2H). 1.71-1.58 (m. 6H). 1.36 (s. 6H). Example 384: 2-Methyt-2-(4-r2-p MS: mass calcd. for C25H28F3N7O2S. 535.2672; m/z found. 536.3 [M+H]". 1H NMR (CDCI3): 8.42-8.36 (m. 1H). 7.88 (dd. J = 1.8. 7.8 Hz. 1H). 7.62-7.57 (m. 2H). 7.44-7.40 (m. 2H). 6.96-6.92 (m. 1H). 6.40 (s. 1H). 3.78-3.72 (m. 4H). 3.65-3.54 (m. 4H). 3.11-3.06 (m. 2H). 2.89-2.84 (m. 2H). 1.75 (s. 6H). 1.71-1.58 (m. 6H). Example 385: 2-Fluoro-4-r2-piperidin-1-yl-7-23-trifluoroniethyt-Pvr«din-2-vl)-6.7.8.9- tetrahydro-5H-Dvricnidor4.5-d1azepin-4-y1aminoVbenzoic acid methyt ester. MS: mass calcd. for C25H28F3N7O2S. 544.221; m/z found. 545.2 [M+H]". 1H NMR (CDCI3): 8.43-8.37 (m. 1H). 7.93-7.86 (m. 2H). 7.75 (dd. J = 2.1. 14.0 Hz. 1H). 7.14 (dd. J =2.1. 8.7 Hz. 1H). 6.98-6.94 (m. 1H). 6.60 (s. 1H). 3.93 (s. 3H). 3.79-3.75 (m. 4H). 3.61-3.55 (m. 4H). 3.13-3.06 (m. 2H). 2.90-2.85 (m. 2H). 1.73- 1.59 (m.6H). Example 386: (6-Methoxv-5-triflupromethyt-pyridin-2-vl)-r2-plperidin-1-v1-7-(3- trifluoron2thyl-p\n1diri-2-v amlne. MS: mass calcd. for C25H28F3N7O2S. 567.2181; m/z found. 568.2 [M+H]\ 1H NMR (CDCI3): 8.43-8.39 (m. 1H). 7.93-7.87 (m. 2H). 7.83 (d. J = 8.5 Hz. 1H). 7.16 (s. 1H). 6.98-6.94 (m. 1H). 4.00 (s. 3H). 3.81-3.75 (m. 4H). 3.65-3.55 (m. 4H). 3.14- 3.09 (m. 2H). 2.96-2.92 (m. 2H). 1.73-1.60 (m. 6H). Example 387: 4-(2-Piperidin-1-yl-7-(3-trifluorom9thyt-pyridin-2-vlV6.7.8.9- tetrahvdro-5H-pyrimldo[4.5-dlazep)n-4-v1aminol-berizoic add methyi ester. • MS: mass calcd. for C25H28F3N7O2S. 526.2304; m/z found. 527.2 [M+H]". 1H NMR (CDCI3): 8.41-8.39 (m. 1H). 8.04-7.99 (m. 2H). 7.88 (dd. J - 1.8. 7.8 Hz. 1H). 7.67-7.60 (m. 2H). 6.97-6.92 (m. 1H). 6.56 (s. 1H). 3.92 (s. 3H). 3.79-3.73 (m. 4H). 3.63-3.55 (m. 4H). 3.12-3.07 (m. 2H). 2.91-2.86 (m. 2H). 1.71-1.58 (m. 6H). j Example 388: 4-(2-PiperkJin-1-vt-7-(3-trifluoromethyt-Pvridin-2-vl)-6.7.8.9- tetrahvdro-5H-pyrimido[4.5-d1azepln-4-v)amlno1-benzolcacid. : MS: mass caJcd. for C25H28F3N7O2S. 512.2148; m/z found. 513.2 [M+HJ". 1H NMR (CD3OD): 8.47-8.42 (m. 1H). 8.03-8.00 (m. 1H). 7.93-7.88 (m. 2H). 7.62-7.58 (m. 2H). 7.14-7.09 (m. 1H). 3.76-3.69 (m. 4H). 3.49-3.44 (m. 4H). 3.07-3.03 (m. 2H). 3.02-2.97 (m. 2H). 1.72-1.65 (m. 2H). 1.63-1.55 (m. 4H). Example 389: 2-i4-(2-Moroholin-4-vf-7-(3-trifluonomethyl-ovridin-2-vt)-6.7.8.9- tetrahvdro-5H-pyrimlclo[4.5-dTa2epln~4-v1amino]-phenyl)-oroDan-2-ol. MS: mass calcd. for C25H28F3N7O2S. 528.246; m/z found. 529.2 [M+HJ". 1H NMR (CDCI3): 8.42-8.38 (m. 1H). 7.88 (dd. J = 1.8. 7.8 Hz. 1H). 7.53-7.49 (m. 2H). 7.48-7.44 (m. 2H). 6.97-6.93 (m. 1H). 6.40 (s. 1H). 3.82-3.72 (m. 8H). 3.67-3.56 (m. 4H). 3.12-3.07 (m. 2H). 2.90-2.86 (m. 2H). 1.62 (s. 6H). Example 390: (6-Chloro-6-trifluoromethyl-Pvridin-2-v1)-r2-o MS: mass calcd. for C25H28F3N7O2S. 571.1686; m/z found. 572.2 [M+H]". 1H NMR (CDCI3): 8.44-8.39 (m. 1H). 8.34 (d. J = 8.7 Hz. 1H). 7.95 (d. J = 8.7 Hz. 1H). 7.89 (dd. J = 1.8. 7.8 Hz. 1H). 7.43 (s. 1H). 7.00-6.95 (m. 1H). 3.81-3.73 (m. 4H). 3.57-3.52 (m. 4H). 3.13-3.09 (m. 2H). 2.94-2.90 (m. 2H). 1.74-1.59 (m. 6H). Example 391: 2-22-Ruoro-4-(2-Dlperidin-1-v 6.7.8.9-tetrahvdro-5H-PVrimldo[4.5-d1azeDin24-vlamlno1-phenvt)-prOPan-2-0+. MS: mass calcd. for C25H28F3N7O2S. 544.2574; m/z found. 545.3 [M+H]". 1H NMR (CDCI3): 8.41-8.35 (m. 1H). 7.86 (dd. J = 1.8. 7.8 Hz. 1H). 7.61 (dd. J = 2.2. 14.9 Hz. 1H). 7.45-7.40 (m. 1H). 7.08 (dd. J = 2.2. 8.5 Hz. 1H). 6.95-6.90 (m. 1H). 6.38 (s. 1H). 3.78-3.71 (m. 4H). 3.62-3.53 (m. 4H). 3.10-3.03 (m. 2H). 2.87-2.80 (m. 2H). 2.09 (d. J = 3.5Hz. 1H). 1.69-1.57 (m. 12H). Example 392; 2-Methyl-2-(4-(2-morpholin-4-v 6.7.8.9-tetfahvdro-5H-pyrimido[4.5-dTa2epln-4-v1amlno1-Dhenv1)-proDlonic add. MS: mass calcd. for C25H28F3N7O2S. 556.241; m/z found. 557.2 [M+H]". 1H NMR (CDCI3): 8.46-8.42 (m. 1H). 8.02 (dd. J = 1.8. 7.8 Hz. 1H). 7.55-7.51 (m. 2H). 7.35-7.32 (m. 2H). 7.13-7.10 (m. 1H). 3.76-3.65 (m. 8H). 3.49-3.44 (m. 4H). 3.08- 3.03 (m. 2H). 3.01-2.97 (m. 2H). 1.55 (s. 6H). Example 393: 5-Chk?ro-6-(2-piperidin-1-y1-4-24-trifluorometfiyl-D}ienvlamino)- 5.6.8.9-tetrahvdro-pyrimido[4.5-dlazepin-7-vt]-nicotinic acid methyi ester. MS: mass calcd. for C25H28F3N7O2S. 560.1914; m/z found. 561.2 [M+H]\ 1H NMR (CDCI3): 8.77-8.62 (m. 1H). 8.38-7.86 (m. 1H). 7.73-7.63 (m. 2H). 7.61-7.55 (m. 1H). 7.35-7.28 (m. 1H). 6.62-6.37 (m. 1H). 4.03-3.79 (m. 7H). 3.80-3.70 (m. 4H). 3.21-3.04 (m. 2H). 2.98-2.88 (m. 2H). 1.74-1.61 (m. 6H). Example 394: |5-Chloro-6-r2-Diperidin-1-vM-r4-tr}fluoromethy 5.6.8.9-tetrahvdro-ovr)mldor4.5- NMR ((C03)2CO): 8.20-8.09 (m. 2H). 7.96-7.88 (m. 2H). 7.71 (d. J = 2.0 Hz. 1H). 7.61 (d. J = 8.7 Hz. 2H). 4.66-4.48 (m. 2H). 3.84-3.69 (m. 4H). 3.60-3.47 (m. 4H). 3.13-2.97 (m. 4H). 1.75-1.49 (m. 6H). The compounds in Examples 395-518 are prepared using methods analogous to those described in the preceding examples. Biological Testing: Functional assay: block o[ capsaidn-lnduced Ca2" Influx A. Human Assay HEK293 cells were transfected-with human TRPV1 doned in pcDNA3.1zeo(+) using the Effectene non-liposomaJ lipid based transfection kit (Qiagen) (hTRPV1)HEK293). hTRPV1)HEK293 cells were routinely grown as monolayers under selection in zeocin (200 ng)mL; Invitrogen) in Dulbecco's Modified EagJe Medium (DMEM. Glbco BRL) supplemented with 10% fetal bovine serum. and penicillin)streptomycin (50 units)mL) in 5% CO2 at 37 °C. Cells were passaged frequently. every 3-5 days. to avoid overgrowth. depletion o[ essential medium components. or acidic medium exposure. Cells were passaged using a brief wash In 0.05% trypsin with 1 mM EDTA. followed by dissociation In divalent- froo phosphate-buffered saline (Hyclone #SH30028.02). Dissociated cells were seeded onto poly-D-lysine coated black-walled 96-well plates (Biocoat; Becton Dickinson #354640) at about 40.000 cells per well and grown for approximately 1 day in culture medium to near confluency. The assay buffer was composed o[ o[ 130 rriM NaCI. 2 mM KCI. 2 mM MgCI2. 10 mM HEPES. 5 mM glucose. and either 2 mM or 20 uM CaCl2. On the day o[ the experiment. the culture medium was replaced with 2 mM calcium assay buffer using an automated plate washer (ELx405; Biotek. VT). The cells were incubated in 100 nL)wetl Fhjo-3)AM (2 \iM; TEFUjibs #0116) with Pluronic F127 (100 ug)mL; Sigma #P2443) for 1 h at rt In the dark. A(ter loading the cells. the dye solution was replaced with 50 uL)welt o[ 20 uM calcium assay buffer using the ELx405 plate washer. Test compounds (50 uL)well) were added to the plate and incubated for 30 min. Intracellular Ca2" levels were subsequently assayed using a Fluorometric Imaging Plate Reader (FLIPR™ instrument. Molecular Devices. CA) to simultaneously monitor Fluo-3 fluorescence in all wells (X"xdtatkx) = 488 nm. A"i"e)on = 540 nm) during challenge with agonist (capsaicin). The lCso values were determined. Cells were challenged with 150 nM capsaicin and the fluorescence counts were captured following agonist addition at a sampling rate o[ 0.33 Hz. The contents o[ the wells were mixed 3 times (40 jxL mix volume) immediately a(ter the additions were made. Concentration dependence o[ block was determined by exposing each well o[ cells in duplicate rows o[ a 96 well plate to a serial dilution o[ test compound. The concentration series usually started at 10 uM with a three-(old serial decrement in concentration. The magnitude o[ the capsalcin response was determined by measuring the change in fluo3 fluorescence before and 100 seconds a(ter the addition o[ the agonist Data were analyzed using a non-linear regression program (Origin; OriginLab. MA). Results for the compounds tested in this assay are presented in Table 1. IC50 values 3hown are the average (mean) o[ the results obtained. B. Rat Assay The assay was'performed as described above. using HEK293 cells transfected with rat TRPV1 (rTRPV1)HEK293). These cells had a genoticin selection marker and were grown in Dulbecco's Modified Eagle Medium (DMEM. Gibco BRL) supplemented with 10% fetal bovine serum. penicillin)streptomycin (50 units)mL). and 500 ug)mL genetidn in 5% CO2 at 37 "C. Results for the compounds tested in this assay are also presented in Table 1. IC50 values shown are the average (mean) o[ the results obtained. Where activity is shown as greater than ()) a particular value. the value is the solubility limit o[ the compound in the assay medium. Table 1 While the Invention has been illustrated by reference to exemplary and preferred embodiments. It will be understood that the invention is intended not to be limited to the foregoing detailed description. but to be defined by the appended claims as property construed under principles o[ patent law. What is claimed is: 1. A compound of Formula (I): wherein: R1 is-H; -NRaRb; -OH; a -C1-6alky1, -OC1-6alkyl. -O-(saturated monocydic cycloalkyl), -OC1alkyHsaturated monocyclic cydoalkyl). -O-(saturated monocyclic heterocycloalkyl), -O-phenyl, -O-benzyl. -S-C1-6alkyl, -S-(saturated monocyclic cycloalkyl), -SC1alkyl-(saturated monocyclic cydoalkyl), -S- (saturated monocyclic heterocycloalkyl), -S-phenyl, -S-bonzyl, or -SO2-C1-6alkyl group unsubstituted or substituted with one or two moieties independently selected from the group consisting of -C1-6alkyl, -OH, -OC1-4alkyl, -NReRf, and halo substituents; or a phenyl. monocyclic cycloalkyl, or monocyclic heteroaryl group unsubstituted or substituted with a -C1-6alkyl, -OH, -OC1-4alkyl, -NR"R', or halo substituent; where Ra and Rb are each Independently -H; -C1-6alkyl; a -C2-3alkyl group substituted with a -OH, -OC1-4alkyl. -NRcRd, or halo substituent; or a saturated monocydic cydoalkyl, -C1alkyl-(saturated monocydic cydoalkyl). saturated monocyclic heterocydoalkyl, -C1alkyl-(saturated monocyclic heterocycloalkyl). phenyl. benzyl. or -C1alkyl-(monocyclic heteroaryl) group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of -C1-6alkyl, -OH, -OC1-4alkyl, -NRpRq, and halo substituents; or Ra and Rb taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl or bridged bicydic heterocycloalkyl group unsubstituted or substituted with one. two. or three moieties independently 'selected from the group consisting of -C1-6alkyl. -C1-4alkyl-OH, C1-2alkyl- OC1-2alkyl, -OH. -OC1-4alkyl, -NRpRq, halo, -CO2H, and benzyl substituents; where Rc and Rd are each independently -H or, -C1-6alkyl; or Rc and Rd taken together with their nitrogen o[ attachment form a saturated monocydic heterocycloalkyl; where Rp and Rq are each independently -H or -C1-6alkyl; or Rp and Rq taken together with their nitrogen o[ attachment form a saturated monocycllc heterocycloalkyl; where Re and Rf are each independently -H or -C1-6alkyl; or Re and Rf taken together with their nitrogen o[ attachment form a saturated monocydic i heterocycloalkyl; R2 is-H or-C1-6alkyt; R3 is a monocyclic cydoalkyl. phenyl. benzyl. phenethyl. indanyl. tfiiazolyi. thiophenyl. pyridyl. pyridylmethyl. pyrimidinyl. pyrazinyl. pyridazinyl. benzothiadiazolyl. quinolinyl. isoquinoJinyl. tetrahydroquinolinyf. or tetrahydroisoquinolinyl group unsubstituted or substituted with one. two. or three R9 substituents; where each R° substituent is -C1-6alkyl; -Ci_«alkyl-OH unsubstituted or substituted with -CF3; saturated monocyclic cycloalkyt; -OH; -OC1-6alkyl; phenoxy. -CN; -NO2; -NJR")2; -Ci-4alkyl-N(Rh)R1; -CCOJNCR2R1; -N(Rn)C(O)R'; -N(Rh)SO2Ci«alkyl; -C(O)C1-6alkyl; -S(0)o.2-C1-6alkyl; -SO2CF3; -SO2N(Rh)R'; -SCF3; halo; -CF3; -OCF3; -CO2H; -CO22Ikyl; -CCR2R-2N; -C(RJ)(RX)-OH; 2(R'XR2OaCLealkyt; -C(RJ)(RX)-CO2H; -C(RlXRx)-C(O)N(Rh)Rl; phenyl; or monocyclic heteroaryl; or two adjacent R° substituents taken together form -OCvzalkylO-; where Rh and R1 are each independently -H or -C1-6alkyl; or Rh and R1 (when both are present) taken together with their nitrogen o[ attachment form a saturated monocydic heterocycloalkyl group; R1 is independently-H.-C1-6alkyl. or-CF3; R" is -H or -Ci-aalkyl; or R1 and Rx taken together with the carbon to which they are attached form a monocydic cydoalkyl ring; and Ar is a phenyl. pyridyl. imidazolyl. pyrimidinyl. pyridazinyl. or fused-bicyclic heteroaryl group unsubstituted or substituted with one. two. or three R" substituents; where each Rk substituent is Independently -C.2alkyl. -Ci-2alkyl-OH. -OH. -OC1-6alkyl. phenoxy. -CN. -NO2. -N(R")Rm. -C(O)N(Rl)Rro. -N(R')C(O)Rm. -N(R')SO2C1-6alkyl. -N(R')SOaCF3. -C(O)C.2lky1. -S(0)o.a-C..«alkyl. -SO2CF3. -SO2N(R')Rm. -SCF3. halo. -CF3. -OCF3. -CO2H. or -COzd-aalkyl; or two adjacent RK substituents taken together form -OCi-2alkylO-; where R1 and Rm are each independently -H.-Ci-ealkyl. saturated monocydic cycloalkyl. or -CF3; or a pharmaceuticaliy acceptable salt. pharmaceutically acceptable prodrug. or pharmaceuticalry active metabolite o[ such compound. 2. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 is -H or -OH. 3. A compound. pharmaceuticafly acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 is -NR'R". 4. A compound. pharmaceutically acceptable salt. pharmaceuticalry acceptable prodrug. or pharmaceutically active metabolite as defined in daim 1. wherein R1 is a -Cilealkyl group unsubstituted or substituted with a -OH. -OC1-6alkyt. -NR"Rf. or halo substituent. 5. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 is isopropyl or cydopropyl. 6. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In daim 1. wherein R is a -O- unsubstttuted or substituted with one or two moieties Independently selected from the group consisting o[ methyl. ethyl. and isopropyl substituents. 7. : A compound. pharmBceutically acceptable salt. pharmaceutlcaliy acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 is a -S-Ci.6alkyl. -S-(saturated monocyclic cycloalkyl). -SCialkyl-(saturated monocydic cydoalkyl). -S-(saturated monocydic heterocydoalkyl). -S-phenyl. or -S-benzyl group unsubstltuted or substituted with a methyl. ethyl. or isopropyl substituent. 8. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 1. wherein R1 is methytsulfanyl or methylsulfonyl. 9. A compound. pharmaceutically acceptable salt. pharmaceutlcaliy acceptable prodrug. or pharmaceutically active metabolite as defined In claim 1. wherein R1 Is a monocyclic heteroaryl group unsubst(tuted or substituted with a methyl substituent. 10. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 Is a furanyl. thiophenyl. thiazolyl. or pyridyl group unsubstituted or substituted with a methyl substituent. 11. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 3. wherein R" and Rb are each independently-H; methyl. ethyl. propyl. Isopropyl. butyl. Isobutyl. sec-butyl. tert-butyl. pentyl. isopentyl. or hexyl; an ethyl or propyl group substituted with an -OC1-6alkyl or-NRcRd substituent; or a cydopropyl. cyclobutyl. cyclopentyl. cyclohexyl. cycloheptyl. cyclopropylmethyl. cydopentylmethyl. cyclohexylmethyl. aziridinyl. pyrrolidinyl. tetrahydro[uranyl. piperidinyl. tetrahydropyranyl. piperazlnyl. morpholinyl. thiomorpholinyl. 1.1-dioxo-1A8-thiomorpholin-4-y). phenyl. or furanylmethyJ group unsubstituted or substituted with a methyl or methoxy substrtuent. 12. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 3. wherein R" and Rb are each independently -H. methyl. isopropyl. methoxyethyi. cydopropyl. cydohexyl. cydopropylmethyl. 2-piperldin-1-yl-ethyJ. or2-dimethylamino-ethyl. 13. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in dalm 3. wherein R" and Rb takon together with their nitrogen o[ attachment form an aziridinyl. pyrrolidinyl. piperidinyt. 2-oxo-plperidin-1-yl. piperazinyl. oxc-piperazJnyt. morpholinyl. thiomorphollnyl. 1.1-dioxo-1A6-thiomorpholin-4-yl. i.1-dtoxo-1A6- [1.2]thlazinan-2-yl. azep8nyl. 1.4-oxazepanyl. or 7-azabicydo[2.2.1lhept-7-yi group unsubstituted or substituted with a -Chalky!. hydroxymethyi. hydroxyethyl. methoxymethyl. methoxyethyt. fluoro. -OH. or -CO2H substituent. 14. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 3. wherein Rc and Ra are each independently -H. methyl. or ethyl. 15. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceuticalry active metabolite as defined in claim 3. wherein Rc and Rd taken together with their nitrogen o[ attachment form plperidinyi. morpholinyl. or pyrrolidinyl. 16. 'A compound. pharmaceutically acceptable sa(t. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 3. wherein Rp and Rq are each independently -H. methyl. or ethyl. 17. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 3. wherein R" and R1 are each independently-H. methyl. or ethyl. 18. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R2 Is -H. 19. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R3 is a phenyf. pyridyl. pyrimidinyl. pyrazinyl. quinolinyl. or isoquinolinyf group unsubstituted or substituted with one or two R° substrtuerrts. 20. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R3 is a monocydic cycloalkyl. pyridylmethyl. benzothiadlazotyl. tetrahydroquinolinyl. or tetrahydroisoquinolinyl group unsubstituted or substituted with one. two. or three R9 substituents. 21. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R3 is a pyridyl. pyrimidinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two R8 substituents. 22. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 1. wherein R3 is a pyridyl. thia2olyl. or pyridazinyl group unsubstituted or substituted with one or two R8 substituents. 23. 'A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 1. wherein R3 is a phenyt group substituted with one or two RB substituents. 24. A compound. pharmaceutJcally acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R3 is a benzyl or phenethyl group unsubstituted or substituted with one or two R8 substituents. 25. A compound. pharmaceutically acceptable salt. pharmaceuticaily acceptable prodrug. or pharmaceuticaily active metabolite as defined In claim 1. wherein R3 is a 2-pyrklyl group unsubstrtuted or substituted with one or two R8 substituents. 26. A compound. pharmaceuticaily acceptable salt. pharmaceuticaily acceptable prodrug. or pharmaceuticaily active metabolite as defined in claim 3. wherein R3 is a 2-pyridyt group unsubstituted or substituted with one or two R° substituents. 27. A compound. pharmaceuticaily acceptable salt. pharmaceuticaily acceptable prodrug. or pharmaceuticaily active metabolite as defined in claim 1. wherein R3 Is a 3-pyridyl group unsubstituted or substituted with one R° substituent 28. A compound. pharmaceutically acceptable salt. pharmaceuticaily acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein two adjacent RB moieties taken together form -OCi.zalkylO-. 29. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein each R° substituent is independently methyl. isopropyl. tert-butyl. -CF3. fluoro. chloro. bromo. -OCF3. -SO2NH2. -OCH3. phenoxy. -C(CH3)2-CN. -C(CH3)2-OH. -NO2. -CN. -NH2. -C(O)CH3. -SO2CF3. -SCF3. -CON(CH3)2. -CC2H. phenyl. cyclohexyl. pyrrolldinyl. piperidinyl. morpholinyl. -SCH3. oxazolyl. -SO2-(pyfTolidinyl). -SO2fCHsfe. -C(CH3)z-CO2CH3. -C(CH3)2-CO2H. 1-hydroxy-ethyl. 2-hydroxy-1.1- dimethyl-ethyl. 3.3.3-trifluoro-1-hydroxy-propyl.3.3.3-trifluoro-1-hydroxy-1-methyl- propyl. or -SO2CH3; or two adjacent RB substituents taken together form -OCi. 2alkyl6-. 30. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 1. wherein each R° substituent is independently methyl. isopropyl. tert-butyl. fluoro. -CF3. chloro. -C(CH3)2-CN. -C(CH3)2-OH. -C(CH3)2-CH2OH. -C(CH3)z-CO2H. acetyl. -SO2CH3. or -SO|jCF3. 31. A compound. pharmaceutJcally acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 3. wherein R3 Is phenyt or pyridyl substituted with one or two R° substituents. and each R8 subslituent is independently methyl. teopropyl. tert-butyl. fluoro. -CF3. chloro. -C(CH3)z-CN. -CfCHaJrOH. -CfCH2HzOH. -C(CH3)rCO2H. acetyl. -SO2CH3. or -SO.CF3. 32. A compound. pharmaceutically acceptable salt. pharmaceutJcally acceptable prodrug. or pharmaceutically active metabolite as defined in claim 3. wherein R3 is a 2-pyridyl group unsubstituted or substituted with one or two R° substituents. 33. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 1. wherein R"1 and R1 are each independently -H. methyl. or ethyl. 34. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutJcally active metabolite as defined in claim 1. wherein R" and R1 taken together with their nitrogen o[ attachment form pyrrolidinyl. piperidinyl. piperazJnyl. or morpholinyl. 35. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 1. wherein R1 Is - H. methyl. or -CF3. 36. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R" Is -41 or methyl. 37. ' A compound. pharmaceutically acceptable salt. pharmaceuticaUy acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 and R" taken together with the carbon to which they are attached form a cyclopropyl ring. 38. A compound. phanmaceutjcally acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein Ar is a phenyl group substituted with a -NO2. -NfR'jR'". -C(O)N(RI)R'T\ -NfR'jCtOJR1". 2(R2SOaC1-6allcyi. -N(R')SO2CF3. -SO2CH3. or -SO2CF3 substituent. 39. . A compound. pharmaceutically acceptable saJt. pharmaceutlcally acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein Ar is a fused-bicyclic heteroaryl group unsubstituted or substituted with one or two Rk sub6tituents. 40. A compound. pharmaceutically acceptable salt. pharmaceutlcally acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein Ar is 2-pyridyl substituted with -CF3. -NO2. or -N(R')Rm. 41. A compound. pharmaceutically acceptable salt. pharmaceutrcally acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein Ar is 2-pyridyl substituted with -CF3. 42. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein Ar Is 2-pyridyl substituted with -Cl. -Br. -F. methyl. -SO2CH3. or -SO2CH2CH3. 43. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodalg. or pharmaceutical active metabolite as defined In claim 1. wherein Ar is quinoxalinyi or phthalizinyt. 44. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 1. wherein Ar is a pherlyl. pyridyl. pyrimidinyl. or fused-bicyclic heteroaryl group substituted on a carbon ring atom at a position ottHo to the point o[ attachment with an Rk substituent. 45. ; A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 1. wherein each Rk sub3tituent is independently -N(R')Rm. -NO2. -N(R")SO2CF3. or -N(R')SO2CH3. 46. A compound. pharmaceutteally acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein Ar is 2-pyrfdyl. substituted with one or two R" substltuents independently selected from the group consisting o[: -CF3. fluoro. chloro. bromo. -SO2CH3. -NH2. -NO2. -CO2CH3. -NHSO2CH3. -CN. -CONH2. -SOzCHzCHa. -SO2NH2. -SOjNH- cyclopropyl. -SC2NH-isopropyt. -CO2H. -CH2OH. and methyl. 47. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 1. wherein R1 and Rm are each independently-H. methyl. ethyl. isopropyl. -CF3. or cydopropyl. 48. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 3. wherein Ar is 2-pyridyl. substituted with one or two R" substituents independently selected from the group consisting o[: -CF3. fluoro. chloro. bromo. -SO2CH3. -NH2. -NO2. -CO2CH3. -NHSO2CH3. -CN. -CONH2. -SO2CH2CH3. -SO2NH2. -SO2NH- cydopropyl. -SO2NH-lsopropyl. -CO2H. -CH2OH. and methyl. 49. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 31. wherein Ar Is 2-pyridyl. substituted with one or two R" substituents independently selected from the group consisting o[: -CF3l fluoro. chloro. bromo. -SO2CH3. -NH2. -NO2. -CO2CH3. -NHSO2CH3. -CN. -CONH2. -SO2CH2CH3. -SO2NH2. -SO2NH- cydopropyl. -SOzNH-lsopropyl. -CO2H. -CH2OH. and methyl. 50. I A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceuticaJly active metabolite as defined In claim 31. wherein Ar fe 2-pyridyl substituted with -CF3. -NO2. or -NfR'jR"1. 51. A compound o[ Formula (I) as defined in daim 1. wherein: R1 is-H; -NR"Rb; a -Cealkyt. -OC1-6alkyt. -S-C1-6alkyl. or-SOC1-6alkyl group unsubstitutod or substituted with a -OH. -OC1-6lkyl. -NR'R1. or halo substituent; or a monocydic cycloaJkyl group unsubstituted or substituted with a -C1-6alkyl. -OH. -OC1-6alkyl. -NR'Rf. or halo substituent; where R" and Rb each independently Is -H; -C1-6alkyt; a -Czoalkyl group substituted with a -OH. -OC1-6alkyl. -NR02. or halo substituent; or a saturated monocydic cydoalkyl. -Cialky1-(saturated monocydic cydoalkyt). saturated monocydic heterocydoalkyl. -dalkyl-(saturated monocydic heterocydoalkyl). phenyl. or benzyl group unsubstituted or substituted with one. two. or three moieties independently selected from the group consisting o[ -C1-6alkyl. -OH. -OCi_«alkyl. -NRpRq. and halo substituents; or R" and Rb taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl group unsubstituted or substituted with one. two. or three moieties independently selected from the group consisting o[ 1 -Chalky!. -OH. -OCi-«alkyl. -NRpRq. halo. -CO2H. and benzyl substituents; where Rc and Rd are each Independently -H or -d-ealkyl; or R° and R"1 taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl; where Rp and Rq are eadi Independently -H or -C1-6alkyl; or Rp and Rq taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl; where R" and R' are each independently -H or -C14alkyl; or R" and Rf taken together with their nitrogen o[ attachment form a saturated monocydic heterocydoalkyl; R2 te -H or -Chalky!; R is a phenyt. benzyl. phenethyl. fndanyl. thiazolyl. thiophenyl. pyridyl. pyrimidinyl. pyrazinyl. pyridazlnyl. qulnolinyf. or isoquinolinyl group unsubstituted or substituted with one. two. or three Rg substituents: where each R° substituent is -Chalky). -OH. -OCimalkyl. phenoxy. -CN. -NO2. .N(Rh)R'. -C(O)N(Rh)Rl. 2(R2OR1. -N2JSOaC2lkyl. -C(O)C.-8alkyt. -StOJo-s-C2alkyl. -SO2CF3. -SO2N(Ril)Ri. -SCF3. halo. -CF3. -OCF3. -CO2H. -COzCvealkyl. -C(RJ)2-CN. or-C(R')2-OH; or two adjacent R° substituents taken together form -OC2alkylO-; where Rh and R1 are each independently -H or -C1-6alkyl; where each R" is independently -H or -C1-6aJkyl; and AT is a phenyl. pyridyl. imidazolyl. pyrimidinyl. pyridaztnyl. or fused-bicydic heteroaryl group unsubstituted or substituted with one. two. or three Rk substituents; where each Rk substituent is independently-C1-6alkyl. -OH. -OC2alky). phenpxy. -CN. -NO2. -NCR'jR'". -C(O)N(R')Rm( -N(RI)C(O)R'1'. -N(R')SO2C1-6alky1. -N(R')SO2CF3. -C(O)C1-6alkyl. -S(OXw-C1-6alky1. -SO2CF3. -SO2N(R')Rm. -SCF3. halo. -CF3. -OCF3. -CC2H. or -CO2Ci4)alkyl; or two adjacent Rk substituents taken together form -OCi.2alkylO-; where R1 and Rm are each Independently -H.-C..ealkyl. or -CF3; or a pharmaceutically acceptable 6alt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite o[ such compound. 52. A compound. pharmaceuticalty acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 51. wherein R Js -H. ' 53. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceuticalry active metabolite as defined in daim 51. wherein R1 Is -NR'R". 54. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R1 is a -C..8alky1 group unsubstituted or substituted with a -OH. -OC1-6alkyl. -NReRf. or halo substituent. 55. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 54. wherein R1 is methyl or isopropyf. 56. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R1 is a methyl group substituted with a -OC2Ikyl or-NR"R" substituent. 57. A compound. pharmaceutically acceptable salt. pharmacoutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 56. wherein R1 is methoxymethyl or piperidinylmethyl. 58. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutlcally active metabolite as defined in claim 51. wherein R1 is methoxy. methytsulfanyl. or methylsulfonyt. 59. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 51. wherein R1 is cyclopropyl. 60. A compound. pharmaceutically acceptable salt. pharmaceutlcalty acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R" and Rb are each independently-H; methyl. ethyl. propyl. isopropyl. butyl. isobutyl. sec-butyl. tert-butyl. pentyl. isopentyl. or hexyl; an ethyl or propyl group substituted with an -OC1-6alkyl or -NR°Rd substituent; or a cyclopropyl. cydobutyl. cyclopentyl. cydohexyi. cycloheptyl. cyclopropylmethyl. cyclopentylmethyl. aziridinyl. pyrrolidinyl. tetrahydro[uranyl. piperidinyi. tetrahydropyranyl. piperazinyl. morphoJInyl. thlomorpholinyi. 1.1-dloxo.n6-thioiriorpholin-4-y1. or phenyl group unsubstituted or substituted with a -Chalky!. -OC2alkyl. or halo substituent 61. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 53. wherein R" and Rb are each independently-H; methyl. ethyl. propyl. isopnopyl. butyl. isobutyl. sec-butyl. tert-butyl. pentyl. isopentyi. or hexyl; an ethyl or propyl group substituted with an -OC1-6alkyl or -NRcRd substituent; or a cyclopropyl. cyclobutyl. cyclopentyl. cydohexyl. cycloheptyl. cyclopropylmethyl. cydo pentyl methyl. aziridinyl. pyrrolidinyl. tetrahydro[uranyl. piperidinyl. tetrahydropyranyl. piperazinyl. morpholinyl. thiomorpholinyl. 1.1-dtoxo-1A6-thiomorpholin-4-yl. or phenyl group unsubstituted or substituted with a -C1-6alkyl. -OC1-6alkyl. or halo substituent i 62. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R" and Rb are each Independently -H. methyl. methoxyethyf. cyclopropyl. cyclopropylmethyl. 2-piperidin-i-yi-othyl. or 2-dlmethylamino-ethyl. 63. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Ra and Rb taken together with their nitrogen o[ attachment form an aziridinyl. pyrrolidinyl. piperidinyl. 2-oxo-piperidin-1-yl. piperazinyl. oxo-piperazinyl. morpholinyl. thiomorpholinyl. 1.1-dioxo-1A8-thiomorpholin-4-yl. 1.1-dioxo-1A6- [1.2]th!azinan-2-yl. or azepanyl group unsubstituted or substituted with a -C1-6alkyl. -OH. or -CO2H substituent. 64. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Rc and Rd are each independently -H. methyl. or ethyl. 65. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Rc and Rd taken together with their nitrogen o[ attachment form piperidinyl. 66. A compound. pharmaceutlcally acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 51. wherein Rp and Rq are each independently -H. methyl. or ethyl. 67. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R" and Rf are each independently -H. methyl. or ethyl. 68. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R2 Is -H or methyl. 69. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 68. wherein R2 is -H. 70. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 51. wherein R3 is a phenyl. pyridyl. pyrimldinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two Rg substituents. 71. A compound. pharmaceutically acceptable salt. pharmaceuticelly acceptable prodrug. or pharmaceutically active metabolite as defined in dalm 51. wherein Rs is a pyridyl. pyrimidinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two R8 substituents. 72. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 51. wherein R3 is a pyridyl. thiazoiyl. or pyridazinyi group unsubstituted or substituted with one or two R° substituents. i 73. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R3 Is a phenyl group substituted with one or two R9 substituents. 74. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 51. wherein R3 is a benzyl or phenethyl group unsubstituted or substituted with one or two R° substituents. 75. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R3 is a 2-pyridyl group unsubstituted or substituted with one R° substituent 76. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein each R° substituent is independently -C.2alkyl. -OH. -OC1-6alkyl. phenoxy. -CN. -NO2. -NfR2R1. -C(O)N(Rh)R'. -N(Rh)C(O)R'. -NfR2SO2i-ealkyl. -C(O)C1-6alkyl. -S(O)o.2-C.2alkyl. -SO2CF3. 2O2N(R")RI. -SCF3. halo. -CO2H. -CO2C2alkyl. -C2Jz-CN. or-C(R))2-OH. 77. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein two adjacent R° moieties taken together form -OCi-2alkylO-. 78. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein each R° substituent \s independently isopropyl. tert-butyl. -CF3. chloro. -OCF3. -SO)JH2. -OCH3. phenoxy. bromo. -C(CH3)2-CN. -C(CH3)2-OH. -NO2. -CN. -NH2. -C(O)CH3. -SO2CF3. or -SCF3; or two adjacent RB substituents taken together form -OCi.2alky1O-. 79. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 51. wherein each RB substituent is IndependentJy isopropyl. tert-butyt. -CF3. chloro. -C(CH3)2- CN. -C(CH3)2-OH. or -SO2CF3. 80. A compound. pharmaceutically acceptable salt. pharmaceutfcally acceptable prodrug. or pharmaceutically active metabolite as defined In claim 51. wherein Rh and R1 are each independently-H. methyl. or ethyl. 81. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R1 is -H methyl. or ethyl. 82. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Ar Is a phenyl group unsubstituted or substituted with one or two Rk substituents. 83. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Ar is a phenyl group substituted with a -NO2. -N(Rl)Rm. -C(O)N(R')Rm. -N(R')C 84. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 51. wherein Ar is a fused-bicydic heteroaryl group unsubstituted or substituted with one or two RK substituents. 85. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in daim 51. wherein Ar is 2-pyridyl substituted with -CF3. -NO2. or -N(R')Rm. 86. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Ar Is 2-pyridyl substituted with -Cl. -Br. methyl. or -SO2CH3. 87. A compound. pharmaceuticaliy acceptable salt. pharmaceutically acceptable prodrug. or phanmaceutically active metabolite as defined in claim 51. wherein Ar Is quinoxalinyd or phthaHzinyl. 88. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein Ar is a phenyl. pyridyl. pyrimidinyl. or fused-bicyclic heteroaryl group substituted on a carbon ring atom at a position ortho to the point o[ attachment with an Rk substituont. 89. A compound. pharmaceuticalty acceptable salt. pharmacoutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein each Rk substituent is independently-C2.ealky1. -OH. phenoxy. -CN. -NO2. -N(tfJFT. -C(O)N(R')Rm. -N(R')C(O)Rm. -r2R'2OaCKalkyl. -N(R')SO2CF3. -C(0)Ci4alkyl. -SfO2C1-6alkyl. -SOzCFg. -SO2N(R1)Rm. -SCF3. -OCF3l -CQjH. or -COzCi-ealkyl; or two adjacent Rk substituents taken together form -OCt2alkylO-. 90. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined In claim 51. wherein each R" substituent is independently -NfR2R"1. -NO2. -N(R')SO2CF3. or -N(R')SO2CH3. 91. A compound. pharmaceutically acceptable salt. pharmaceutically acceptable prodrug. or pharmaceutically active metabolite as defined in claim 51. wherein R1 and R" are each independently -H. methyl. ethyl. or -CF3. 92. A compound or pharmaceutically acceptable salt as defined in claim 51. wherein: R1 is -H. -NR"Rb. -C1-6alkyl. -O-C14alkyl. -S-d-aalkyl. -SOy-Ci-aalkyl. -CHz-O-C2alkyl. or -CH2-NR"Rf; R2 is -H; R3 is a pyridyl. pyrimidinyl. pyrazinyl. quinolinyl. or isoquinollnyl group unsubstituted or substituted with one or two RB substituents; and Ar is a phenyl group substituted with one or two RK substituents. 93. A compound or pharmaceutically acceptable salt as defined in daim 51. wherein: R1 is -H. -NR"Rb. -C1-6alkyl. -O-C1-6alkyl. -S-C1-6alkyl. -SOrCi-ealkyl. -CH2-OTCiwjalky1. or -CHrNR2R'; R2 is -H; R3 is a benzyl. phenethyi. indanyl. pyridyl. pyrimidinyt. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar is a phenyl group subsUtuted with one or two Rk substituents. where each Rk substituent is -C2Hcyi. -OH. phenoxy. -CN. -NO2. -N2R1". -C(O)N(Rl)Rm. -N(Rl)C(O)Rrn. -NtR'jSOaC2alkyl. -N(R')SO2CF3. -C(O)C1-6alkyl. -SfOo2d-ealkyl. -SO2CF3. -SO2N(R')Rm. -SCF3. -OCF3. -CO2H. or -CO2C1-6alkyl. or two adjacent Rk substituents taken together form -OCi.2alkylO-. 94. A compound or pharmaceutically acceptable salt as defined in daim 51. wherein: R1 is -H. -NR82. -C1-6alkyl. -O-Ci-oallcyl. -S-d-ealkyl. -SOz-C2alkyl. -CHa-O-C1-6alkyl. or -CH2-NR8Rf; R2 is -H; R3 is a benzyl or phenethyi group unsubstituted or substituted with one or two R° substituents; and Ar is 2-pyrklyl substituted with -CF3. -NO2. or -N(R')Rm. 95. A compound or pharmaceutically acceptable salt as defined in daim 51. wherein: R1 is -C2lkyl; R2 is -H; R3 is a phenyl. pyridyl. pyrimidinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar is a phenyl. pyridyl. pyrimidinyl. or fused-bicydic heteroaryl group unsubstituted or substituted with one or two Rk substituents. 96. A compound or pharmaceutically acceptable salt as defined in daim 51. wherein: R1 is -H. -NR'Rb. -C2alkyt. -O-C2alkyl. -S-C1-6alkyl. -SOa-d-ealkyl. -Cyi2-O-C2a\ky\. or -CHJ-NR'R'; R2 is -H; R3 is a phenyl. benzyl. phenethyi. Indanyl. pyridyl. pyrimidinyl. pyrazinyl. quinolinyl. or isoquinolinyl group unsubstituted or substituted with one or two R° substituents; and Ar is a fused- blcydic heteroaryl group unsubstituted or substituted with one or two R" substituents. 97. A compound or pharmaceutically acceptable salt as defined in daim 51. wherein: R1 is -NR'R"; R2 is -H; R3 is a phenyl group substituted with one or two R° substituents. where each R° substituent is -d-ealkyl. -OH. -OCi-«alky1. phenoxy. -CN. -NO2. -N(Rh)R'. -C(O)N(Rh)R'.'-N(Rh)C(p)Rl. -NtR2SOzd-ealkyl. -C(O)C1-6allcyl. -S(O)02-C1-6alky1. -SO2CF3. -SO2N(Rh)R'( -SCF3. halo. -CO2H. -CO2Ci-8alkyl. -C(R')2-CN. or -C(R')2-OH. Or two adjacent R8 substltuents taken together form -OCi.2alky10-; and Ar is a phenyl. pyrtdyl. pyrimidinyl. or fused- bicyclic heteroaryl group unsubstituted or substituted with one or two Rk substituents. 98. A compound or pharmaceutically acceptable salt as defined in claim 51. wherein: R1 is -NR'R6; R2 is -H; R3 is a phenyl. benzyl. phenettiyl. indanyi. pyridyl. pyrimidinyl. pyrazinyl. quinolinyi. or isoquinolinyl group unsubstituted or substituted with one or two R° substltuents; and Ar is a phenyl group unsubstituted or substituted with one or two R" substituents. 99. A compound selected from the group consisting o[: (4-tert-Butyl-phenyl)[7-(3-trifluoromethylHpyridin-2-yl)-617.8.9-tetrahydro-5H- pyrimfdol4.5-d]azeptn-4-yl]-amine; (4-Trlfluoromethyl-phenyl)-t7-(3-trifluoromethyl2yi1din-2-yl)-6.7.8.9-tetra-hydro-5H- pyrimido[4.5-d]azepin-4-yf}-amine; (4-tert2utyl-phenyl)[2K2clopropy1-7- 5H-pyrimido[4.5- pyrimldo[4.5-d]azepin-4-yf]-amine; [22yclopropyl-7-(3-trifluorcHnethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimldo{4.5- d]azepin-4-yf]-(4-trifluoromethyl-phenyl)-amine; (4-tert-Butyl-phenylH2-phenyt-723-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H- i pyrimido[4.5-d]azepin-4-yl]-amlne; [2-Phenyl-7- 4-yl]-{4-trifluoromethyl-phenyl)-amine; (4-tert2utyl-phenyl)-[2-isopropyl-7-(3-trifluorc)methyl-pyrWin-2-yl)-6.7.8.9-tetrahydro-5H- pyrtmklo[4.5-d]azepin-4-yl]-amine; [2-lsopropyl-7- d]azepin-4-yl]-{4-trifluoromethyl-phenyl)-amine; [2-lsopropyl-7-(3-trlfluoro[nethyl.pyridin-2-yl)-€.7.8.9-tatrahydro-5H-pyi1mido{4.6- d]azepin-4-yf]-{3-trifluoromethyl-pheny1)-annine; [2-lsopropy1-7-(3-trifluc)romethyl-pyridin-2-yl)-6.7.8.9-tetrahydfo-5H-pyrimldo[4.5- d]azppin-4-yl]-{4-ti1fluoromethx)xy-phenyl)-amine; [2-(4rFluoro-phenyl)2thylH2-isoprQpyl-7-(3-Wfluoromethy+-pyi1din-2-yl)-6l7.8.9- tetrahydro-5H-pyrimMo[4.5-d]azepin-4-yt]-ernine; [2-(2-ChlorcH3henyl)2thy(]-[2-isopropyl-7- tetrahydro-5H-pyrimido[4.5-d]azepin-4-yl]-amine; (3.4-Dichloro-benzylH2-isopropy1-7-(3-trifluoromethyl2yridin-2-yl)-6.7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepir)-4-yll-amlne; (42ert-Buty2phefiyl)-[2-methyl-7K3-trifluoromethyl-pyridin-2-yl)-(f.7.8t9-tetrahydro-5H'- pyrimkJo[4.5-d]azepin-4-yf]-amlne; [2-Methyl-723-trifluoromethyli3yridin-2-yl)27.8.9-tetrahydrcH5H-pyrimido-{4.5-d]a2epln- 4-yl]-24-trifluoromethy2pheny1)-amlne; (5-Trifluoromethyl-pyrklin-2-y1)-[723-trifluororneUiy pyrimido[4.5-cJ]azepir+-4-ytI-amine; lsoquinolin-1-yH7-{3-trifhJoromethy(-pyrWin-2-yl)2.7.8.9-tetrahydn)5H-pyrimido[4.5- i d]azepin-4-y(]«annine; [22yclopropyl-723-trifluoromethyl2yrid)n-2-yl)-67.8.9-tetrahydfO-5H-pyrirnido[4.5- d]azepin-4-ylH5-trifluoromethyf-pyridin-2-y1)-amine; [2-lsopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- dJazepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine; [2-lsopropy)-723-trifluorome+hyt2yridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrirTiido{4.5- d]azepin-4-yl]-quinolin-3-yl-amine; [2-Ph4nyl-7-(3-tiifkjoromethyH)yrMin-2-yl)27.2 i 4-ylJ- [2-1 sopropyl-7- d]azepin-4-yl]-(6-trifluonomethyl-pyridin-3-yl)-amine; [2-Met|iy1-7- 4-yl]-{S-tf1fluoromethyl-pyridin-2-yl)-amine; [2-lsopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azeptn-4-yl]-(4~phenoxy-pheny1)-amine; (4-Trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrirnidin-2-yl)-6I7.8.g-tetrahydro-5H- pyrirnido[4.5-d]azepin-4-yl]-amine; (7-Pyrimidin-2-yl-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-yl)-(4-trifluoromethyl- pherjyl)-amine; (7-Pyrazin-2-yI-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-yl)-(4-trifluoromethyl- pheriyO-amine; (7-Q(jinoxalin-2-yl-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-yi)-(4-trifluoromethyl- phen'yl)-amine; [7-(3tChloro-pyridin-2-yl)-6.7.819-tetrahydro-5H-pyrimido[4.5-d]azepin-4-yl]-(4- trifluciromethyl-phenyl)-amine; (4-tert-Butyl-phenylH7-(6-cf1loro-5-methyl-pyrimidin-4-yl)-6I7)8.9-tetrahydro-5H- pyriniido[4.5-d]a2epin-4-yl]-amine.' (4-teit-ButyJ-phenyl)-[7-(3-methyl-quinoxalin-2-yl)-6.7.8.9-tetrahydro-5H-pyrinriido[4.5- d]azepin-4-yl]-amine; (4-ter|t-Butyl-phenyl)-t2-isopropyl-7-(3-methyl-quinoxa!in-2-yl)-6.7J8.9-tetrahydro-5H- pyrimido[4.5-djazepin-4-yl]-amine; [2-lsopropyl-7-(3-methyl-quinoxalin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido-[4.5-d]azepin-4- y)]-(4-irifluoromethyl-phenyl)-amine; [2-lsobropyl-7-(3-trifluoromethyl-quinoxalin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-lsopropyl-7-(3-methanesulfonyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-annine; (4-tertrButyl-phenyl)-(7-phthalazin-1-yl-6.7.8.9-tetrahydro-5H-pyrimido-[4.5-d]azepin-4- yl)-am|ne; (4-tertTButyl-phenylH7-(5-methyl-pyrimJdin-4-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.6- dJazep|in-4-yl]-amine; [2-Pip4ridin-1-y|-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine [2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4r5- d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine; P-Mor2hoIin2-yl2-CS-trifluoromethyl-pyridin2-yO-ej.e.Q-tetrahydro-SH-pyrimido2.S- d]azepin-4-yl]-(5-trifluoromethyl-pyridjn-2-yl)-amine; (42ert2utyl-phenylH22poridin-1-y1-723-triflubhbmethyl-pyrWin-2-yl)2.7.8.9-tetrahydro- 5H-pyrimklo[4.5-d]azepin-4-yf]-amine; N2.N2Dimethy(-N4-(6-trifluoromethyl-pyridin-3-y()-7-(3-trifluoro-methyl-pyridin-2-yl)- 6.7.8.9-tetrahydro-5H-pyrimiclo[4.5-d]a2epine-2.4-diamine; N2.N2-Dimethyl-NV2triflucwx)methyl-pyridin-2-yl)-7-(3-trifluoro-methyl-pyrtdin-2-yl)- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d}a2epine-2.4-diarrHne; N423-Chloro2trifluoromethyt-phenyl)-N2.N2-dimeth2723-trifIuoro-methyl-pyridin-2-yl)- 6.7.8.9-tetrahydro-5H-pyTimWo[4.5-d}azepino-2.4-dlamine; (4-Brpmo-phenyl)-[2-i3opropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-yl}-annine; (4-tert-Butyl-pheny(H2-morpholin-4-yt-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-yl]-amine; N424-tert2utyJ2heny1)-Na.N2-dimethyJ-7-{3-tiifluoromethyt-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azeplne-2.4-dlamir+e; N2.N2-Dlmethyl2424-trifluoromethyl-pheny1).7-(3-trifIuoromethyl-pyridin-2-yl)2.7.8.9- tetrahydro-5H-pyrimido[4.5-d]a2epine-2.4-diamlne; N424-Chloro-pheny1)-N2.N2 N4-(4-Trifluoromethyl-pheny1)-723-trifluoromBthyl-pyridin-2-yl)-617.8.9-tetrahydro-5H- pyrimido[4.5-d]azeplne-2.4-diamine; I2-Methyl5ulfany1-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepin-4-yTJ-(4-trifluoromethyl-pheny1)-amine; [2-Methanesulfonyi-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydr d]a2epin-4-yl]-(4-trifluoromethyl-phenyl)-amine; N2-Phenyl-N4-(4-trifluoromelhyl-phenyl)-7-(3-trifluorDmethyl-pyridin-2-yl)-6.7.8.9- tetrahydro5H-pyrimido[4.5-d]azepine-2.4-dlamlne; N22ydoprop2N424-trH1uororT)ethyl2henyl)-7-(3-trifluoro[Tiethyl-pyrkl+n-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]a2epine-2.4-diamine; [2-Azetidirv1-y«-723-trifluoromathyl-pyridin-2-y1}-€.7.8.9-tetrahydro-5H-pyTimidol4.&- d]azepfn-4-yO- 1-[4.(4.Trifluorc)methy"-pheny1amino)-7-(3-trifluoromethyl-pyl]din-2-yl)-6.7.8.9-tetrahydro- 5H-pyrimkJo[4(5- N2-(22iperidin-1-y2ettiy))-N424-trifhJoromethyt-phenyJ)h723-trifluoro-methyl"pyridin-2-yf)- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; 1-[4«(4-Trifluoromelhyl-phenylamirio)-7-(3-trifluorornethyl-pyridin-2-yl)-6.7.8.9-tetrahydro- 5H-pyrimido[4.5-d]azepin-2-y1)-piperklin-4-ol; (2-(4-lsopropy1-piperaz]n-1-yi)-7-{3-trifluorom8thyl-pyridin-2-yl)-6.7.8.9-tetrahydrt)-5H- pyrimido2.S-dlazepin-2ylH2-trtfluoromeUiyi-phenylJ-amine; N2 [2-Methoxy-7- dlaz©pJn-4-ylH4-trifluoromethyl-phenyl)-amine; N4- tetrahydro-5H-pyrimido{415-d]azepine-2.4-diamine; N"242etlx)xy2trffIuoromethy2phenyt)-N2lN2Klimethyl-7-(3-trifluoromothyf-pyrkJin-2-y2 617.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; 2-{4-);2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6.718.9-t6trahydro-5H- pyrimido[4.5-d]azepin-4-ylamino]-phenyl}-2-methyli3ropionrtrile; (4-tert-Buty2phenylH2-piperidin-1-ylmethyl-7-(3-trifluoromethy2-pyridin-2-y1)-6)7.8.9- tetra2ydro-5H-pyrimidot4.5-d]azepin-4-yJ]-amine; (4-tert-Butyt-pheny1)-[2-methoxymethyl-7-(3-trinuoromethyl-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimidot4.5-d]azepin-4-yJ]-amine; NV2.3-Dihydro-benzo[1.4]dioxirv2y1)22.N2KJimethyl-723-trifluoronnethy+-pyridin-2-yl)- 6.7.8;9-tetrahydro-5H-py(imido[4.5-d]arepine-2.4-diamine; [2-Methyl-723-trffluoromethyf-pyridJn-2-y))-6.7.8.9-tetfahydro-5H-pyiimldo{4.5-d]a2epin- 4-y1]-{5-trifIuoromethyJ-pyl]dir)-2-yl)-amin«; N4-Benzy1-N2.N2 422-pimethylamincH7-(3-trifluoromethy(-pyrtdin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimkio[4.5- d]azepin-4-ylamino]-benzene3ulfonamide; N2.N2-Dimethyl-N4-(4-nitro-phenyl)-723-tiifluorornethyl-pyridin-2-yf)-6.7.8.9-tetrahydrc)- 5H-pyrimfdo{4I5-d]azepine-2.4-diamine; N"-(3.42fchloro-benzyl)-N2.N2HJimothyl-723-trifluorornethyl-pyridin-2-yl)-6.7.8.9- tetrah\ydro-5H-pyrimkJot4.5-dJazepine-2.4-diamine; p-Methylsulfanyl-723-trifluoromethyl-pyiidin-2-yl)2J.8.9-tetrahydro-5H-pyrimido[4.5- d]azepirv4-ytH5-trifluoromethyl-pyridio2-y1)-amine; [2-Methylsulfanyl-7-(3-trifluorome1hyl2yridin-2-yl)2J.8.9-tetrahydro-5H-pyrimido[4.5- d]az©ptn-4-ylH6-trifluo[omethyl-pyridin-3-yl)-amine; [22ethoxymethyl-7-(3-triflucH2methy(-pyriditv2-yl)2y.8.9-tetrahydro-5H-pyrimido{4.5- d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine; 4-[22imethylamino-7232fluoromethyf-pyridin-2-yt)-6.7.8.9-tetrahydro-5H-pyrimkJo[4.5- dJazepin-4-ylamino]-benzoic acid methyl ester; 4-[2-0imethylamirK)-7-(32rifluoromethyl-pyridin-2-y1)-6.7.8.9-tetrahydrc)-5H-pyrimidor4.5- d]azepin-4-ytamino]-benzonttrile; N4-(4-Dimethylamino-pheny1)-N21N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; (3-Chloro-4-trifluoromettiyl-phenyl)-[2-methoxymethyl-7-{3-trifluoromethyl-pyridin-2-yl)- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-dJazepin-4-yl]-amine; 2-(42ethoxy-phenyl)-N2.N22imethyt-7-(3-trifluorometJiy1-pyridin-2-y tetrahydro-5H-pyrimldo[4.5-d]azeplne-2.4-diamlne; N"-lndan-2-yl-N2.N2-dimethyt-7-(3-trifluoromethyl-pyridir+-2-yJ)-6.7.8.9-tetrahydro-6H- pyrimfdo[4.5-d]azepine-2.4-diamine; I7-(5-AmincH3-methyJ2yrklirv2-yl)-2-isopropy+27.8.9-tetrahydr()-5H-pyrimido{4.5- d)azeplr)-4-y!]-{4-trifluoromethyl-phenyl)-amine; [7-(2-Amino-pheny1)-2-isopropy1-6.7.8.9-tetrahydro-5H-pyrimido[4.5-dJazepin-4-yl]-(4- tiifluoromethyl-pheny1)-amine; [2-tsopropyl-7-{2-nrtro-pheny1)-6.7.8.9-tetrahydro-5H-pyrimido[4.5-cnazeP'n-4-y'I-(4- trifluorbmethyl-pheny})-amine; (7-(3-AmUio-pyridirH2-yl}-2-isopropyl2y.8.9-tetrahydfX)-5HH3yrirnido[4.5-dlazepin-4-yll- (4-trffluoromethyl-phenyl)-amine; [2-lsopropyl-7-(3-methyl-5-nitro-pyridin-2-yl)-617.8.9-tetrahydro-5H-pyrimldo[4.5- d]azep|n-4-yl]-(4-trifluoromettiyl-phenyl)-amine; [2-lsopit)pyl-723-nitro-pyr1din-2-yl)2J3.9-tetrahydro-5H2yi1mWo[4.5KJ]azepirv4-yJH4- trifluoromethyl-phenyl)-amlne; N2-{2-lsopropy1-4-(4-trifluoromethyl-pheny1amino)-5.6.8.9-tetrahydro-pyrimldo[4.5- d]azepin-7-yl]-phenyl}-(Tiethanesulfonamlde; 4-[4-(4-Trifluoromethyl-phenylamlno)7-(3-tiifluoromethyi-pyi1din-2-y«)-6.7.8.9-tetrahydrD- 5H-pyrlmido[4.5-d]azepin-2-yl]-piperazin-2-one; (R)-H424-Trifluorornethyf-phenyIamino)-7-{3-trifluoromethyl-pyridin-2-y()-6.7.8.9- tetrahydro-5H-pyrimkJo[4.5- pyrimido[4.5-d]azepin-4-yl]-(4-trlfluoromethyl-pheny))-amine; N2-(2-Mettioxy-ettiy1)-N2-methy4-N4-{4-trifluoromethyl-phenyl)-7- 2-yl)-6.718.9-tetrahydro-5H-pyTimldo[4.5-d]azepine-2t4-dlamine; (S)-1-{4-(4-Trif?uoromethyt-phenylamino)-7-(3-trifIuoromethyi-pyridin-2-yf)-6.7.8.9- tetrahydro-5H-pyrimido[4.&-d]azepin-2-yl]-piperidin-3-o); N2-Cydoptx)pylmethyl-N"- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepino-2.4-diamine; H4-|2-lsopropyl-723-trif1uoromethyl-pyr}din-2-yl)-6.7.8.9-tetrahydro-5H-pyrinnldo[4.5- d]azepin-4-ylamino}-phenyl}-ethanone; 4-(2-lsopropyl-7-(3-trifluo[Dmethyl-pyridin-2-yl}-6.7.8.9-tetrahydro-5H-pyrlnnldo[4.5- d]azepin-4-ylamino}-benzonrtrile; (3.4-Dichloro-benzy [2-Plperazin-1-yl-723-trifluorornethy2pyridirH2-y))273.9-tetrahydrc)-5H-pyrimido[4.5- d]azepin-4-ylH4-trifluoromethyl-phenyl)-amlne; [2-Thiomorpholin-4-y1-7-{3-trlfluoromethyl-pyrklin-2-yl)-6.7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-y)]-(4-tiifluoromeUiyl-phenyl)-amine; [2-lsopropy)-7-(3-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- dJazepin-4-ylH4-trifluoromethanesulfonyl-phenyl)-amine; [2-(4-Benzyl2iperazin-1-y«27-(3-trifluororT)ethyl-pyf1din-2-yl)-e.7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-y)]-(4-trifluoromethyl-phenyl)-amlne; M2-lsopropyl-723-trifluorornothyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepSin-4-ylanriino)-benzoic acid methyl ester. [2-lsopropy+-7-(3-trifluonomethy+-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimldo[4.5- d]azep)n-4-yl]-(4-trifluoromethylsulfany+-pheny1)-amlne; [2-lsopropy1-7- d]azepin-4-yf]-pyrimidin-4-yl-amine; [2-Pyrrolidin-1-yl-7-(3-trif1uorom©thyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepin-4-yl}-(4-trifluo[omethyf-pheny1)-amine; [2-lsopropyl-7-(3-trifluoromethy2pyridin-2-y1)-6.7.8.9-tetrahydro-5H-py2imido{4.5- d]azeplr)-4-yl}-pyrimidin-2-y1-amine; [2-(3.4-Dichloro-pheny1)2thyl]-[22sopropy1-7-(3-trtfluoromettiy1-pyridin-2-yi)-6.7.8.9- tetrahydro-5H-pyrlmido[4.5-d]azepin-4-yll-annine; (3.4-Di pyrimido[4.5-d]azepin-4-yll-amine; N-{2-{2-lsopropyl-4-(4-trifluoromethyl-phenylamino)-5.6.8.9-tetrahydro-pyrimidol4.5- d]azepin-7-yf]-pyridin-3-yf}-methanesulfonamJde; N-{2-{2-lsopropyl-4-(4-trifluoromethyl-phenylamino)-5.6.8.9-tetrahydro-pyrimido[4.5- d]azepin-7-yf]-phenyl)-(nethanesulfonamide; 224-l2-AzetidlrKi-yl-7-(32fluoromethyl-pyridin-2-y1)-6.7.8.9-tetrahydrD-5H-pyrimido[4.5- d]azepln-4-yiamino]-phenyl}-propan-2-ol; 22422-Azeparv1-yJ-7-(3-trifluoromethyl-pyTidin-2-yl)-6.7.8.9-tetrahydro-5H-pyrinnkJo[4.5- d]azepin-4-yiamino]-phenyl}-propan-2-ol; and N2-(22imethylamino-«thyl)-N2-methyt-N4-(4-trifluoro[Tiethyf-phenyl)-7- pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- 100. A compound selected from the group consisting o[: N-{[4-Chloro-3-(trifluoromethyl)pheny1]methyl)-2- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido(4.5-dla2epin-4-amine; 221-Methylethyl)-7-[32trifluoromethyl)pyridin-2-yI]-NHI62tr}fluoromethyl)pyridin-3- ylJmethylJ-e2.S.Q-tetrahydro-SH-pyrimido2.S-dlazepin2-amine; 221-Meth;ylethyl)-N2[42trifluoromethyl)phenyl]methyl}-7-[32tn2uoitxTiethyl)pyrtdin-2-yq- 6.7.8.9-tetrBhydro-5H-pyrimido[4.5-d]azepin-4-amine; N2222-Fluoraphenyl)ethyl)-2-(1-methylethyl)-7-{3-(trifluoromethyl)pyrldin-2-yl]-8.7.8)9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; N-p2-Bromophenyt2thyq22i-methylethylK-IS2trifluoromethyiJpyridin2-yl]-ej.S.g- tetrahy!dro-5H-pyi1nnido[4.5-d]azepln-4-amine; N2(2.62lchlorophenyl)methyQ-2-(1-methylethylV7-{3-(trifluoromethyi)pyridin-2-yJ}-6.7.8.9- tetrahydro-5H-pyrimido{4.5-cl]azepln-4-amlne; N-[(2-Chlorophenyf)methyJJ-2-{1-methytathy tetrahydro-5H-pyrimido[4.5-dJazepin-4-amine; N-[4- 67.8r£Metrahydro-5H-pyrimido[4.5-dJazepin-4-arnine; N2223-Chtorophenyl)ethyt]-2- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; N-j2-(4-ChJorophenyl)ethyq-2-(1-methy+ethyl)-7-[3-(trinuoromethyl)pyridin-2-yll-6.7.8.9- totrahydro-5H-pyrimkJo[4.5-d]azepin-4-amine; N-|2-(2.6-Dichl(xopheny+)ethyl]-2-(1-methylethyl)7.[3-(trlfludfomethyl)pyridin-2-yl]-6.7.8.9- tetrahydrD-5H-pyrimido[4.5-d]azepin-4-amine; 2-(1-Methylethyl)-N-{2-I2-{m8thyloxy)phenyl]ethy))-7-[3-(trifluoromethyl)pyridin-2-yl|- e2.S.O-tetrahydro-SH-pyrlmldo2.S-dlazepin2-amine; N.N-D|methyl2-({2-(1-niethylethy))7H3-(tiiflLKDromathyJ)pyrWirw2-yl]27.8.9-tetrahydro-5H2 pyrimido[4.5-d]azepln-4-y0amlno)benzamide: rH3-ChlorcMHtrifluoromemyl)pheny1]-2-(1-methylethyl)-7-[32trifluoromethyt)pyrklin-2-22 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; 2-Methy«-2-[4-({2-(1-methylemy1)7-[3-(trifluoromethyl)pyrkiin-2-y1]-6.7.8l9-tetrahydro-5H- pyrimklol4l5-d]azepin-4-y1}amino)phenyl]propanenHri)e; 4.({221-MethyJethyl)-7-[3-(trifluoromethy))pyridin-2-y027.8.9-tetrahydro-5H-pyrimido[4.5- d]a2epin-4-y1}annino)benzoic acid; N-Biphenyl2y1-221-methyfethyl)-7-(32trifIuoromethyl)pyrldin-2-yll-6.7.8.9-tetrahydro.5H- pyrimido[4.5-dlazopin-4-anriine; N- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; 2-{1-Mdthy+ethyl)-N- tetrahydro-5H-pyrimJdo[4.5-d]azepin-4-amine; 2K1-Methytemyl)-N-(4MTiorpholin2-y1pheny1)-7-[3-(trifluorornethyl)pyridin-2-26.7.8.9- tetrahydro-5H-pyrimido{4.5-d]a2epin-4-amine; 221-Meihy)othyt)-N-[4-(methylsu)fanyt)phenyl]-7-[3-0rifluoromethy+)pyridir)-2-yl}-6.7.8.9- tetrahydro-5H-pyrimldo[4.5-d]azepin-4-amine; 2K1-Methylethyl)-NH4-nitrophenyl).7-[3-{trinuoromethyl)pyridin-2-ylJ-6J.8)t8trahydro-5H2 pyrimido[4.5-d]az©pin-4-amine; 221-Methylethyl)-N24-(iHT+ethylethyl)phenyl]-7-[3-(triflUbromethyl)pyridin-2-yll-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepJn-4-amine; 2-(1.1 -DJmethylethyl)-N-[4-(1.1 -dimethylettiy1)phenyl]-7-[3- 2-{1.1 -Dimethylethyl)-N24-(trifluoromethyl)phenyl]-7-[3- N-[32luoro2trifluoromethyl)phenyl]-221-methylethyl)-7-[34trifluoromethyl)pyridin-2-yl}- 6.7.8.9-tetrahydro-5H-pyl]mido[4.5-d]azepin-4-am!ne; N-(2.32ihydn)1H-inden-5-y1)-2-(1-iT«thylethyl)-7H32trifIuoromefr+y1)pyTidin-2-yl}-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepln-4-annine hydrochloride add salt; 2-(1-Methylethyl)-N-t4K1.3 tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; N-[4-(1.1 -Dimethylethyl)-3-nrtrophenyl]-2-(1 -methy2ethyl)-723-{trifluo2omethy2)pyTWin-2-y2]- 6.7.8.9-tetrahydro-5H-pyrimido[4t5-d]azepin-4-amine; 2-Furan-2-yl-N-[4-{trifluoro methyl )phenyt}-7-{3-(trifluoromethyl)pyri N24_(1.1-Dimethylethyl)phenyl]-2-(uran-2-y1-7-[3- 2-Furan-3-yl-N-[4-(trifluoronnethyl)phenyl]-7-[3-(trifluoromethyl)pyrklin-2-yil-6.7.8.9- i tetrahydro-SH-pyrimido2.S-dlaMpin-2-anrrin6; N-l4-(1.1-Dirnethytethyl)pheny1]-2-(uran-3-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahydro-5H-pyrlmldo[4.5-dlazepin-4-amine; Benzo[1.2.5]thladiazol-5-yH2-lsopropyt-7- 5H-pyrimido[4.5-d)azepin-4-y1}-amine; 2-(2-Thieny1)-N-[42trifluoromethyl)ptienyq-7-I3-(trtfluoromethyl)pyTidin-2-yl]-6I7.8.9- tetrahydro-5H-pyrimldo[4.5-d]azepir)-4-amine; 223-Thienyl)-N-[4Ktrifluoromethyl)pheny1]-7-l3- 2-(12ethylethyl)224-methylpheny1)-7H32trmuoror7+ethyl)pyridin-2-yl]-6.7)8.9-tetnahydro- 5H-pyhmldo[4.5-d]azepin-4-amine; 2-(12ethylathyl2N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[32trifluort)nnethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5hH3yrimido[4.5- 2-(2-Methyl-132hiazol2y1)-N-[42trffluoromethy 6.7.8]9-tetrahydro5H-pyrimkto[4.5-d]azepin-4-amine; N.N-DimethyM-22i-methylethyiK-p-CtrifiuoromethylJpyridin2-yfKy2.Q-tetrahyditvSH pyrirnldo[4.5-d]azepin-4-yl}amino)benzenesulfonamide; N-[2-Fluoro2trifIuotx5methyl)phonyl]-2-(1-methylethyl)-7-[3-(triflucKomethyl)pyrJdin-2-yq- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepln-4-amine; 1-[4-({2-Piperidin-1-yl-723-(trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5- d]azepin-4-yl}amino)phenyl]ethanone; N-[3-FluorcM-(trifIuoromethyl)pheny(l-2-piperfdin-1-yl-7-[3-{trffluoromethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5H-pyrfmklo[4.5-dJazepin-4-amine; N.N-DimothyM-({22iperidirHi-yl-7-[32trifluoromethyl)pyrklin-2-ylJ-6.7.8.9-tetfahydfO-5H- pyrimido[4.5-d]azepin-4-yl}amino)b©nzenesulfonamlde; N-[4-(1.1 -Dimethylethyl)-3-nltrophenyl]-2-piperidin-1 -yl-7-[3-(ti1fluoromelhy1)pyridin-2-ytl- 6.7.8.9-letrahydro-5H-pyrimidoI4.5-d]azepin-4-amlne; N-[4-(Methylsulfanyt)pheny1]-2-piperkiin-1-yJ-7-[3-(trifluoromethyl)pyTWirv2-yf}2.7.8.9- tetrahydro-5H-pyrimido[4.5-clJazepin-4-amin0; 2-(12ethylethyl)221-methyl-1.2.3.4-tetrahydroquinolin-7-yl)-7-[3-{trifluorc)methyl)pyridin- 2-yf]-6.7.8.9-tetrahydro-5H-pyTimido[4.5-dlazepln-4-amine; 2- tetrahydroquinolin-7-yI)-6.7.8.9-tetrahydro-5H-pyrimido[4.6-d]azepin-4-amine; N- y1]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-Piperidin-1-y1-7-{3-(trifluoromeUiyl)pyridin-2-yll-N-(114.4-trimethy«-1.2.3)4- tetrahydroquinolin-7-yl)-6.7.8.9-tetrahydro-5H-pyrimldo[4.5-d7azepln-4-amlne; N-I4-(i]i-Dimethyle2y1)pheny1]-2-pyridin-4-yJ-7-{3-(trifIuoromethyl)pyridin-2-y1]-6.7.8.9- tetrahydro-5H-pyrimido[4.5- 6.7.8.92etrahydro-5H-pyTimido[4.5-d]azepin-4-yf]-amine; 2-Pyridip2-yl-N-{4-(trifluoromethyf)pheny1}-7K3-(trifluoromethyl)pyridin-2-ylJ-6.7.8.9- tetrahydro-5H-pyrim(do{4.5-d]azepln-4-annine; N24-(-|.'l2jmBthylethyl)phenylJ-2-pyridin-4.yl-7-[3-{tiifluoromethyf)pyridin-2-yl]-6.7.8.9- tetrahyd)o-5H-pyrimido[4.5-d]azepin-4-amlne; N-[3-Chk)ro-4-(trifIuoromethyl)phenyl]-2-pyridin-4-yJ-7-[3-(trifluoromethyJ)pyridin-2-yfl- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; 2-Pyrtdin2yl-7-[3-(trtfluoromethyl)pyridin-2-yO-N-[62trffluoromethyl)pyrWirv3-yf]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepitv4-amine; N-[421J-Dimethyfethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluorDmethyl)pyridin-2-yl]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-arnine. 2-Pyrklirv2-yl-r4-I4-(trifluoromethyl)phenyl]-7-[3.(trifluoromethyl)pyridin-2-yfJ-6.7.819- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; NK3-Chlc«'o2-(trifluoromethyl)phenyl}-2-p)2in-2-yl-7-(3- Methyl 2-methyl-2-[4-({2-(1-niethylethyl)-7-{3- i Methyl 2-methyl-2-[4-({2-piperidin-1-yl-7-{3-(trinuoromethyl)pyridin-2-yt]-6.7.8.9-tetrahydro- 5H-pyrimido{4.5-d]azepln-4-yl}amlno)phenyQpropanoate; 2-Pyridin-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3- 2-[4-({2-Piperidin-1-yl-7-[3-(trifluoromemyl)pyridin-2-yll2).8.9-tetrahydrcH5H-pyrimido(4.5- d]azepln-4-yl)amlno)phenyl]propan-2-ol: 2-{4-({2-{1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-ylJ-6l7.8.9-tetrahydro-5H- pyrimido[4.5-d]azepin-4-yl}amino)phenyl]propan-2-ol; 1.1J-Trifluoro-244-({221-nr)ethylethyl)-7-[3-(triflua-omethyl)pyridlrh2-ylHJ.8.9-tetrahydrD- i 5H-pyrImldo[4.5-d]azepin-4-yt}amino)phenyqpropan-2-oJ; 1.1.1 -irifluoro-2-[4-({2-piperidin-1 -yl-7-[3-(trifluorcHnnethyl)pyridin-2-yl]-6.7.8.9-tetrahydro- 5H-pyrimido[4.5-dlazepin-4-yt}amino)phenyl]propan-2-ot; 2-Meth2-224-({2-(1-methylethyl}-7232trifluoromethyl)pyi1din-2-yd)67)8.92etrahydro-5H- pyrimido[4.5-d]azopin-4-yl}amino)phenylJpropan-1-ol; i-I222i-MethylethyiH-lMtrtfluorornethylJpyridin2-yll-ej.S.g-tetrahydro-SH- pyrimido[4.5-d]azepin-4-yl}am{no)phenyl]ethanol; 2.2.2-Trifluoro-H4-({2K1-methylethyl)-7-I3-{trifluc)rornethyl)pyridin-2-yl]-6.7.8.9-tetrahydro- 5H-pyrihiido[4.5-d]azepln-4-yl}amlno)pheny)]ethanol; 22ethyl-2-[42{2-{1-methylethyl)-7-[32trifluoromethyl)pyridin-2-yr|-6.7.8.9-tetrahydro-5H- pyrlmldo[4.5- 42{2-(12ethylethyl)-723Ktrifluoromethyl)pyTkJin-2-yiK7.8.9-tetrahydrcK5Hijyrimido[4l5- d]azepin-4-y1}amino)benzoic ackj; 2-Maithyl-2-[4-({2-piperidin-1-yl-7-[32triflLHDroniettiyl)pyridJn-2-yl]-6.7.8.9-tetrahyd(X)-5H- pyrimido[4.5- N-[62hloro-52trifluoromethyl)pyridin-2-yl]-2-(12ethylethyl22 yf)-€.7.8.9-tetrahydro-5H-pyrimldo[4.5- 4-y!]-(6-methoxy-5-trifiuoromethyt-pyridin-2-yl)-amine: 2-Pyridirv2-yl-7-[32trifluoromethyl)pyrkJin-2-yl]-N-[5-(trtfluoromethyl)pyridhi-2-y tetrahyd ro-5H-pyrim idoJ4.5-d]azepln-4 -a mine; [2-lsopropyl-7-(3-U1fluoromethyl-pyrldin-2-y1)-€.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin- 4-ylH5-trifiuo[t)methyl-pyrazJn-2-yl)-amine; [2-Piperidin-1-yJ-723-trifluoromethyl-pyridin-2-yl)-6.7.8.9-tetrahydro-5H-pyt1rnido[4.5- d]azepin-4-yf]-(5-trifluoromethyl-pyrazin-2-yl)-amine; 2-(4-MethylpiperazJn-1-yl)7-[3-(trifuoromelhyt)pyrldin-2-yl)-N-[5-(trifluoromethyi)pyridin-2- yl]-€.7.8.9-tetrahydro-5H-pyrimldo[4.5-d]azepin-4-amine; 2-Az©parHi-yl-7.[3-(trifluoromethyl)pyrkJin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yO-6.7.8.9- tetrBhydro-5H-pyrimido{4.5-d]azepin-4-amine; N2-[2KDImethytamino)ethyl]-N2-nnethyl-7-[3-(trifluorc)m©thyl)pyridin-2-yl]-N4-{5- (trifluoromethyl)pyridin-2-yf]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-dla2:epine-2.4-diamine; N2-Methyl-N2-[2-(methytoxy)eUiytj-7-{3-{trifluororT)ethyl)pyridin-2-yl)-N4-I5- (trlfluoir)methyl)pyridin-2-yf]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; 2-Azetibin-1-yl-7-[3-(trifluoromethyl)pyridin-2-y+]-N-I5-(trifluoromethyl)pyridin-2-yll-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; N22-(1j2ethylethy2)-7-[32trffluoromethyl)pyrkJin-2-)1]-6J.8.9-tetrahydro-5H-pyr1midot4.5- d]azepin-4-yl}benzene-1.4-diamine; 4-(1.1 -Dimethylethyl)-N 1-{2-( 1 -methylethyl)-7-[3-(trifluoromethyl)pyrkJin-2-yl]-6.7.8.9. tetrahydro-5H-pyrimido[4.5-d]azep(n-4-yt)bonzone-1.3-dlamlne; 4-(1.1-pimethyiethyl)-N 1 -{2-plperidin-1 -yl-7-{3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-yt}benzeno-1.3- 7-{5-Amino-3-(trifluoromethyl)pyridin-2-yi]-N-[4.(1.1-dimethylethyl)phenyt]-2-(1- methyJethyl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5- 6.7.8.9-tetrahydro-5H-pyrimido{4.5-d]azepin-4-amine; N-[22hloro2-(trinuoromethy+)phenyl]-2-{methylsulfanyl)22 6.7.8.9-tetrahydro-5H-pyrimido[415-d]azepin-4-amine; 2-(Methytsulfanyl)-N-r2-methyt2-(trifluoromethyl)phenyl]-7-{3-(trifluorornethy()pyiidir)-2-yfl- 6.7.8(9-tetrahydro-5H-pyrimWo[4.5-d]azeplrv-4-amine; 22Methylsulfanyl)-NK1-rnethyt-1.2.3.4-tetrahydroquinolin-7-yl)-7-{3-{trifluoromelhyl)pyridin- 2-yl}-6.7.8.9-tetrahydfx)-5H-pyrimldo[4.5-d}a2epin-4-amine; 2-(Methylsu!fanyl)-7-[3-{trifluo[omethyl)pyridin-2-yt]-N-(1.4.4-trimethyl-i .2.3.4- tetrphydroquinolin-7-yl)-6.7.8.9-tetrahydro-5H-pyrimido(4.5-d]azepin-4-amine; N-[4-(i.1-Dimethylethyl)phenyl}-2-(methylsulfonyI)-7-(3-(trtf]uoromethyl)pyridin-2-yl}- 6.7.8.9-tetrahydro-5H-pyiimldo[4.5-d]azepln-4-amine; 2-{Methylsulfonyl)-7-t3-(trifluoromethyl)pyridin-2-y1]-N-(1.4.4-trimethyl-1.2.3.4- tetrahydroqulnolln2-yl22.S2tetrahydro-SH-pyrimido2.S-dJazepin-2amine; 2-(Methylsulfonyl)N-I2-rnothyl-4-(trifluoromethyl)phenyt]-7-{3-(trifIuoromelhy1)pyridin-2-yi]- 6.7.8.9-t0trahydro-5H-pyrimidoI4.5-d]azepln-4-amine; 2-(1-Wl2thylethyl)-N-{4-(methylsulfony1)phenyl]-7-(3-{trifluoromethyl)pyrjdlr)-2-yQ-6.7.8.9- tetrahydro-5H-pyrimido[4.5- 221.12loxkicHi.24hia2lna22-yl)-N-[4-(trifluoramethyl)pheny1]-7-[3-(trifluoromethyl)pyrld!n- 2-yf}-6.7.8.9-tetrahydro-5H-pyrimido[4.5-dlazepin-4-amine; N2-[22Methyloxy)ethyf]-N4-[42trifluoromethyl)phenyf]-7H3-(trifluorDmethyl)pyridin-2-ylJ- 6.7.8.9-tetrahydro-5H-pyrimkJo(4.5-d]a2epine-2.4-diamine; 2-(3-(Methyloxy)piperidin-1-yl]-N-[4-(trifluoromethyl)phenyf]-7-{3-(trtfluoromethyl)pyr1din-2- ylj-e2.S2-totrahydro-SH-pyrimido2.S-dlazepin2-amine; 22(2S)-2-[(Methytoxy)methyl]pyrrDlidin-1-yl}-NK4-(trifiuoroniethyl)phenyq-7-[3- (trifluoro[Tiethyl)pyridlrH2-y1]-6.718.9-tetrahydrc)-5H2yTimido{4.5-cl]a2epin-4-amine; N2-(Furain-2-ylmethyl)-N2-methyl-N4-[4-(trinuoromethyt)pheny1J-7-[32 (trifluoromethyl)pyridin-2-yf]-67.8.9-tetrahydrt)-5H-pyrirnido[4)5-d]azepine-2.4- 2-Azetdin-1-yl-7432trifluoromethyl)pyridin-2-y tetra2ydro-5H-pyrimldo[4.5-d]azepin-4-amine; N2.N2-Dimethyl-7-l3-(trifluorome1hy1)pyridirv2-yll-N4-{[6-(tr1fIuoromethyl)pyridin-3- yl]methy)}-6.7.8.9-totrahydro-5H-pyriinido[4.5- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-dJa2epine-2.4-dlamino; 2-(4-Methylpiperazirv1-yl)-7-l3- NK32Noro-4-(trtfluoromethyl)phenyl]-2-(4-methylpiperaz]n-1-yl)-7-i3- (trifluoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4)5-d}azepin-4-amine; 2-Azepan-1-yl-NH4-(trifluoromethyl)phenyt]-7-{3-(trifluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-annine; 2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yt]-N-[6-(trifluoromethyl)pyridin-3-yl]-6.7.8.9- .tetrahydro-5H-pyrimkJo[4.5-d]azepin-4-amine; 2-Azepan-1-y+-N-l3-chloro-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-y1)- e2.a.2tetrahydro-SH-pyrimido2.S-dlazepirv2-amlne; N2-[2-(0imethylamino)ethyt]-N2-methyi-7-[3-{trifluorDmethyl)pyridin-2-yl]-N4-{6- (trifluorDrnethyl)pyridin-3-y1]-6t7.819-tetrahydnc)-5H-pyrimido[4.5-d]azepine-2.4-diamino; N4H32hloro-4-(trifluoromethyl)phenyl]-N2-[2-(dimethy (trifluoromethyl)pyridin-2-yl]2J.8.9-tetrahydro-5H-pyrimldoI4.5-d)azepine-2.4-dlamine; N2-Methyl-N2-[2-(methyloxy)ethyt]-7-[3-{trifluoromethyl)pyridin-2-yl}-N4-[6- (trifluoromethyt)pyridin-3-yf]2J.8.9-tetrahydro-5H-pyrimklo[4.5-d]azepine-2.4-diamine: N4-{3-Chloro2-(trifluoromettiyl)phenyl]-N2-methyl-N2-[2-(methyloxy)ethyI]-7-{3- (trifluoromethy))pyTidin-2-yl]2.7.8.9-tetrahydrcH5H2yrirnido(4.5-dJazepine-2.4- 2-AzetWin-1-y1-N-[32htoro2trifluoromethyt)phenyf]-7-[3-{trifluorornethyl)pyridir)-2-yl}- 6.7.8.9-tetrahydro-5H-pyrimklo[4.5-d]azepir)-4-amine; 2-Azeitidin-1-y1-N-[(3.42lchloropheny1)methyll-7-l3-(trifluoromethyl)pyridin-2-yIl-6.7.8.9- tetrahydro-5H-pyrimidot4.5-d]azepin-4-anrilne; i N-{3-Chloro22trifluoromethyl)pheny1J-2-piperidin-1-y1-7-{3-(trifluoromethyl)pyridlr)-2-yI)- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-Piperidirv1-yl-7232trifluoromethyl)pyridin-2-22 tetrahydro-5H-pyrfmldo[4.5-dJazepin-4-amine; 222.6-Dimethylmorpholin2y1)2242trifluoromethyl)phenyf]-7-[32trifluoromothyl)pyrtdirv-2- yl]-6.7.8.9-tetrahydro-6H-pyrimido[4.5-dJazepin-4-amine; 2-[(2R.6S)-2.6-Dimethylmorpholin-4-yq-N-[4-(tiifluoromethyl)phenylJ-7-[3- (trlfluoromethyl)pyridin-2-yl]-€.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-(1.4-Oxazepan2yl)-N-[4-(trifluoromethyl)phenyfJ-743-(trifluo[X)methyl)pyr$din-2-yl)- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-(3.3-Difluoropiperidlrv1-yl)-N44-(trifluoromethyl2 6t7.8.9-tetrahydro-5H-pyr1mldo[4.5-d]azepin-4-amine; 224-Methylpiperidin-1-y1)-N242trifluoromethyl)phenyf]-7-[3-(trtfluoromethyl)pyridin-2-y2 6.7.8.9-tetrahydro-5H-pyi1mido[4.5-d]azepin-4-amine; 2-(3-2ethylpiperidin-1-yt)2-[42trifluorometliy1)pheny(]-7-[3-(trifluoromethyl)pyridin-2-ytI- ej.S.O-tetrahydro-SH-pyrimklo2.S-dJazepin2-amine; 2-(3.32DifluoroazetidirHi-yl)-N-[4-(trifluoTOmethyl)pheny1]-7 6.7.8.b-tetrahydro-5H-pyiimldo[4.5-d]azepin-4-amine; 224.4rDifluoropiperidin-1-y1)-N-[42trifluoromethyl)phenyl]-743-(trifIuoromethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-(3#3-Difluoropyrrolidin-1-y1)-N242trfflLK)romethyl)pheny1]-7-[3- 2-(2-Methylpyrrolidin-1-y1)-N-[4- N23-Chloro2trifluoromethyl)phenyf]-221.4-oxazepan2-y1)-7232trtfluoromettiy1)pyridin-2- yl]-6.7.8.9-tetrahydro-5H-pyrimido{4.5-d]azepin-4-amine; 2222ethylpiperidirHi-yJ)224-(trifluoromethyl)phenyf]-7-[32trifluoromethyl)pyridlrv2-yI]- 6.7.8.9-tetrahydro-5H-pyrimldo[4.5-dlazepln-4-amine; 2- 2-yl]-6.7.8.9-tetrahydro-5H-pyrimido{4.5-dJazepin-4-amine; N-[4-(1.1-Dimethytethyl)pbenyf]-2-pyrrcilidin-1-yl-7-[3Ktnfluoromethyl)pyrtdin-2-yfl-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; 2-AzetidJn-1 -yl-N-[4-(1.1 - 2-PiperWin-1-yl-7-(3-(trifluoromethyl)pyiidin-2-yl]-N-[52trifluoromethyl)pyr1din-2-yll-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azeplr)-4-amine; N-[(3;4-Dichlorophenyl)methylh2i3lperidin-1-yl-7-I32trtfluoPomethyl)pyrklin-2-yJ]-€.7 tetrahydro-5H-pyrimldo[4.5-d]azepin-4-amine; N-[421.1-Dimethylethyl)phenyl)2-(4-rTiethylpiperazin-1-yl)-7-t3-(trifluoromethyl)pyridin-2- yl]-6.7.8.9-tetrahydro-5H-pyiimkJo[4.5-d]azepin-4-amlne; 2-Azepan-1-yi-N24-(1J N2-[2- 2-Azepan-1-yW)J-[(3.42ichk)roph©nyl)methyl]-7-{3-{trifluoromeUiy1)pyridin-2-yO-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; N-[(3.4-Dichlorophenyl)methytJ-224-methylpiporazin-1-y1)-723-(trifluororneUiyl)pyiidin-2- yf]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amino; N"-[4- (trifluoromethyl)pyridin-2-yf]-6.7i8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; N-[32hloix)4-(trifluoromethyl)phenylJ-2-pyrTOlidin-1-yl-723-(trifIuoromethyl)pyrkJin-2-yl]- 6.7.8.9-tetrahydro5H-pyrimido[4.5-d]azepin-4-amine; l1-(4-{|4-(Trif1uoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yll-6.7.8.9- tetrahydro-5H-pyr1mkJo[4.5-d]azopin-2-yl)piperidin-2-yl]methanol; [(2S)-1-(4-{[4-(TrifluoromethyJ)phenyl]amlno}-7-I3- [(2R)-1-(4-{[42TrinucKomethyl)phenyl]amlno}-7-[3-(trifhjorornethyl)pyridin-2-y1]-6.7l8.9- tetrahydro-5H-pyrimido[4.5-d]a20P|n-2-yl)pyrrolidin-2-yl]metlianol; [(2S)-iK7-[3-(Trifluoromethyl)pyridin-2-yO2-{I52trtfluoromethyl)pyridin-2-y1]amino}-6.7.8.9- tetnahydro-5H-pyrimido[4.5-d]azepin-2-yl)pyrrolWln-2-yl]methanol: N2-[(3R)-Tetrahydro[uran-3-yl]-7-[3- N4-{4-{i. 1 -Dimethytethyl)phenyrj-N2-I(3R)-tetrahydro[uran-3-yl]-7-{3- (trifIuoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4- N2-(Tetrahydro-(uran-3-yl)-N4- 6.7.8.9-tetrahydro-5H-pyrimtdo[4.5-d]a2epine-2.4-dlamlne; N2Methyl-N2I-rnethyletliyl2Z-ia2tiifluorornothyOpyridin2-yl]-N4-!2 (trifluoromethyl)pyrklln-3-y1]2J.8.9-t8trahydro-5H-pyiimldo[4.5-d]a2epine-2.4-dtemlne; N'-Cydohexyl-N2methyl-r2-p-methyl2CtrifluoroniethyJJphenyl]-?-2 (trifluoromethyl)pyridin-2-yl]-6.71819-tetrahydro-5H-pyrlmldo[4.5-d]azepine-2.4-diamlne; 2- 2-yI)-6.7.a.9-tetrahydro-5H-pyrimido[4.5-d]a2epin-4-amine; 2-[2-(2ethyletliyl)pyl]x)lidin-1-yl]2-[2-methyl-4-{trifluoromethyl)phenyJ]-7-{3- (trtfluoromethyl)pyridin-2-yl}-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; N2-(Cydohexy1methyl)7232trtfluoromethyl)pyrkJin-2-yl]-N4-[62trifluororT)ethyl)pyridin-3-ylh 6.7.8.9-tetrahydro-5H-pyrimldo[4.5-d]a2epine-2.4-diamlne; {4- tetrahydro-5H-pyrimido[415-d]a2eP'n-2-yl)morpholin-2-yf]methanol; N2-Methyl22-(iHTiethylethyl)-N444-(trifluoromethyl)phenyl]-723-(trinuoromethyl)pyridin-2- ylJ-ej.S.Q-tetrahydro-SH-pyrimido2.S-dJazepine-Z2-dlamJne; [4-(42I2-MethyM-(trifluoromethyl)phenyl]amino}-7-[3-{trifluoromethyl)pyridin-2-yl]-6.7.819- tetrahydro-5H-pyrimido[4.5-d]azepin-2-yl)nnorpholin-2-y1]methanol; 2-[2- (trifluoromeUiy1)pyridin-3-ylJ-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; N2-CycJohexyl2-methyl-723Ktrffluoromethyt)pyTkJin-2-yl]-N4-[6KtrifIuoroniethyf)pyridin-2 yt]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; 2-[(2S or 2R)-2-Methylplperidin-1-yl]-N-[4-(trifluoroinethyl)phenyq-7-[3- (trifluoromethyl)pyridin-2-yt]-6.7.8.9-tetrahydro-5H-pyiimidol4.5-d]azepin-4-anilnB: 2-[(2S or 2R)-2-Methylpiperldin-1-yf}-N-[4-(trrfluoronnethyl)phenyl]-7-[3- (trifluoibmethyl)pyridin-2-yt]-6.7.8.9-tetrahydro-5H-pyi1mido(4.5- 6.7.8.9-tetfahydro-5H-pyi1mido{4.5-d]azepine-2.4-dlamlne; N2-(32ethylphenyd)-N"-[42trifluoromethyl)phenyl]-7-I3-(trifluoromethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin6-2.4-diamine; N224-Methylphanyl)-N4-[4-{ti1fluoromethyl)pheny0-7-[3-(trifluoromethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepine-2.4-diamine; N222I-MethyJethyfH-(l22uoromethylJphenyllamino2S.e.e.Q-tetrahydrD-TH- pyrimido[4.5-d]arepin-7-yJ]pyridin-3-y1}mettianesulfonannklo; l 2-(1-Methyl ethyl )-7-[3-{methylsulfony1)pyrklin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-ylh 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 7-[3-(Methylsulfony1)pyridin-2-yl)224-(trlfluoronTethyl)phenyl]-6.7.8.9-tetrahydro-5H- pyrimklo[4.5-d]azepin-4-amine; 7-(3-Amlnopyridin-2-y1)-N-[4- tetrahydro-5H-pyrlmldo[4.5-d]azepin-4-amine; 7-{3-Chloro-5-(trifluoromethyl)pyridin-2-yl}-N-[4-(1.1-dimethylethyl)phenyq-2-(1- methylethyl)-6.7.8t9-tetrahydfx)-5H-pyrimido[4.5-d]azepin-4-amine; 725-Bromo2- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 7232hloro-5-(trifluoromethyl)pyridin-2-yl]-2-{1-rnethylethyl)-N-[4-{trifIuoromethyl)phenylJ- 6.7.8.9-tetrahydro-5H-pyrlmldo[4.5-d]azepin-4-amine; 52h N-[4-(1.1 -Dimethylethyl)phenyl]-2-(1 -methylethyJ)-7-(3-methyl-5-nitropyTidin-2-yl)2.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amin0; N-(4-(1.1 -Dimettiylethyl)phenyl]-2- 6.7.8.9rtetrahydro-5H-pyrinnldo[4.5-dJazepin-4-amine; 221-Methylemy1)-7-[5-nitro-3-(trifluorom©thyl)pyi1din-2-yI]-N-[4-(trtfluoromethyl)phenyl)- e2.S.Q-tetrahydro-SH-pyrimido2.S-dlazepin2-amlne; N-[4-j(ili-Dimethylemyl)phenyl]-7-(5-(luorcK3-methylpyiidin-2-yl)-2- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-(4-{[4-(TrHluoromethyl)phenyl]amino}-5.6.8.9-totrahydro-7H-pyrlrtikk)[4.5-d]azepln-7- yl)pyridine-3-carbonitrile; 2-(4242(Trifluoromethyl)pheny(]amino}-5.6.8.9-tetrahydro-7H-pyrirnido[4.5-d]azepln-7- yl)pyridjn©-3-carboxamide; 7-(3-Ruoropyrklin-2-yl)-N-[4-(trifIuoromethyl)phenyl]-67.8.9-tetrahydro-5H-pyrlmido(4.5- d]azepirv4-amine; N-[4-(1.1 -Dimettiy1ethyl)phenyfl-7.[3-{e«hytsulfonyl)pyridin-2-yih2-(1-mefoy\e\hy\y8.7.9.9- tetrahydro-5H-pyrimido[4.5-d]a2epin-4-amine; 7-[3-(Ethytsulfonyl)pyridirv2-y1J-2-plperWin-1-yl-N-[4-(trffludromethyJ)phenytl-6.7.8.9- tetrahydro-5H-pyrimldo[4.5-d]azepin-4-afnlne; 2K2-PiperWin-1-yl2{[4-(tiifluoromethyl)pheny1]amiix)25.6.8.9-tetrBhydro-7H-pyrlmido{4.5- d]azepin-7-y1)pyridine-3-suIfonamlde; N-Cyck)propyf-2-(2-plperidin-1-y1-4-{[4-(trifluoromethyl)phenyl]amino}-5.618l9-tetrahydfD- 7H-pyrimido[4.5-d]azepin-7-y1)pyrWine-3-sulfonamide; N21-Methylethyl)-222-piperidirHi-yt-4-{[4-(trifluoromethyl)phenylJamJno}-5.6.8.9- tetrahydro-7H-pyrimido[4.5-d]azepin-7-yl)pyridine-3-sulfonamWe; 723-(Ethylsutfonyl)pyrklin-2-yfl-r242trifluoromethyl)pheny1J2J.8.94etmhydro-5H- pyrlmido[4.5-d]azep yt)pyridine-3-3ulfonamide; Methyl S-chloro-e-P2methylsulfanyO2-(2trifluoromethylJphenylJaminoKS.e.e.S- tetrahydro-7H-pyrimido[4.5-d]azepin-7-yf]pyridine-3-cartx)xy(ate; 2-{MethylsuJfanyl)-7-{3-(methyl6ulfonyl)pyridin-2-y1]-N-[4-(trifluoromethyf)plienyl]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; [723-EthanesulfonyH)yrfdin-2-yl)-2-methylsuffanyl-6.7.8.9-tetirahydro-5H-pyrirTiido[4.5- d]azepin-4-y1]-(4-trif1uoromethyl-phenyl)-amine; {52hloro22-(methylsuIfanylH2[2t'2"oroniethyl)phenyI]amino}-5.618.9-tetrahydro-7H- pyrimldo(4.5-d]azepin-7-yf]pyridjn-3-yf}methanol; 2- (trifluorbmethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimldoI4.5-d]azepin-4-amJne; 2- 2-[(1-CydohexyJethyl)oxy]-N-[2-(nethyl-4-(trifluoromethyl)pheny1]-7-[3- (trifluor6methyl)pyridin-2-y1]-6.718.9-tetrahydrD-5H-pyrimldo[4.5-d]azepin-4-amine; 2- 2-C(12ethylpiperldin2-yt)oxyJ-N-t4-(trtfluoromethyl)phenyl]-7-[3-(trffIuoromethyl)pyridin-2- ylJ-«.7.8.9-t©trahydro-5H-pyrimido{4.5-dJazepin-4-amine; N-[2-MethyM2trifluoromethyl)phenyl)-2- N-t2-Methyl-4- N-[4-(Pyrrolidin-1-ylsulfonyl)pheny1]-2-(tetrahydro[uran-3-yloxy)-7-{3- (trifli2oromethyJ)pyridin-2-yl]-6.7.8.9-tetrahydr()-5l+pyrimldo[4)5-d]a2epln-4-annine; 2-{[1.-(1-MethyIethyl)pyrrolidin-3-yl}oxy}-N-[4-(tJifluoromethyl)phonyf]-7-[3- (tri(luoromethyl)pyridin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]a2epin-4-amine; 2-[(1 -Cydohexylethyl)oxy]-N-(1-nnettiyM.2.3.4-tetrahydroquinolln-7-yl)-7-[3- (trifluoromethyl)pyrkJin-2-yl]-6.7.8.9-tetrahydro-5H-pyrimido[4.6-ct]azepin-4-amine; 2-l(1-Cyclopropy1ethyl)oxy}-7-{3-(trifluoromethyl)pyridin-2-yl]-N-{4- ((trifiuoromethyiJsulfonylJphenyl2.).S.Wetrahydrx2SH-pyrirnido2.S-dJazepin2-amine; 2-[(1-Cyclohexylethyl)oxy]-7.[3-(trifluoromethyl)pyridin-2-yl]-N-{4- [(trifluoromethyl)sutfonylJphenyl)-6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]a2epin-4-amine; 22Cydopentyloxy)-7-[32trifluoromethyl)pyridin-2-yt]-N-{4-{(tr}fluoromethyl)sulf6nyl]pheny1] 6.7.8.9-tetrahydro5H-pyrimido[4.5-d]azepin-4-amine; 22(1-Cydohexylethyl)oxy)N-[4-(pyTTOlidin-1-yfsuJfonyl)phenyO-7-[32trffluoromothyl)pyr2 2-yl]-6.7.8.9-tetrahydn)5H-pyrimido[4.5-dlazepin-4-amin©; 2-[(1-Cyclopropylethyl)oxy]-N-(1-methyH.2.3.4-tetrahydroquinolln-7-yJ)-7-[3- (trfflLroromethyt)pyridin-2-yI}27.8.9-tetrahydrc)-5H-pyrimido[4.5-d]azepin-4-amine; 2-{Tetrahydro-2H-pyran-4-yloxy)-7-{3-(trifluoromethyl)pyr1din-2-yt]-N-{4- [(trifluoromethyl)sulfonylJphenyl}-e.7.8.9-tetrahydro-5H-pyrimido(4.5- (triflu'oromethyl)pyiidin-2-yl]-6J.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; 2-(Cyclopentyloxy)-N-(1 -methyH 2.3.4-tetrahydroquinolln-7-yl)-7-(3- (triflJororTWthyl)pyrklln-2-yl]-8y.8.9-tetrahydrc)-5H-pyrimido[4.52azepin-4-annine; 2-l(1+Cydopropylethyl)oxy]-N-[2-methyI-4- 2-(Cydohexyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl)-7-[3-(trifluoromethyl)pyridiiv2-yl}- 6.7.8.9-tetrahydro-5H-pyr1mido[4(5-d]azepin-4-amine; 2- 2-(Cydohexyloxy)-N-(1-methyl-1.2.3.4-tetrahydroquinolin-7-yl)-7-[3-{tr1f}uoromethyl)pyrWin 2-ylJ-6.7.8.9-totrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; N- (triflu6romethyl)pyrklirv2-yI]217.8.9-tetrahydro-5H-pyrimido[4.5-d]arepin-4-amine; 2-({K4R)2.2-Dimethyl-1.3 2- 2-[(1-Cydohoxy1ethyt)oxy]-N-[4-(trlfluoromethyl)phenyl]-7-{3-(trinuoronnethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5H-pyrimJdo[4.5-d]azepin-4-amine; 2-(CycJopentyloxy)-N-{4- 2-[( 1 -Cyclopropylethyl)oxy]-N-[4-(pyfTolidin-1 -y)sulfony))phenyl]-743- (trifluQromethyl)pyridin-2-y)]-6.7.8.9-tetrahydro-5H-pyrimldo[4.5-dJazepin-4-amine; N-{4-(f+yiTolidin-1-ylsuJfonyl)phenyQ-2-{tetrahydro-2H-pyran-4-y1oxy)-7-{3- (trinuoromethyl)pyridin-2-ylJ-6.7.8.9-tetnahydro-5H-pyrimido[4.5-dIazepin-4-amlne; 2-(Cycloheptyloxy)-N-[42trifluoromethyl)phenyt]-7-[3-(trifluorDmethyl)pyr1din-2-yl]-6.7.8.9- tetrahydro-5H-pytimido[4.5-d]azepJr+-4-amine; 2-(Cyclopenty1oxy}-N-(42trifluoronTethyl)phenyl}-7-[3- 2- 2-(Tetrahyd«)2H2yran-4-yloxy)-N-[42trifluoromethyl)phenylJ-7-(3-{trifluoromethyl)pyridin- 2-yl]-6.7.819-tetrahydro-5H-pyrimido[4.5-dlazepin-4-amine; 2-(Tetrahydro[uran-3-yloxy)-N-[42trtfluoromethyl)phenyl}-7-[32trifluoromethyl)pyridin-2-yf}- 6.7.8.9-tetrahydro-5H-pyrimkJo[4.6-d]azepin-4-amine; 24(1-Methylethyl)oxyJ2242trifluoromethyl)phenylJ-743-(trifUjoromethyl)pyridin-2-yl]- 6.7.8.9;tetrahydro-5H-pyrlmldo[4.5-d]azepln-4-amine; 2-(Phehyloxy)-N-[4-(trif]uoromethyi)phony1}-7-t3-(triJluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amlne; 2-(ButyJoxy)-N242trifluoromethyt)phenyt]-7-{3-{trifluoromethyl)pyridin-2-yl]-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]a2epln-4-amine; 424-(Twuoromethyl)phenyllamino}-7-t32trifluo[X)methyl)pyridin-2-yJ]2J.8.9-tetrahydrx) 5H-pyrimido{4.5-d}azepin-2-ol; 2-{Ethyioxy)-N-[4-(trifluoromethyl)phenyI]-7-[3-(trifluoromethyl)pyridin-2-ytl-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-[(Mi9thyloxy)methyi]-7-[3-(trifluoromethyf)pyridin-2-yO-N-I62trifluoromethyl)pyrklin2-y2 6.7.8;9-tetrahydro-5H-pytimkio[4.5- 5H-pyrimido[4.5-d]azepin-4-yl}annino)phenyl]propaneniliile; 2-(Methylsulfonyl)-7-[32trlfluororriethyl)pyrkJin-2-yt)N-[5-(trifluoromemyl)pyrkiifv2-y2 6.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepin-4-amine; 2-(Phenylsulfanyl)-N-[4-(trifIuorornethyl)phenyfl-7-[3- 22Phenylsulfany1)-7-[3-(trifluoronr«thyl)pyridin-2-yl]-N-{4-{(trifiuoromethyl)8uJfonyl]phenyI}- 6.7.8.9-tetrahydro-5H-pyr1mido[4.5- 6.7.8.9-tetrahydro-5H-pyrimldo[4.5-d]azepin-4-amine; 2-{PhenyJsulfanyl)-7-[3-(trffluoromethyl)pyridin-2-y(]-N-(1.4.4-trimethyM .2.3.4- tetrahydroquinolin-7-yi)-6.7.8.9-tetrahydro-5H-pyrimldo[4.5-d]azepin-4-amlne; 22(Phenylmethyl)su+fanyl]-N-[4-(tjifluoromethyl)phenyl}-7-{3-(trifluoromethyl)pyridin-2-yl]- 6.7.8.9-tetrahydro-5H-pyrimido{4.5-d]azepin-4-amine; 22Cyclohexytsulfanyl)-N-[4-{trifluoromethyl)pheny+]-7-[3-(trifluoromethyl)pyridir)-2-yl]- 6.7.8.9-tetrahydro-5H-pyrimJdo[4.5-d]azepin-4-amine; 2212ethylethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-l32trifiuorornethyl)pyridin-2-yl}- 6.7.8.9-tetrahydro-5H-pyrimkJo[4.5- tetrahydro-5H-pyrimldo[4.5-d]azepJn-2-yi)suffanyl]pfopan-2-ol; [2-(2-Methyl-tetrahydro-(uran-3-yisulfanyl)-7-{3-trifiuo[Drnethyl-pyridin-2-yJ)-6.7.8.9- tetrahydro-5H-pyrimklot4.5-d]azepln-4-yIH4-trifluoromethyl-pheny1)-amino; [2-(2-M9thyl-tetrahydro-(uran-3-ylsuffanyl)-7-(3-tTifluoromethyl-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepin-4-yl}- 2-{(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4- [(trffluo[DmethylJsulfonylJphenylJ-Sy.S.g-tetrahydro-SH-pyrirnidoK.S-dlazeplrv2-arnlne: 2- 2-{(1-MethylethyJ)sulfanyl]-7-{3-(trtfluo[Dmettiyl)pyridin-2-yO-N-{4- I(trifluoromethyl)suKonyl]phenyl}27.8.92etrahydro-5H-pyrimidot4.5-d]a2epln-4-afTiine; 12{7H[32rifIuoromethyl)pyridin-2-yl]2({4-[(trifluoromethyt)suffcmy(]phenyl}amino)-6.7I8.9- tetra2yd ro-5H-py ri m Wo[4.5-d]azepin-2-yl}su Ifa nyl)propa n-2-ol; [2-(2-Methyl-tetrahydro-(uran-3-yteulfanyl)-7-(3-trffIuoromethyl-pyridin-2-yl)-6.7.8.9- tetrahydro-5H-pyrimido[4.5-d]azepln-4-yl]-(4-trffluoromethanesulfonyl-phenyt)-amin6; N-[2-Methyl-4-(trifluoromethyl)phenyO-2-[(phenyfmethyl)3ulfany(]-7-I3- (trifIuoromethyl)pyridin-2-yi}-€.7.8.9-tetrahydro-5H-pyrimido[4.5-d]azepJn-4-amine; 22Cyqk)hexylsulfany1)-N22-methyM-{trtfluoromettiyl)phenyl]-7-{3-(trifluoromethyl)pyridin- 2-yf]-6.7.8.9-tetrahydro-5H-pyrimldo[4)5-d]azepin-4-amlne; 2-[(1-Methylethyl)8ulfanyQ-N-I2-nnethyl-4- 1-[(422-Methyl-4-(trifluoromethyl)phenyl}amino}-7-[3-(trifluoromethyl)pyrldin-2-yl]-6.7.8)9- tetrahydro-5H-pyrimido[4.5-d]azepin-2-yl)sulfanyl]propan-2-ol; 2.5-Anhydro-1.4-dideoxy-3-S-(4-d2-(nethyl-4- tMopentitol; 2.5-Anhydrx)-1.4KJideoxy-3-S-(4-{I2-(Tiethyl-4- |
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4100-KOLNP-2008-(22-09-2014)-CORRESPONDENCE.pdf
4100-KOLNP-2008-(22-09-2014)-EXAMINATION REPORT REPLY RECIEVED.pdf
4100-KOLNP-2008-(22-09-2014)-FORM-13.pdf
4100-KOLNP-2008-(22-09-2014)-PETITION UNDER RULE 137-1.pdf
4100-KOLNP-2008-(22-09-2014)-PETITION UNDER RULE 137.pdf
4100-KOLNP-2008-(25-09-2014)-ANNEXURE TO FORM 3.pdf
4100-KOLNP-2008-(25-09-2014)-CORRESPONDENCE.pdf
4100-KOLNP-2008-ASSIGNMENT.pdf
4100-KOLNP-2008-CORRESPONDENCE 1.1.pdf
4100-kolnp-2008-correspondence.pdf
4100-kolnp-2008-description (complete).pdf
4100-kolnp-2008-specification.pdf
| Patent Number | 265351 | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 4100/KOLNP/2008 | |||||||||||||||||||||||||||
| PG Journal Number | 08/2015 | |||||||||||||||||||||||||||
| Publication Date | 20-Feb-2015 | |||||||||||||||||||||||||||
| Grant Date | 19-Feb-2015 | |||||||||||||||||||||||||||
| Date of Filing | 10-Oct-2008 | |||||||||||||||||||||||||||
| Name of Patentee | JANSSEN PHARMACEUTICA N.V. | |||||||||||||||||||||||||||
| Applicant Address | TURNHOUTSEWEG 30, B-2340, BEERSE | |||||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07D 487/02, A61K 31/55 | |||||||||||||||||||||||||||
| PCT International Application Number | PCT/US2007/007166 | |||||||||||||||||||||||||||
| PCT International Filing date | 2007-03-21 | |||||||||||||||||||||||||||
PCT Conventions:
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