TW200948790A - Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase - Google Patents

Abstract

Certain aryl-hydroxyethylamino-pyrimidine and triazine compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). Methods of synthesizing such compounds are also disclosed.

Description

200948790 · VI. Description of the invention: [Technical field to which the invention pertains] Providing specific aryl-hydroxyethylamino-pyrimidine and tri-till compounds, pharmaceutical compositions containing the same, and treatments thereof using fatty acid indoleamine hydrolase ( FAAH) A method by which an activity mediated a disease state, disorder, and condition. Specific methods of preparing such compounds are also disclosed. [Prior Art] The medical benefits have been imposed on cannabis plants for centuries. The main bioactive component of the cannabis plant is Δtetrahydro-cannabinol (THC). The discovery of THC ultimately resulted in the identification of two endogenous cannabinoid receptors that responded to their medical effects, namely CB^CB2 (G〇ya, £:c;? 〇/H>2

TTzer·2000, 70, 1529). These findings not only establish the site of action of THC, but also trigger the investigation of endogenous agonists or "endogenous cannabinoids" of these receptors. The first endogenous cannabinoid identified was the fatty acid decyl arachidonic acid ethanolamine (AEA). AEA itself triggers the medical effects of many exogenous cannabinoids (Piomelli, iviwr_z. 2003, 4 (7 from 873). The catabolism of AEA is mainly due to the integral membrane-bound protein fatty acid guanamine hydrolase (FAAH), which will AEA is hydrolyzed to arachidonic acid. FAAH was characterized by Cmvatt and working colleagues in 1996 (Cmvatt, 1996, 3, 83). It was subsequently determined that FAAH additionally caused many important lipid messages to transfer the catabolism of fatty acid guanamine, including: A major endogenous cannabinoid '2-arachidonyl glycerol (2_ag) (*SWedan 1992, 258, 1946-1949); a substance that induces sleep, oil amide (〇EA) drink viscera 995 , Shi, 1506); appetite suppressant, N_oleylethanolamine (R〇driguez such as 200948790

Fonescajai Teng 2001, 209); and anti-inflammatory agents, palmitoylethanolamine (PEA) (Lambert, Cwrr. Med C/zem. 2002, 9 net, 663) 小FAAH small molecule inhibitors should enhance these endogenous sources Sexual messages convey the concentration of lipids in order to produce a beneficial medical effect. There are certain records regarding the effects of various FAAH inhibitors in preclinical models. In particular, two anthracene phthalate-based iFAAH inhibitors have been described as having analgesic properties in an animal model. In rats, BMS_i (see w〇 02/087569) - having the structure shown below - has an analgesic effect in the 2Chung spinal nerve ligation model of the neuropathic pain and the Hargraves acute thermal nociception test. URB-597 is efficacious in the rat anxiety plus maze model and has analgesic effect in rat hot plate and fumarin test Kathuria, K Med 2003, 9 (7 people) 76). Sulfonyl fluoride AM3 74 has also been shown to significantly reduce sputum in chronic recurrent experimental autoimmune encephalomyelitis (CREAE) mice - an animal model of multiple sclerosis

Further, the oxazolopyridone OL-135 is a potent inhibitor of FAAH and has been described as having analgesic activity in the hot plate and tail dipping test of rat thermal nociception (WO 04/033652). 5 200948790

The results of OL-135 on the effects of specific exogenous cannabinoids indicate that FA A Η inhibitors can be used to treat a variety of conditions, diseases, conditions or syndromes. This includes pain, ° nausea, vomiting, anorexia, spasticity, dyskinesia, epilepsy, and glaucoma. Currently, approved therapeutic uses of cannabinoids include soothing nausea and vomiting due to chemotherapy in cancer patients and increasing appetite in HIV/AID patients who are anorexia due to consumption of syndromes. In some countries, two products for use in these indications are available on the market, namely dronabinol ^ (Marinol®) and nabilone. In addition to the approved indications, the therapeutic field of cannabinoid use, which is subject to many attentions, is painful, that is, to treat pain. Five small randomized controlled trials showed that THC was superior to placebo and produced dose-related analgesia (Robs〇n, val. 2001, 107-115). According to Atlantic.

Pharmaceuticals will develop 1,1-dimethylheptyl derivatives of the synthetic cannabinoid CT-3, a slow acid metabolite of tetrahydrocannabinol, as an orally active analgesic and anti-inflammatory agent. CT>3 in the second pilot trial of chronic neuropathic pain ❹ was carried out in Germany in May 2002. It is claimed that many individuals with behavioral activity-related diseases (such as multiple sclerosis) have the benefits of disease-related pain and paralysis simultaneously with cannabis, supported by small control trials (Croxford et al.

Neuroimmunol, 2008, 193, 120-9; Svendsen, Br. Med. J. 2004, 329, 253). Similarly, various victims of spinal injuries, such as paralysis of the lower extremities, are reported to relieve their painful convulsions after smoking marijuana. It is evident that the cannabinoids control the sputum state and tremor in the multiple sclerosis CREAE model. The records of 200948790 confirm that these effects are derived from the CBi and Cl receptors. The sputum chest 2_, tear, 84_87). Phase III clinical trials of a mixture of THC/CBD in a narrow ratio have been performed in patients with multiple sclerosis and spinal injury. It has been documented that FAAH* is consistently returned to the wild-type control group because of knockout mice, and this improvement is not anti-inflammatory! However, it may reflect a certain neuroprotective or myelin regeneration promoting effect lacking the enzyme (Webb et al., 2_, v〇1 439, 106-110). ’ ’ 记载 There have been records of small-scale control trials investigating other potential market uses of cannabinoids. Volunteer tests have confirmed that oral, injection, and smoking cannabinoids reduce dose-related intraocular pressure (IOP), thus relieving glaucoma syndrome. Ophthalmologists have prescribed cannabis prescriptions for glaucoma patients who are unable to properly control their intraocular pressure with other drugs (Robson, 2001, supra). The use of small molecule inhibitors to inhibit FAAH may be advantageous compared to the use of direct acting 匸6^foot agents. Administration of exogenous CB agonists can produce a series of responses, including reduced nociception, tonic fainting, hypothermia, and increased

Add eating behavior. These four are especially referred to as "cannabinoid quaternary bodies". The FAAH small paper experiment showed a lower response in the nociceptive test, but no tonic fainting, hypothermia or increased feeding behavior (Cravatt, jy〇c Λ^·々ad *SW. t/like 2001, 9 Haiku, 9371). Fasting leads to an increase in the concentration of sputum at the forebrain margin of the rat 'but other brain regions do not provide evidence that the stimulation of αεα biosynthesis can be anatomically localized to the S2CNS pathway (Kirkham, J. J. ^(7), 2〇〇2, to 乂550). The local but not systemic increase in AEA suggests that inhibition of FAAH by small molecules may enhance the role of AEA and other fatty acid guanamines in the development of these signaling molecules in a specific pathological state. 200948790 and released tissue regions (Piomelli , 2003, mentioned above). In addition to the effects of FAAH inhibitors on AEA and other endogenous cannabinoids, other lipid mediators of FAAH catabolic inhibitors can be used to treat specific other therapeutic indications. For example, PEA has been inflamed (Holt et al., corpse/zormaco/. 2005, 146, 467-476), immunosuppression, analgesia, and neuroprotection (Ueda, J. and W. 2001, 27 (5 "3 from 35552)) The biological effect was confirmed in the animal model. Oily amine--FAAH is another type of receptor-induced sleep (Boger, Proc. Shi/. Jcai/. 5W. {/like 2000, 97(10)^ 5044; MendQlson, Neuropsychopharmacology 2001, Z5, S36). The inhibition of FAAH also involves cognition (Varvel et al., /P/zamaco/.5xp. TTzer. 2006, 317(1), 251-257) and melancholy (Gobbi et al., iVoc. #扣/_ Jcai/· *Scz·. [/like 2005, 102(51), 18620-18625). Recent data support two additional indications for FAAH, data showing FAAH receptor-activated receptors in energy metabolism And the importance of bone constants (Overton et al., 5r·*/· corpse/zflrmaco/· 2008, in press; and Plutzky, and from 2007, 4 such as / S12-4). FAAH catabolic lipid-transfer fatty acid guanamine-oil-based ethanolic amine (OEA)-- is the most active GPCR 119 (GPR119) (also known as glucose-dependent insulinotropic receptor) One of the agents. This receptor is mainly expressed in the human pancreas, which activates glucose-dependent insulin release in pancreatic cells to improve glucose constant. GPR119 agonist can be administered during the oral glucose tolerance test. Inhibition of glucose fluctuations, and 〇EA, when administered to rodents that may contribute to the benefit of energy metabolism disorders (such as insulin resistance and diabetes), also 200948790 independently showed regulation of food intake and weight gain. FAAH receptor palmitoylethanolamine (PEA) is an agonist of the PPARa receptor. The evidence of a surrogate marker in a human study using the PPARa agonist fenoflbmte supports the notion that PPARa agonism provides the potential to induce a coordinating PPARa response, This agonistic effect can improve dyslipidemia, suppress inflammation and limit atherosclerosis in metabolic syndrome or type 2 diabetic patients. FAAH-accepting arachidonic acid ethanolamine (AEA) is 1>1> An agonist. Arachidonic acid ethanolamine treatment induces 3T3-L1 differentiation into fat fine cells and triglyceride droplet accumulation and adiponectin performance (Bo Uaboula et al., V. 2005, 577, 174-181). Low-dose-cannabinoid therapy has been shown to reduce atherosclerosis in mice, further indicating the efficacy of FAAH in inhibiting dyslipidemia, fatty liver, steatohepatitis, obesity, and metabolic syndrome (Steffens et al., Applied % 2005, 782-6) . - Osteoporosis is one of the most common degenerative diseases. It is characterized by a decrease in bone mineral density (BMD) and an increased risk of fracture. The lack of Cb2_ mice has a greatly accelerated age-related loss of sponge bone and cortical bone expansion. CB2_selective agonism enhances the number and activity of osteoblasts in the cortex, and limits the formation of osteoclasts and reduces the loss of oophorectomy-induced bone loss (Ofek et al.' iVodw/. 2006, Sichuan 3, 696-701) » BMD has substantial genetic factors, but the genetic factors involved in the pathogenesis of human osteoporosis are largely unknown. Genetic studies have pointed to the applicability of human BMD, and it has been found that the important relevance of single polymorphism and simplex covers the CNR2 gene on human chromosome 1ρ36, confirming the role of peripheral CB2 receptors in the pathogenesis of osteoporosis. (Karsak et al., Shi / 2005, to 3389-96). Studies have also confirmed the role of osteoarthritis. 9 200948790 μ ^ H should be used to treat various causes of pain, anxiety, multiple sclerosis, Parkinson's disease (ρ_η_this and other movement disorders, heart (5) vomiting, eating disorders, _, glaucoma, inflammation, itching, Immunosuppression, neuroprotection, (d), cognitive enhancement, and sleep disorders' and potentially have less side effects than (iv) sex-like treatments. Specific amino-substituted pyrimidine compounds have been described in the literature. Specific 2,6- Substituted-4-monosubstituted pyrimidines have been disclosed as prostaglandin D2 receptor antagonists (pct patent application publication number w〇2〇〇6/〇44732).

The specific 2,4-♦ fixed diamine compound appears in the kUs patent application publication number US 2006/0058525. U.S. Patent Application Publication No. 2003/0187026 describes specific heterocyclic compounds as kinase inhibitors. U.S. Patent No. 6,881,740 shows a specific arylalkyl heterocyclic compound as a pharmaceutical agent. Specific piperage and piperidinyl urea, heteroaryl piperazine urea and heteroaryl substituted urea are disclosed in U.S. Patent Application Publication No. US 2006/0173184, U.S. Patent Application Publication No. 2007/0004741

Revealed as a FAAH inhibitor. Specific alpha-keto-oxo- and oxazolyl-based compounds are disclosed in the PCT Patent Application Publication No. WO 2007/061862 and WO 2007/14005 A. special

The β-mercaptoheterocyclic compound is disclosed as FAAH in US Patent Nos. 6,462,054 and 6,891,043, US Patent Application Publication No. US 2005/0239785, and US 2006/0111359, and PCT Patent Application Publication No. WO 2004/033652 Inhibitor. The specific oxadiazolone compound is disclosed as a FAAH inhibitor in U.S. Patent Application Publication No. US 2006/0100212 and PCT Patent Application Publication No. WO 2006/044617. The specific oxazolone compound is in US Patent Application Publication No. US 200948790. The information on the PCT patent application for the toilet face is 142 and the nuclear transfer slaves are disclosed as FAAH inhibitors ^ 〈 The population was specifically identified in the present invention as an example of a cut-to-tear and control compound in spite of the existing 'still sensitive' FAAF modulator. Strong effect of hanging biomass [invention]

Description of the invention has been found to have FAAH, nodal activity = arylamino group and tri-derivatives. The present invention relates to a bis-molybdenum patent range independent and dependent on one of the 妒-like forms, and the system is then implemented in a general state. The invention is related to a sample compound: N^N R2

Ar2 乂 X person n person 〆 "1 (丨_八)

R3 OH wherein: R1 is _H, -Cl.4 alkyl, -OC]_4 alkyl, _S(o)0_2Ci 4 alkyl, _CF3, _CN, -N(Ra)Rb or monocyclic cycloalkyl , wherein Ra and Rb are each independently _H, optionally substituted by _〇H, N(Rm)Rn, and ten Rm and _H, Ci 4 alkyl; or Ra^ 1^ The attached nitrogens together form a 4 to 7 membered heterocycloalkyl ring;

Ar1 is a phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl group at the point of attachment or a 9 or 10 membered bicyclic heteroaryl group at the point of attachment, each unsubstituted or via the following group Substituted; (i) one, two or three Rc moieties, 200948790 wherein each moiety is independently -Cm alkyl, -Cm alkyl-OH, -Cm alkyl-CN, -CF3, -OH, - OCw alkyl, -〇CF3, -〇CHF2, -OCH2CF3, 4(0)0-2(^-4 alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -CC^Cw alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN, -phenyl, pyridyl or halo, wherein Rd&Re are each independently -H or -Cm alkyl, or Rd and Re together with the attached nitrogen form a 4 to 7 membered heterocycloalkyl ring; or (ii) two or three Re moieties, wherein the two Re moieties are adjacent to each other and form together -OCCHOwO-' substituted or substituted with one or two fluoro groups and the third Rc moiety (when present) is -Cm alkyl, -Ci_4 alkyl-OH, -Ci_4 alkyl-CN, _CF3 , -OH, -OC1.4 alkyl, -OCF3, -OCHF2, _OCH2CF3, -scovw"alkyl, -SCF3, -S02CF3, -CHO, -COCm , -CC^Cm alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN or halo, wherein Rd&Re are each independently -H Or -Cw alkyl; X is N or C(Rf), wherein Rf is -Η or methyl;

The Ar2 system is: (1) a phenyl group substituted by the following groups: (a) one, two or three Rg moieties each located in the meta or para position, and optionally one or two additional in the ortho position Rg moiety; wherein each Rg moiety is independently -Ci 4 alkyl, _c] 4 alkyl 〇H, _c] 4 alkyl-CN, fully dentylalkyl, perhaloalkoxy, _〇Ci 4-alkyl, -OCw alkyl-((monocyclic cycloalkyl), _s(〇)<) & *alkyl, _SCf3, 12 200948790 S02CF3, _CHO, -COCm alkyl, -CC^Cm , -co2h, -NCRh)!^, -S02NRjRk, -NRhsC^R1, -C(0)NRjRk, -N02, -CN or a halogen group; or a phenoxy group which is unsubstituted or substituted by the following group, Benzyl, phenethyl or benzhydryl: _C _ 4 alkyl, -OCu alkyl, perhaloalkyl, perhalo alkoxy, _N02, _CN or halo; wherein Rh is -H or - Cw alkyl; R is -Cm alkyl or monocyclic cycloalkyl; or Rh and R1 together with the atom to which they are attached form a monocyclic heterocycloalkyl ring; Rj is -H or -Ci_4 alkyl; And R is -H, -C!-4 alkyl or monocyclic cycloalkyl; or Rj and Rk together with the atom to which they are attached form a monocyclic An alkyl ring; or (b) two adjacent fluorene moieties together form -0(0^)^0-; unsubstituted or substituted with one or two fluoro groups; (II) is replaced by the following group Monocyclic heteroaryl: one, two or three Rg moieties wherein each Rg moiety is independently or two adjacent Rg moieties are taken together to form an unsubstituted or substituted one or two fluoro groups - 〇(CH2)N2〇-; or (III) a naphthyl or bicyclic heteroaryl group which is unsubstituted or substituted with one, two or three Ri moieties, wherein each R1 moiety is independently 々4 alkyl, _〇Ci 4 alkyl, all-dentylalkyl, all-li-alkoxy, _N〇2, _CN or halo; R2 is -H or methyl; and R3 is -H or fluorenyl; The restriction condition is that when Ari is an unsubstituted phenyl group, Ar2 is not -CHO or a para-substituted __〇CF3; 13 200948790 and § hai·# compound pharmaceutically acceptable salt, pharmaceutically acceptable Pre-medicine and medical active metabolites. /' In another general aspect, the present invention relates to a compound of formula (j_B)··

Wherein: R1 is -Cm alkyl, -0Cl 4 alkyl, _s(〇)()_2Ci_4 alkyl, _CN, -CF3, -N(Ra)Rb or monocyclic cycloalkyl, wherein Ra and Rb are each Independently _H, optionally substituted with _〇H, 4(4) N, N(Rm)Rn ' wherein RiRn is _H, Q 4 alkyl; or 4 to 7 members together with the nitrogen to be attached Heterocycloalkyl ring,

Ar1 is a phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl group at the point of attachment or a 9- or 1-membered bicyclic heteroaryl group at the point of attachment, each unsubstituted or via Substituted by a group; (1) one, two or three Re moieties, wherein each Re moiety is independently _(^_4 alkyl, -Cw alkyl-OH, -Cm alkyl-CN, -CF3, -OH, - 〇C].4 alkyl, _〇cf3, -〇CHF2, -〇CH2CF3, -SCO^Cm appearance base, _SCF3, -S02CF3, -CHO, -COCm alkyl, -CC^Cw alkyl, _c〇2H , -N(Rd)Re, -S02NRdRe, -NRdS02Re, _c(0)NRdRe, _n〇2, -CN, phenyl, 10 hydrazide or halo, wherein RlRe are each independently _H or -Cm Or, together with the nitrogen to which it is attached, form a 4 to 7 membered heterocycloalkyl ring; or (11) two or three Re moieties, wherein the two Re moieties are adjacent to each other and form an unsubstituted or a Or two fluorine groups are substituted for -OCCH^O- of 200948790, and the third Rc moiety (when present) is -Cm alkyl, -Ci_4 alkyl-OH, -Ci_4, -CN, -CF3, -OH, -OCj.4 alkyl, -OCF3, -OCHF2, -OCH2CF3, -SCO^Cw alkyl, -SCF3, -S02CF3, -CHO, -COCw alkyl, -CO/m Alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN or a halo group, wherein Rd and Re are each independently -H or -Cm alkyl X is N or C(Rf), D wherein Rf is -Η or methyl;

The Ar2 series are: (1) a phenyl group substituted by the following groups: (a) one, two or three Rg moieties each located in the meta or para position, and optionally one or two additional Rg in the ortho position* a portion; wherein each Rg moiety is independently _Cl 4 alkyl, _Ci 4 alkyl 〇H, _c14 alkyl-CN, all-alkyl, perhaloalkoxy, 〇Ci 4 alkyl, -◦Cm alkyl-(monocyclic cycloalkyl), _s(〇)〇2Ci*alkyl, _SCF3, ❹ _S〇2CF3, -CH0, -COCw alkyl, alkyl, -(:02Η, •NKR 'R1, -S02NRjRk, -NRhsOW, -C(0)NRjRk, -Ν〇2, -CN or a functional group; or a phenoxy group, a benzyl group, a phenethyl group or an unsubstituted or substituted group Benzyl fluorenyl 4 alkyl, 〇 〇 Ci 4 alkyl, perhaloalkyl, perhaloalkoxy, -N02, -CN or halo; wherein Rh is -H or -Cm alkyl; R system Is a -C!_4 alkyl or monocyclic cycloalkyl group and R and its attached atom - finely entangled into a monocyclic heterocyclic ring; R is -H or -C]-4 alkyl; R is a _H, yl or monocyclic cycloalkyl; 15 200948790 (9) two adjacent (four) points - forming unsubstituted or via - or two gas groups Substituted -0(012)^0-; (11) monocyclic heteroaryl substituted by the following groups: one, two or three Rg files wherein each R moiety is independently or two phases The adjacent Rg moieties together form -(CH2)i-2〇- which is unsubstituted or substituted with one or two fluoro groups; or (ill) is unsubstituted or substituted by one, two or three R1 moieties Or a bicyclic heteroaryl group, wherein each R1 moiety is independently an alkyl group, a 〇Ci4 alkyl group, a homodentate alkyl group, a perhaloalkoxy group, a _no2, a _CN or a halogen group; Is -H or thiol; and R3 is -H or methyl; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds. In another general aspect, The invention relates to a compound of formula (J_c):

Wherein: R1 is -H, -Cm alkyl, ·0 (:1·4 alkyl, _s(〇)() 2Ci 4 alkyl, _CN, -CF3, -N(Ra)Rb or monocyclic ring Alkyl, wherein R and Rb are each independently, optionally substituted by -OH, _Ci 4 alkyl, N(Rm)Rn, wherein Rm and Rn are -H, Cm ndyl; or 尺 3 and 16 200948790 # together with the nitrogen to be bonded to form a 4- to 7-membered heterocycloalkyl group;

Ar1 is a phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl group at the point of attachment or a 9 or 10 membered bicyclic heteroaryl group at the point of attachment, each unsubstituted or via the following group Substituted; (1) one, two or three Rc moieties, wherein each Re moiety is independently -Cm alkyl, _匸14 alkyl_〇11, _Ci 4 alkyl-CN, -CF3, -OH, -OCw Alkyl, _〇cf3, -〇CHF2, -OCH2CF3, alkyl, _SCF3, -S02CF3, _CHO, -COCm alkyl, -CC^Cm alkyl, -C02H, -N(Rd)Re, -S02NRdRe, - NRdS02Re, -C(〇)NRdRe, -N02, _CN, phenyl, n-bite or halo, wherein Rd and Re are each independently -H or -Cu alkyl, or Rd and Re and the attached nitrogen Forming 4 to 7 membered heterocycloalkyl groups together; or (ii) two or three 1^ moieties, of which two feet. The moieties are adjacent to each other and together form -0(CH2)"-3〇- which is unsubstituted or substituted with one or two fluoro groups, and the third rc moiety (when present) is _Ci 4 Alkyl, -Cm alkyl-OH, -Cm alkyl-CN, -CF3, -OH, -OCm alkyl, -OCF3, -OCHF2, -〇CH2CF3, AObCw alkyl, -SCF3, -S02CF3, -CHO , -COC].4 alkyl, -CC^Cw alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN or a dentate group, wherein R And R are each independently -H or -Cm alkyl; X is N or C(Rf), wherein Rf is -Η or fluorenyl;

Rx, Ry, and rz are each independently &) to 〇): a) Rx and R2 are each H, and Ry is _n〇2, _C2 3 alkyl, 〇 (: 2 4 alkyl, 17 200948790 or phenoxy; b) R and R are each _h, Ry is -OCF3, and Ar1 is substituted phenyl or unsubstituted or substituted pyridyl; or c) Rx, Ry and Rz One is -CBu-F or -CF3, and the other two are: (1) independently ugly or 胪, with the constraint that when Ry is seven, then RX&RZ is not _CF3; 11 § part is _C〗 4 alkyl, -Q-4 alkyl-OH, -Cm alkyl-CN, perhaloalkyl, perhaloalkoxy, _〇Ci * alkyl, _ 〇q * alkyl-(monocyclic cycloalkyl), 4(0)0-2^4 alkyl, _SCF3, S02CF3, -CHO, -COCM alkyl, -cc^Cw alkyl, -C〇2H , ❿ -N(Rh)Ri, _S〇2NRjRk, _NRhs〇2Ri, _c(〇)NRjRk _n〇2 -CN or _ group; or phenoxy group, benzyl group which is unsubstituted or substituted by the following groups, Phenylethyl or benzhydryl: _Ci4 alkyl, _0Ci 4 alkyl, -perhaloalkyl, perhaloalkoxy, _N〇2, _CN or halo; wherein Rh is -H or -Cm Base; - R is -Ci_4 base or single a cycloalkyl group; or R and R together with the atom to which they are attached form a monocyclic heterocycloalkyl ring; RJ is -H or -Cm alkyl; and 〇R is -H, -Cm alkyl or a single a cyclic cycloalkyl group; or Rj and Rk together with the atom to which they are attached form a monocyclic heterocyclic courtyard soil; or (1 〇 two adjacent sub-portions of which are unsubstituted or substituted by one or 〇(CH2)i 2〇— or (m) unsubstituted or substituted by one, two or three “partially substituted naphthyl or bicyclic heteroaryl groups; wherein each R1 moiety Is the sole iL ground, Oh Hyun, full dentate 18 200948790 alkyl, perhaloalkoxy, -N〇2, -CN or halo; R2 is -H or fluorenyl; R3 is -H or a thiol group; and a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, and a pharmaceutically active metabolite of the compound. In a particularly preferred embodiment, the invention is related to the following detailed description. Or a pharmaceutically acceptable salt thereof. In another general aspect, the invention relates to a pharmaceutical composition comprising the following components: (a) at least one effective amount selected from the group consisting of formula (1) Medicament, a pharmaceutically acceptable salt of the formula (1), a pharmaceutically acceptable anthraquinone of the compound of the formula (1) and a pharmaceutically active metabolite of the formula (1):

among them:

R1 is -H, -Cm alkyl, _0Cl 4 alkyl, s(〇)q_2C"alkyl, ·cn, •CF3, -N(Ra)Rb*monocyclic cycloalkyl, wherein Ra&Rb Independently _H, as appropriate by _〇H (Μ alkyl b, N(Rm)Rn ' where RiRn is VII, q 虞; or together with the nitrogen attached to form 4 to 7 members Cycloalkyl ring;

Ar is a phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl group at the point of attachment or a 9- or 1-membered bicyclic heteroaryl group at the point of attachment, each unsubstituted or via Substituted by the group; ® one, two or three Re parts, wherein each Rc part is independently _c] 4 炫, "Μ烧基_〇H, alkyl-CN, -CF3, _〇H, _ 〇(^_4 alkyl, _〇Cf3, _〇CHF2, 19 200948790 〇CH2CF3, -SCO^Cw alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -CC^Cualkyl, -C02H , -N(Rd)Re, -S02NRdRe, _NRdS02Re, -C(0)NRdRe, -N〇2, -CN, a base, an n-bite group or a halogen group, wherein R and R are each independently _H or a -Ci_4 alkyl group, or Rd and Re together with the nitrogen to be bonded form a 4 to 7 membered heterocycloalkyl group; or (ii) two or three in part 'where two of the core portions are adjacent to each other and form together -CHCHb^o-' substituted or substituted with one or two fluoro groups and the third Re moiety (when present) is _Ci 4 alkyl, -Cm alkyl-OH, -Cw alkyl-CN , -CF3, -OH, -OCm alkyl, _ocf3, -ochf2, -〇CH2CF3, alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -C0 2Q-4 alkyl, -C02H, -N(Rd)Re, -S〇2NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN or i group, wherein Rd and Re are each independently _H Or -Cm alkyl; X is N or C(Rf), wherein Rf is -Η or fluorenyl;

The Ar2 system is: (1) a phenyl group substituted by the following groups: (a) one, two or three Rg moieties each located in the meta or para position, and optionally one or two additional in the ortho position Rg moiety; wherein each R% fraction is independently -Cw alkyl, -Cm alkyl-OH, -Cm alkyl-CN, all-alkyl, perhaloalkoxy, -OCm alkyl, - 〇C]_4 alkyl-(monocyclic cycloalkyl), alkyl, -SCF3, -S02CF3, -CHO, -COQ-4 alkyl, -C02Q.4 alkyl, -C02H, -N(Rh) Ri, -S02NRjRk, -NRhS02Ri, -C(0)NRjRk, -N02, 20 200948790 -CN or a halo group, or a phenoxy group, a benzyl group, a phenethyl group or a benzyl group which is unsubstituted or substituted by the following groups Mercapto group: _Cm alkyl, _〇Ci 4 alkyl, perhaloalkyl, perhaloalkoxy, _N〇2, _CN or halo; wherein Rh is -H or -C.4 alkyl R is a benzyl or monocyclic ring-shaped group; or R and R1 together with the atom to which they are attached form a monocyclic heterocycloalkyl ring; Rj is -H or -C丨_4;

Rk is _H, -Cm alkyl or monocyclic cycloalkyl; ❹ or 尺 1 and # together with the atom to which they are attached form a monocyclic heterocycloalkyl ring; or (b) two adjacent Rg The moiety together form an unsubstituted or substituted one or two fluoro groups - (CHH; (11) a monocyclic heteroaryl substituted by the following groups: one, two or three Rg - 4 knives' Wherein each of the ... is independently or two adjacent R8 moieties are formed together to be unsubstituted or substituted by one or two fluoro groups; or G (111) unsubstituted or via -, two or three R1 Partially substituted naphthyl or bicyclic heteroaryl, wherein each R1 moiety is independently _c] 4 alkyl, -〇Ci4 danyl, fully dentylalkyl, perhaloalkoxy, _N〇2 , _CN or a halogen group; R2 is -H or methyl; and R3 is -H or methyl; and (b) a pharmaceutically acceptable agent. In another general aspect, the invention relates to a A method of treating an individual having or diagnosed with a disease, disorder, or medical condition mediated by FAAH activity comprising: administering to an individual in need of such treatment an effective amount of at least one of 21 200948790 selected from the group consisting of a compound, a pharmaceutically acceptable salt thereof, a pharmaceutically active prodrug, and a pharmaceutically active metabolite. In a preferred embodiment of the method of the present invention, the disease, condition or medical condition is selected from the group consisting of: anxiety, depression, pain, Sleep disorders, eating disorders, inflammation, multiple sclerosis and other movement disorders, ΗIV consumption syndrome, mild head trauma, stroke, learning and memory disorders, Alzheimer's disease, _Epilepsy, Tori (Tmirette's Syndrome), Niemann-pick disease, parkinson's disease, Huntington's chorea, optic neuritis, autoimmune uveitis, drugs Or alcohol withdrawal syndrome, nausea, vomiting, sexual dysfunction, sputum post-traumatic stress syndrome, cerebral vasospasm, glaucoma, large inflammatory bowel disease, immunosuppression, itching, gastroesophageal reflux disease, pruritus, intestinal secretion, secretion Diarrhea, gastric ulcer, rheumatoid arthritis, unwanted pregnancy, hypertension, cancer, hepatitis, allergic airway disease, autoimmune Urinary diseases, intractable itching, neuroinflammation, diabetes, metabolic syndrome, and osteoporosis. The specific embodiments, features, and advantages of the present invention will become apparent from the following detailed description of the invention. The following is a more complete understanding of the present invention, including the following vocabulary and examples of conclusions. For the sake of brevity, the disclosures of the publications (including patents) listed in this specification are The terms "including", "including" and "including" are used in the context of the invention. The term "alkyl" means a straight chain having from 丨 to 12 carbon atoms in the chain or a 22 200948790 branched alkyl group. Examples of alkyl groups are represented by the symbol / symbol, ethyl (10), n = methyl (Me, also structurally pentyl, benzyl, isopropyl, butyl, isobutyl first butyl Dibutyl (fluorene) hexyl, isohexyl, etc. >, amyl, diane

〇. □.0 €0 00.003⁄43⁄43⁄43⁄4

〇>

And

"~, dfiu · constitutive, potting means monocyclic or fused, bridged or spiro polycyclic ring knots selected from saturation, and each ring structure has 3 to 12 = slave atoms and -, two or three Independently selected from the group consisting of nitrogen, oxygen and sulfur t atoms. The ring structure may optionally contain up to two pendant oxy groups on the 'two's. The examples of the heterowei group (iv) include the following chemical entities in the form of appropriate knives. : , ,,0郢

23 200948790. "The term "heteroaryl," means a fused bicyclic or fused polycyclic aromatic heterocyclic ring having from 3 to 12 ring atoms per heterocyclic ring (having a carbon atom selected from the group consisting of four atoms selected from the group consisting of carbon atoms and The ring structure of the ring atom of the hetero atom of oxygen and sulfur. The description of the wire includes the following chemical entities in the form of a bond: Ο. 〇>, 〇>00, CO, CO.

,and

Surgery. • The prime system indicates chaos, fluorine, bromine and exchange. The term "halo" means a chloro group, a fluoro group, a bromo group and an iodine group.

The term "substituted, meaning that a particular group or moiety bears one or more substituents. The term "unsubstituted" means that a particular group does not carry a substituent. The term is optionally substituted" means that the particular group is not Substituted or substituted with one or more substituents. Where the term "substituted" is used to describe a structural system, and instead is meant to refer to any position on the system where the valence is permitted. When a particular moiety or group is not meant to be substituted or substituted by any particular substituent as appropriate, it is to be understood that the moiety or group is unsubstituted. The terms "," "," and "neighbor" are understood by the technical community. Thus, for example, a fully substituted phenyl group has a substituent at the two adjacent (〇) positions adjacent to the phenyl ring, two "inter" (W) positions, and a pair b) from the point of attachment. The text explains. 24 200948790 ortho meta para ‘

Meta In a general embodiment, the invention relates to compounds encompassed by formula (IA), (IB) and (ΐ-c) and pharmaceutically acceptable salts of such compounds, pharmaceutically acceptable prodrugs And pharmaceutically active metabolites. In another general embodiment, the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I) and a pharmaceutically acceptable salt of such a compound, pharmaceutically acceptable prior to FAAH·modulator for pharmaceutical and pharmaceutically active metabolites. Compounds of the formula (1), (4), (17) and (1_〇) which are asymmetric or incompatible with the formula may exist in different mirror image isoforms. All stereoisomers of the compound of the formula and The racemates or mixtures of the various combinations are represented by the formula. Thus, the formulas of the present invention represent all racemic isomeric pure forms, non-mirrored, except that the stereocenters are shown to have a stereoisomeric form. a formula, a stagnation isomeric form, and a quinone. In addition, a specific structure may exist as a geometric isomer (ie, a broad anion), a tautomer or a stagnation isomer, and the like == structure In addition, the formula shown in the present invention encompasses the hydrates and solvates of the deuterated materials. The structural formulas shown in the present invention also represent the compounds =;: the form of the isotope-labeled combination. Two sub-forms; the actual isotope of the compound = carbon exchange t and:, such as seven, also 々々, 14, 以, 32 Ρ, 33 Ρ, 35 ς 18 36 丄, υ, ◦, ^, and ί. Isotopically labeled compound 25 200948790, for metabolic studies (preferably HC), reaction Research (using, for example, sputum or H), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (spECT)], inclusion of substance or substance tissue distribution detection, or Radiation active therapy in patients. In particular, 18f- or nc-labeled compounds may be beneficial for PET^SPECT studies. In addition, heavier isotopes such as sputum (ie, 2h) may produce specific therapeutic effects, resulting in greater metabolic stability' For example, a higher in vivo half-life or a lower dosage requirement. The isotopically-labeled compounds and prodrugs thereof of the present invention can generally be carried out by substituting an isotope-labeled reagent for an unisotopically labeled reagent. The embodiments are prepared and prepared by the methods disclosed. When referring to any of the formulas shown in the present invention, the selection of a particular portion from a list of possible categories for a particular variable does not define a portion of the variable that occurs elsewhere. In other words, When the variable occurs more than once, the selection of the species from the particular table column is independent of the type selection of the same variable elsewhere in the formula. ' Equation (1), (Ι-A) Or in a preferred embodiment of (I_C), R1 is -H, methyl, propyl, trifluoromethyl, methylthioalkyl, fluorenyl subunit, hydrazine cans Or a methylamino group, a dimethylamino group, or a cyclopropyl group. In another specific embodiment of the formula (I), (IA) or (Ι-C), R1 is an amine group. In another specific embodiment of I), (Ι·Α) or (Ι-C), r1 is -Η. In a preferred embodiment of formula (IB), "is methyl, isopropyl" a group, a trifluoromethyl group, a methylthioalkyl group, a fluorenyl sulfhydryl group, a methyl group, an amine group, a methylamino group, a dimethylamino group, or a cyclopropyl group. In other specific embodiments, Ri is an amine group. In a preferred embodiment of the formula (I), (I-A), (I-B) or (Ι-C),

Ar1 is a phenyl group, each of which is unsubstituted or via -, two or three. Part of the 26 200948790 replaced. Each of the formulae (I), (IA), (IB trace C) "分域立基基,氯基基基基基基基和三气methoxy, or two =; r concrete "sample = fluoromethyl group, 4 chlorophenyl, 4 - heterophenyl, 4 = =, fluorenyl _3 methoxy phenyl, 3, 4 - dichloro stupyl, Μ ❹

Front group, 3-chlorophenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group 3,5__milylphenyl group, 3-tris-methoxyphenyl group, 3-leginylphenyl group, 4_ Gas _3· fluorophenyl, 3-chloro-4-fluorophenyl, 3-tris-methylphenyl, 2 〇 唆 、, 吼 base, 4-mercapto, 1,3·benzo Dioxolane or 2,2-difluoro-1,3-benzodioxolyl. In another specific embodiment of the formula (1), (I-A), (PR) or (?_c), the Ar1 is an unsubstituted phenyl group, a fluorinated phenyl group or a 4-trifluoromethoxyphenyl group. In a preferred embodiment of the formula (1), (I-A), (I-B) or (Ι-C), the oxime is C(Rf). In another preferred embodiment of the formula (I), (Ι-Α), (Ι-Β) or (ΐ-c), the Rf is -H. In a preferred embodiment of formula (I), (Ι-A) or (I-B), Ar2 is a phenyl group substituted by one, two or three rs moieties at one or both positions in the meta and para positions. In some embodiments of formula (I), (Ι-A) or (IB), the Ar2 is a thienyl, pyridyl, pyrimidinyl or pyrazolyl group, each of which is one, two or three Rg moieties Replace. In some embodiments of the formula (1), (Ι-A) or (IB), each moiety is independently methyl, ethyl, isopropyl, tert-butyl, benzyl, 1 -ylethyl, cyanoguanidino, cyano-diindenyl-methyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy Base, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, cyclopropene 27 200948790 thioloxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, fluorenyl Yellow wine, methyl sulfhydryl, ethyl hydrazino, dimethylamino, morpholin-4-yl, amine aryl, dinonylaminosulfonyl, cyclopropylaminosulfonyl, piperazine Pyridinyl, pyrrolidine-1-sulfonyl, nitro, cyano, carbyl, fluoro, iodo, phenoxy, benzyl, benzhydryl, or phenethyl, or two phases The adjacent ^ portions together form -CKCHWuO- or -0(CF2)0-. In another preferred embodiment of the formula (1), (IA) or (IB), the Ar2 is 3,4-didecylphenyl, 4-t-butylphenyl, 4-cyanophenyl, 4 _Ethylphenyl, 4-methylphenyl, 4-phenylphenyl, 4-fluorophenyl, 4-trifluorodecylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 3_decylphenyl, 3-trifluoromethoxyphenyl, fluorene 4-ethylphenyl, 4-isopropylphenyl, 3,4-diphenyl, chlorophenyl, 3-chloro- 4-trifluoromethylphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, oxime. Phenoxy-phenyl, 3-oxoethoxyphenyl, 3-chloro-4- Isopropoxyphenyl, 3-fluoro-4-indolylphenyl, 4-hydroxydecylphenyl, 4-mercaptophenyl, 3-nonylphenyl, 4-trifluoroethoxybenzene , 3-trifluoroethoxyphenyl, 4-ox'-3-indenylphenyl, 4-chloro-3-hydroxyphenyl, 4-nitro-3-trifluoromethylphenyl, 3-fluoro 4-Trifluorodecyloxyphenyl, 4-ethoxy-3-trifluorophenyl, ethoxylated _3_nonylphenyl, 4-cyclopropylmethoxyphenyl, 4-butoxy 3-fluorophenyl, 4-hydroxybutoxyphenyl, 3-fluoro-4-methylpropenyl, 3-fluoro-4-isopropoxyphenyl, 4-isobutoxyphenyl, 4· Oxy-3-indolylphenyl, 3-ox-4-mercaptophenyl, 3,5-diindolyl, 3-fluoro-4-trifluorodecylphenyl, 3-fluoro-5- Trifluorodecylphenyl, 3-chloro-5-fluorophenyl, 4-propoxyphenyl, 4-isopropoxy-3-methylphenyl, 4-difluoroindolyl-3,5 -difluorophenyl, 4-(cyano-diindenyl-methyl)phenyl, 4-ethenyl-3-fluorophenyl, 3,5-didecylisopropoxyphenyl, 3, 4,5-difluorophenyl, 4-benzylidenephenyl, 3,5-difluorophenyl, 3, fluorodiphenyl, 4-dimethylaminophenyl, 4-mercaptosulfonate醯基笨基,4•环28 200948790 propylaminosulfonylphenyl, 3-fluoro-4-methoxyphenyl, 1,4-benzodioxan-6-yl, 4-diindole Alkyl quinone, decyl phenyl, 4-branched -1- fluorinyl phenyl, 4-pyrrolidin-1-sulfonyl phenyl, 3-chloro-4-fluorophenyl, 4- Methylsulfanylphenyl, 4-carbyl-3-phenylphenyl, 3-oxyl-4-phenylphenyl, 4-isopropylsulfanylphenyl, 4-cyanononylphenyl, 4-ethylsulfanylphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 3-butoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethyl Phenyl, 4-(2-o-tolyl-ethyl) , 3-fluoro-4-(1-trans-ethyl)phenyl, 4-anthracenephenyl, 4-ethoxy-3-dimethylnonylphenyl, 3,4-dimethoxybenzene , 3-methoxyphenyl, 2,4-bis(trifluoromethyl)phenyl, 2-methoxy-4-(trifluoromethoxy)phenyl, 4-ethoxy-2- Methylphenyl, 2,2-diox-1,3-benzoquinone sigma-5-yl, 1,3-benzoquinone sigma-5-yl, 5-ethylidene-π Benz-2-yl, 6-fluorenyl hydrazinyl 11 -3-yl, 6-ethoxy butyl-3-yl, 6-morpholin-4-ylpyridin-3-yl, 6-fluoro-5 -methyl-pyridin-3-yl, 6-cyanopyridin-3-yl, 6-(dimethylamino)pyridin-3-yl, 2-morpholin-4-ylpyrimidin-5-yl or 1 -benzyl-1Η-pyrazol-4-yl. In other preferred embodiments of the formula (1), (Ι-A) or (Ι-Β), the Ar2 is a naphthyl group, a benzooxadiazolyl group, a fluorenyl group, a benzothienyl group, a quinolyl group or Carbazolyl, each unsubstituted or substituted with one, two or three R1 moieties. In some embodiments of formula (I), (Ι-A) or (I-B), each R1 moiety is independently fluorenyl. In another preferred embodiment of formula (I), (IA) or (IB), the Ar2 is naphthyl, 2,1,3-benzoxoxadiazol-5-yl, 1H-indole-5 -yl, 1H-indol-6-yl, 1-indolyl-1H-indol-2-yl, 1-indolyl-1H-σ-bend-5-yl, 5-mercapto-1-benzene And π-cephen-2-yl, benzoquinone cis-phen-3-yl, benzothiophen-5-yl, quinolin-3-yl or 3-mercapto-1 oxime-oxazole-6-yl. In a preferred embodiment of the formula (Ι-C), Rx is -C1 or -F, Rz is -Η, and 1^ is -H4Rg. In a more specific embodiment of the formula (Ι-C) 29 200948790, RX is , Cl or -F, RZ is -Η, and Ry is -Cw alkyl, -CF3, -OCw, _ 〇CF3 or halogen. In other specific embodiments of the formula (Ι-C), the 'Ar2 is 4-nitrophenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-ethoxyphenyl, 4-propoxy Phenylphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-isobutoxyphenyl or 4-phenoxyphenyl. In another specific embodiment of the formula (I-C), the Ar2 is a 4-trifluoromethoxyphenyl group. In other specific embodiments of the formula (I_C), the Ar2 is 4-chlorophenyl, 4-fluorophenyl, 4-trifluorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3 - gas-4-trifluoromethylphenyl, 3-chloro-4-ethoxyphenyl, 3-chloro-4-isopropoxyphenyl, 3-fluoro-4-indolyl, 4· Chloro-3-methylphenyl, 4-chloro-3-trifluorodecylphenyl, 3-fluoro-4-yltrifluorophenyl, 4-butoxy-3-fluorophenyl, 3- Fluoro-4-propoxyphenyl, 3-fluoro-4-isopropoxyphenyl, 3-chloro-4-indolylphenyl, 3-fluoro-4-yl-trifluoromethyl-based 3-fluoro-5-dimur曱 base, 3_chloro-5-fluorophenyl, 4-ethyl fluorophenyl, 3,4,5-trifluorophenyl, 3,5-difluorophenyl, 3,4-difluorobenzene , 3-fluoro-4-decyloxyphenyl, 3-chloro-4-ylfluorophenyl, 4-cyano-3-phenylphenyl, %^yl-4-fluorophenyl, 3-trifluoroanthracene Phenylphenyl, 3-fluoro-4-yl-hydroxy-ethyl)phenyl or 4-ethoxy-3-trifluoromethylphenyl. In a preferred embodiment of formula (1), (I~A), (I-B) or (Ι-C), R2 is -H. In a preferred embodiment of the formula (1), (I-A), (I-B) or (Ι-C), the R3 is -H. In a specific embodiment of the formula (1)^(Ι-Α), (工七) or (Κ), RgA/ or R1 is a *halo-based or perhalo-alkoxy group. The term "alkyl" means a 'soil=bond or a branched aryl group in a chain in which hydrogen is optionally replaced by a halogen. One of the two is a package: a fluorenyl group (CF3), a difluoroantimony group (Cf2H), a monofluoroanthracene. Base π% diterpene 30 pentafluoroethyl 200948790 (a ct2cf3), tetrafluoroethyl (CHFCF3), trifluoroethyl (CH2C(5) tetra-l-fluorodecylethyl (-CF(CF3)2), and general techniques And the teachings provided by the present invention are not equivalent to the groups of any of the foregoing examples. The term "perhalooxyalkyloxy" means having up to 4 carbon atoms f in a chain in which hydrogen is replaced by halogen as appropriate. The chain or branched chain is alkoxy. Examples of all-alkyl alkoxy groups include tri-methoxy (〇α?3), difluorodecyloxy (〇cf2h), monofluorodecyloxy (0CH2F), five. Fluoroethoxy (〇cf2cf3), tetrafluoroethoxy (OCHFCF3), difluoroethoxy (OCJ^CF3), tetrafluorotrifluoromethyloxycarbonyl (-OCF(CF3)2), and general The teachings provided by the skilled artisan and the present invention are considered to be equivalent to the groups of any of the foregoing examples. In a preferred embodiment of the formula (I), (IB) or (Ι-C), the second stage adjacent to Ari Hydroxy system shows the following configuration: , ^γΑΓ1 OH 〇 (I), (Ι-Α), ( A more preferred embodiment of -B) or (Ι-C) encompasses a combination of two or more preferred embodiments of the foregoing R1-3, X, Ari, Ar2, RaM and Rx-z. The present invention also relates to a free acid or a pharmaceutically acceptable salt represented by the formula (1), (IA), (Ι-B) or (Ι-C), preferably in the preferred embodiment described above and herein. The exemplified specific compound. "Pharmaceutically acceptable salt" means a free acid or a non-toxic, bioavailable compound of the compound represented by formula (1), (IA), (Ι-B) or (Ι-C). Salts that are or are biologically suitable for administration to an individual. See generally SM Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19 and Pharmacy/Pharmaceutical Ms, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. 31 200948790 Preferred pharmaceutically acceptable salts are pharmaceutically effective and suitable for contact with tissues or patients without undue For toxic, irritating or allergic reactions. Compounds of formula (I), (I_A), (IB) or (Ι-C) may have sufficient acidic groups and sufficient basic groups. Or both types of functional groups' thus react with a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, Sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, meta-acid salt, pyrophosphate, chloride, evolution, moth, acetate, propionate, citric acid Salt, octoate, acrylate, formate, isoacid salt, hexanoate, heptanoate, propiolate, oxalate, malonate, bismuth succinate, suberate, bismuth Acid salt, fumarate, maleate, butyne-1,4-diate, hexyne-methane, 6-diate, benzoate, gas benzoate, Mercaptobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, benzodicarboxylate, sulfonate, dinonylbenzenesulfonate, stupid acetate , streptopropionate, phenylbutyrate, citrate, lactate, -7-hydroxybutyrate, glycolate, tartrate, methane sulfonate, propane sulfonate, Naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate. If the compound of formula (I), (IA), (IB) or (Ι-C) contains a basic nitrogen, the desired pharmaceutically acceptable salt can be prepared by any suitable method known in the art, for example, The free base is treated with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, Lactic acid, ascorbic acid, maleic acid, hydroxy maleic acid, methotrexate, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, water yang Acid, oleic acid, palmitic acid, lauric acid, "pyranonic acid such as glucose or galactonic acid, alpha-hydroxy acid such as mandelic acid, lemon 32 200948790 citric acid or tartaric acid; amino acid, such as day Aspartic acid or glutamic acid; aromatic acid, 1 such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid; sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methane Sulfonic acid or ethanesulfonic acid, or any compatible mixture of acids such as the examples listed herein. If the formula (I), (IA), (IB) or (IQ compound is an acid such as a sulfonic acid or a sulfonic acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by inorganic or The organic acid is treated organically, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, or any compatible mixture of bases such as those listed herein. Examples include amino acids (such as glycine and arginine), ammonia, carbonates, bicarbonates, primary, secondary and tertiary amines and cyclic amines such as benzylamine, n-precipitate, brigade The organic salts derived from the bite, the lin and the n n wells, and the inorganic salts derived from steel, •, potassium, town, fierce, iron, copper, rhyme, and bell. The invention is also related to formula (I), A pharmaceutically acceptable prodrug of a compound of Ι-Α), (Ι-Β) or (ΐ-c). The term "prodrug" means that the precursor of the indicated compound is administered chemically or in vivo after administration to an individual. Physiological processes (such as solvent Q decomposition or enzymatic cleavage or under physiological conditions (eg, before conversion to physiological sputum, the drug is converted into formula (I) (IA), (IB) or (Ι-C) compound)) produces a compound., a pharmaceutically acceptable prodrug" is a drug that is non-toxic, biotolerable, and biologically suitable for administration to an individual. Selection and preparation Exemplary methods for prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Examples of prodrugs include having covalent attachment to formula (I) via a guanamine or ester linkage, a free amine group of (IA), (IB) or (Ι-C) compound, an amino acid residue of a hydroxy acyl group or having two or more (eg, two, three or four) amino acid residues a compound of a polypeptide chain. Examples of amino acid residues include 33 200948790 for two days, an amino acid ("usually represented by a three-letter symbol"), and a 4-hydroxy amidoxime, a hydroxyl-amino acid, Mosin (dem〇sine), isograsin, Hongjia f group, aminic acid, Ortho-acid, alanine, aglycine, citrulline, homocysteine, homoserine, bird Amino acid and methionine acid. Other types are discussed, for example, by derivatizing the free radicals of formula (I), (I_A), (IB) or (,), and σ. Prepared by indoleamine or vinegar. The indoleamine = is derived from ammonia, -Cl6 silk amine and secondary bis(alkyl) amine derivative. The secondary amine system includes 5 or 6 members. Or a heteroaryl ring moiety. Examples of the decylamine include derivatives derived from ammonia, Cl 3 silk-grade amines, and di & amines. Examples of the invention include Ci-based, Cw cycloalkyl, Phenyl and phenyl (Cw alkyl) esters. Preferred esters include methyl esters. Prodrugs can also be used in accordance with methods such as those described in Adv. £^gDe/iVe〇^ev. 1996, J9, 115. The succinate, phosphate, dimethylaminoacetate, and phosphonium methoxyoxycarbonyl groups are prepared by derivatizing a free hydroxyl group. Hydroxyl and amine carbamate derivatives also produce prodrugs. Hydroxyl carbonate derivatives, sulfonates and sulfates can also provide prodrugs. Derivatizing a hydroxy group to a (decyloxy)methyl group and a (decyloxy)ethyl ether, wherein the fluorenyl group can be an alkyl ester, optionally substituted with one or more ether, amine or carboxylic acid functional groups, or The base is an amino acid ester as described above and can also be used to produce a prodrug. Such prodrugs can be prepared as described in /City, C/zem. 1996, 39, 10. The free amine can also be derivatized as a guanamine, sulfonamide or phosphoniumamine. All such prodrug moieties can incorporate groups including ether, amine, and carboxylic acid functional groups. The invention also relates to a pharmaceutically active metabolite of a compound of formula (I), (I-A), (I-B) or (Ι-C). By "pharmaceutically active metabolite" is meant an active metabolite of a compound of formula (1), (I-A), (I-B) or (Ι-C) or a salt thereof in vivo. Compound prodrugs and active metabolites can be determined using the exemplary techniques known or available in the art world 200948790. See, for example, Bertolini et al., "/· Med C~w. 1997, Yang, 2011-2016; Shan et al., / Pk. 5W. 1997, (7 in 765-767; Bagshawe, Drwg Dev. Res. 1995, 34, 220-230 ; Βοάοχ, Adv. Drug Res. 1984, 73, 224-331 ; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen Et al., Harwood Academic Publishers, 1991). 化合物 Formula (I), (IA), (IB) and (IC) compounds of the invention and pharmaceutically acceptable salts thereof, pharmaceutically acceptable prodrugs and pharmaceutically active metabolism (Generally known as "active agent") can be used as a FAAH inhibitor in the methods of the invention. The active agent can be used in the methods of the invention to treat a medical condition, disease or condition mediated by inhibition or modulation of FAAH, such as the invention The active agent of the present invention can thus be used as an analgesic, antidepressant, cognitive enhancer, neuroprotective, sedative, appetite stimulant or contraceptive. Illustrated medical conditions, diseases and conditions mediated by FAAH activity Package 0 includes anxiety, worry , pain, sleep disorders, eating disorders, inflammation, multiple sclerosis and other movement disorders, HIV-consumption syndrome, mild head trauma, stroke, learning and memory disorders, Alzhdmeris disease, epilepsy, T〇uretteis Syndr〇me, epilepsy, Niemann-Pick disease, Parkinson's disease, Huntington's disease, Huntingt〇n, s chorea ), optic neuritis, autoimmune uveitis, drug or alcohol withdrawal syndrome, group, f pack, sexual dysfunction, post-traumatic stress syndrome, blood stasis, diabetes, metabolic syndrome, osteoarthritis and osteoporosis

disease. A 35 200948790 Thus, an active agent can be used to treat an individual diagnosed with or suffering from the disease, condition or condition. The term "treatment" or "treatment" as used in the present invention means the administration of an agent or composition of the present invention to an individual for therapeutic effect via modulation of FAAH activity. Treatment includes reversing, soothing, alleviating, inhibiting progression, reducing severity, reducing the incidence, or preventing a disease, disorder, or condition mediated by FAAIi activity, one or more symptoms of the disease, disorder, or condition. u The term "individual" means a mammal in need of such treatment, such as a human. "Modulator" includes both inhibitors and activators, wherein "inhibitor means reducing, preventing, reducing, desensitizing or downregulating FAAH a compound that exhibits or is active, and an "activator," which is a compound that increases, activates, promotes, sensitizes, or upregulates FAAH expression or activity. Therefore, the present invention relates to the use of the active agent of the present invention for the treatment of a diagnosis or disease. Methods of individuals having a disease, disorder or condition mediated by FAAH activity, such as: anxiety, pain, sleep disorders, eating disorders, inflammation, dyskinesia (eg multiple sclerosis), glucose and lipid metabolism (eg sugar urinary disease) And bone constant (eg osteoporosis). Syndrome or disease state is intended to be included within the scope of "medical condition, disorder or disease." For example, pain may be related to various diseases, conditions, or conditions, and may include various causes. Types of pain that can be treated using the FAAH modulators of the invention (FAAH inhibitors in one example of the invention) include cancer Pain, postoperative pain, GI tract pain, spinal injury pain, visceral hyperalgesia, thalamic pain, headache (including stress headaches and migraine), lower back pain, neck pain, musculoskeletal pain, peripheral neuropathic pain, central Neuropathic pain, pain associated with neurodegenerative disorders, and menstrual pain. HIV-consumption syndrome includes related syndromes such as loss of appetite and nausea. Parkinson's disease includes, for example, levodopa-induced exercise 36 200948790 Difficulties. Treatment of multiple sclerosis can This includes treatment of symptoms such as paralysis, pain in the gods, central pain, or bladder dysfunction. Drug withdrawal syndrome may be caused by, for example, a disease or nicotine addiction. • Or because of chemotherapy, surgery, or opioid-related causes. Sexual dysfunction = Treatment may include improved sexual desire for delayed ejaculation. Treatment of cancer includes treatment = glioma. Sleep disorders include, for example, sleep apnea, insomnia, and the use of sedative or anesthetic treatments. Obstacles include Ο ❹ =: diseases such as cancer or HIV infection / AIDS An anorexia or a loss of food. In the method of treatment of the invention, an effective amount of at least a disease, a disease or a disease mediated by the personality of the present invention, ",", =,,, =, disease or condition The amount of therapeutic dose required for the patient in the condition. This day's painting (4) is the effective amount? (such as model building, dose escalation studies = pharmacokinetics, disease, condition, or severity of the condition = should be prior or existing treatment, the health status of the individual, and the assessment of the drug 0 0001 to => determine. Exemplary dosages are from about to about 2 grams of active agent per kilogram of body weight per day, preferably from about 0 to about 1 milliliter. , or about 01.01 to 35 mg / kg / day, or about 0.1 QID). Ge 7 ^ / day early or divided dose units (such as BID, TID, to about 7 grams? / 曰 A: humans, the scope of the appropriate dose is about 〇 · 05 about the day ... to improve the patient's disease, disease Frequency or both, 3 adjuster 1 to maintain treatment. For example, the dose or the dose of the drug's record is as low as Jane's. 37 200948790 Of course, if the symptoms have been reduced to the appropriate level, then treatment can be stopped. However, the patient may need to be based on long-term intermittent treatment in the event of any recurrence of symptoms. In addition, the active agent of the present invention may be used in combination with an additional active ingredient for the treatment of the aforementioned conditions. The additional active ingredients may be combined with formula (1), (Ι_Α), (Ι·Β) and

(i-c) The active agent is co-administered or included in the pharmaceutical composition of the present invention together with the agent. In a specific embodiment, the additional active ingredient is known or found to be treatable by a FAAH-mediated condition, disorder or disease, such as another FAAH modulation (IV) or active against a specific subject, disorder or condition. Compound. This combination can be used to increase the efficacy of the active agents of the present invention (e.g., by including a composition that enhances the potency or effectiveness of the active agents of the present invention), reducing or reducing the desired dosage. In an exemplary embodiment, the composition of the present invention may contain one or more selected from the group consisting of sputum-like tablets, NS AID (eg, ibuprofen, cyclooxygenase-2 (COX-2) inhibitors). And naproxine (napr〇xen), gabapentin, pregabalin, tomabao (9) face (four), acetaminophen and aspirin additional active ingredients.

The present hair sauce (4) is used alone or in combination with - or a multi-additional component to prepare a medical rainbow compound of the present invention. The pharmaceutical composition package (a) of the present invention is effective in at least one of the active agents of the present invention; and is pharmaceutically acceptable as a pharmaceutical ingredient, meaning to be added to a pharmaceutical composition or a sodium or a carrier Or a diluent to aid in the administration of the medicament and compatible therewith, such as a material that is biotolerable and biologically suitable for administration to an individual, n = substance. Examples of excipients include the delivery of pharmaceutical compositions including carbonic acid, heterocycles, rolls and types of powders, cellulose derivatives, vegetable oils, and polyethylene glycols 38,487,790 containing active ingredients. Forms can be prepared using appropriate pharmaceutical excipients and techniques known or matured to those skilled in the art. Such compositions may be administered by the methods of the invention by a suitable delivery route, such as orally, parenterally, rectally, or by eye route, or by inhalation. ° The preparation may be a tablet, a capsule, a sachet, a sugar-coated tablet, a powder, a granule, a buccal tablet, a powder for reconstitution, a liquid preparation or a suppository. Preferably, the composition is formulated as an intravenous infusion, a topical administration or an oral administration. Ο

For oral administration, the active agents of the present invention may be provided in the form of a troche or capsule' or in the form of a solution, emulsion or suspension. To prepare a mouthpiece, the active agent can be formulated to produce a dosage of, for example, about W, or about 50 mg to 5 g per day in a single or divided dosage form. For example, it can be done twice, three times or four times per Si, to complete a total of about 5 mg to 5 g / 曰, di wj 祜 祜 有 有 有 有 医药 医药 医药 医药 医药 医药 医药 医药 医药 医药 医药 医药 医药 医药 该 该The agent is such as a diluent, a disintegrant, a binder, a two-filler, a flavoring agent, a coloring agent, and a preservative. Suitable inert glucosinolates and feeds, sodium sulphate and about, lactose, house powder, sugar, = body, magnesium, mannitol, sorbose ^ and such as / excipients include ethanol, glycerin, Water Xue is fine. Tantalum powder, polyvinylpyrrolidone (PVP), starch B microcrystalline cellulose and alginic acid are exemplified as disintegrants. The binder may comprise a layer. Immersed in the gastrointestinal tract, or can be coated with intestines 39 200948790 Oral medicinal capsules include hard and soft gelatin capsules. When preparing a hard gelatin capsule, the active ingredient can be mixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil (such as peanut oil or eucalyptus oil), liquid paraffin, a mixture of mono- and diglycerides of short-chain fatty acids, polyethylene glycol 4 hydrazine or propylene glycol. The liquid for oral administration may be in the form of a suspension, a solution, an emulsion or a sugar form or may be rendered as a dry seam or may be reconstituted with water or other suitable adjuvant. The liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (for example, sorbitol, methylcellulose, sodium, sodium, ethyl cellulose, county methyl fiber) Non-aqueous adjuvants such as oils (eg 'almond oil or coconut oil'), propylene glycol, ethanol or water; preservatives (eg 'p-pyridinic acid' A mercapto or propyl g or sorbic acid; a wetting agent such as lecithin; and, if desired, a flavoring or coloring agent. The active agents of the invention may also be administered by a non-oral route. For example, the composition can be formulated as a suppository for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the agents of the invention may be buffered in a pH sterile aqueous solution or suspension of the field or in a non-enteric acceptable oil. Seven,. Suitable aqueous adjuvants include Ringer's solution and isotonic sodium. Such forms may present a difficulty in riding a horse, such as a multi-dose form of a money or shop-type injection device, such as a vial in which a suitable dose can be taken, or a solid form or pre-concentrate of a ready-to-inject formulation. It is stated that the infusion agent ranges from about 1 to 1000 μg/kg/min in a few minutes to several days. The pharmaceutical carrier is blended. Μ - For topical administration, the agent may be from about 0.1% to about ίο. /. The drug is now available in combination with the pharmaceutical carrier. In another mode of administration, the agent of the present invention 200948790 can be applied by a 4 step for transdermal delivery. #活性性 can be administered by the method of the present invention by nasal or by a woman, for example, in the form of a proper reading.

The following description of the general preparation of the present invention can be carried out by using a synthetic flow chart and a special embodiment to describe (10) the active agent of the method of (4). The skilled artisan, in order to obtain the various compounds of the present invention, the starting materials are suitably selected so that the desired substituents are produced via the reaction scheme under appropriate or dilute conditions to produce the desired product. Alternatively, it may be necessary or desirable to substitute the appropriate substituent for the final desired substituent, which may be carried via the reaction scheme and suitably substituted with the desired substituent. Unless otherwise stated, ς variables are as defined above for equations (I), (Ι_Α), (Ι_Β), and (I_C). For the sake of simplicity, the compounds of formula (IA), (I_B) and (I_C) are specific examples of the compound of formula (1). The compounds of formula (IA), (IB) and (Ι-C) are collectively referred to in the following schemes. Described as a compound of formula (1).

Flowchart A

(II) (III) 1 nucleophilic aromatic, substituted R1

(IV) nucleophilic aromatic substitution

Referring to Scheme A, the compounds of formula (I), (Ι·Α), (IB) and (Ι-C) are prepared from pyrimidines or tri-farmings (II), wherein the lanthanide is a halogen group or another suitable Substituent. Various substituted pyrimidines and three tillages are commercially available or prepared using known methods 200948790. The pyrimidines of formula (III) are prepared by palladium-mediated cross-coupling of reagent (II) with an appropriate citric acid. Preferably, the pyrimidine of formula (II) is in the presence of a base (such as K3P〇4 or KF) in a suitable polar solvent (such as CH3CN, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF). ), water or a mixture thereof, using a conventional heating or microwave reactor at a temperature of from about 50 ° C to about 180 ° C, with the desired citric acid. Pyrimidines (III) via nucleophilic aromatic substitution (SNAr) in the presence of a suitable base (such as NaHC03 '(iPr) 2EtN, Et3N or mixtures thereof, without solvent or in a solvent (such as 1,4-dioxin) Alkane, THF, third pentanol, n-BuOH or mixtures thereof) are converted to the formula (IA), (IB) and (by an aryl-substituted amino alcohol at a temperature of from about 80 ° C to about 150 ° C Ι-C) a compound. Alternatively, the formula (IA), (IB), and (Ι-C) pyrimidine or tri-farming are replaced by an amino alcohol SNAr by a compound (II), followed by palladium mediated by a known method. By cross-coupling, the compounds of formula (I), (IA), (IB) and (Ι-C) are additionally used in a single pot, in the presence of a suitable base (such as NaHC03), in a suitable polar solvent (such as CHgCN), at a temperature of about 50. (: to a temperature of about 180 ° C, the compound (II) nucleophilic aromatic substitution (SNAr) is replaced with an amino alcohol; followed by a base (such as Κ3Ρ〇4) and Lead-cross coupling reagents such as Pd(dppf)Cl2·CH2C12 and hydrazine

In the presence of Pd(OAc)2), it is prepared by a saturating cross-coupling reaction with an appropriate acid at a temperature of from about 50 ° C to about 180 ° C.

Flowchart B

(V) (VI) (丨) Referring to Scheme B, the thioether (v) prepared as described in Scheme A is oxidized using a generally known method of 42 200948790 to provide a sulfone (VI). Those skilled in the art will recognize that compounds (V) and (VI) are specific embodiments of formulas (I), (I-A), (I-B), and (Ι-C). For the preparation of other specific embodiments of formulas (1), (IA), (IB) and (Ι-C), by solvent (such as MeOH, EtOH, n-BuOH, third pentanol, THF, N, N_) Dimethyl decylamine (DMF), dimethyl hydrazine (DMSO), toluene or mixtures thereof, in the presence or absence of a base such as NaOMe, NaOEt, KOtBu, Et3N, (iPr)2EtN, pyridine or mixtures thereof The hydrazine substituent is replaced by reaction with an appropriate amine or decyl alcohol at a temperature from room temperature to the reflux temperature of the solvent. Preferably, the appropriate amine substitution is by means of 130 in the sealed tube. (: The sulfone (VI) is heated in a third pentanol to carry out.

Flow chart C

Nucleophilic aromatic substitution

Referring to Scheme C 'Formula (I), (IA), (IB), and (Ι-C) compounds, wherein X is C(Rf), which is prepared from β-ketoester (νΠ), which is a city It is sold or prepared according to the general techniques known in the art. Β-ketoester (VII) with hydrazine or hydrazine (XII) or with urea or thiourea (XIII) (wherein lanthanide is 〇, s or NRa), for example, in the presence of a test (such as NaOEt or KOtBu) The solvent (such as Et 〇 H, t-BuOH or a mixture thereof) 'reacts at a temperature between about room temperature and the reflux temperature of the solvent' to form a hydroxy-pyrimidine (VIII). Hydroxy-pyrimidines (vm) are then activated by general methods known in the art to be used in SnAi> substitutions. For example, treatment with POClyPBr3 or ΡΟΒι*3 yields the corresponding halopyrimidine 43 200948790 (IX) wherein Z2 is chlorine or desert. Or, in the presence of i, 2-di-ethane-burning, CH2Ci2, THF or a mixture thereof, such as ", qing, _2EtN: K〇tBu or a mixture thereof" to the trifluoroethylene hospital _ continued acid needle _ • stupid The bis-(difluoroanthracene hydrazide) treatment of the thiol-type (Yin) provides a trifluorosulfonate, wherein the Z2 is -OS〇2CF3. Preferably, the hydroxy-pyrimidines (VIII) are treated with p〇Cl3 in CH3CN at a temperature of from about 80 °C to about 1 °C. The chloroforms (ι) are treated as a compound of the formula (I_A), (I-B) and (Ι-C) by a Sn_aryl substitution process as described in Scheme A.

Η

Addition ο (Xi)

Flow chart D

OH (XII)

The racemic or enriched amino group-alcohol (anthracene) is commercially available or can be prepared by generally known methods. For example, in a particular embodiment, the amine-alcohol (X)' wherein R2 and R3 are both - is prepared as shown in Scheme D. To form an amino-alcohol in the presence of a catalyst (such as Znl2), without solvent or

The aldehyde (XI) is treated with a dimercaptopurine cyanide (TMSCN) in a solvent such as diethyl ether (EtsO), THF, 1,4-dioxane or a mixture thereof to provide a cyanohydrin acetone (XII). In order to form an amino group-alcohol () () rich in mirror image isomers, the reaction is carried out in the presence of a palmitic ligand, such as ^(一)-丨,; Preferably, the formed cyanohydrin acetone is formed as a tridecyl decyl ether. The nitrile is reduced using a known general procedure in a solvent such as THF or Et20, such as LiAlH4 or a valane complex (such as boron burned with the following: THF (BH3.THF), dimethyl sulfide (BH3) .DMS), or N-ethylisopropylaniline (ΒΑΟί·ΕΙ), provides an amine-alcohol (X). When trimethylsulfonium 44 200948790 alkyl ether is formed, it is deprotected using standard acidic or basic conditions to yield the racemic or enriched amino group-alcohol (x). When a racemic and non-凊% mixture of the mirror image isomer is obtained, a single mirror image isomer can be isolated using known methods such as palm chromatography and recrystallization. Alternatively, the amino-alcohol (X) is obtained by addition of an azide anion to a suitable halo ketone followed by reduction of the azide group and the ketone. In another embodiment, the appropriate halogen: is reduced to the corresponding halo alcohol and replaced with ammonia, methylamine or dimethylamine to provide an amine-alcohol.

The amino group-alcohol (X) enriched in the mirror image is obtained by other stereoselective synthesis or by a palm separation method. For example, the reduction shown in the scheme 〇 is performed as a borane complex in the presence of a palmitic catalyst such as (R)_2_mercapto_CB s_ oxazolidine borane (CBS) to form a pair Palm product. Stereoselective reduction of α-halo ketone, azido ketone or α-amino ketone can also be used to prepare a palmitic agent.

Η

Addition Addition Ο (XI) Flowchart E R2

0H (XVII) reduction reduction

Or ' racemic amine-alcohol (X), wherein R2 may be -Η or alkyl and R3 is -Η' is obtained by nitro-aldol addition as shown in Scheme ε. Aldehyde (χι) is present in the presence of reagents (such as NaOH, Κ0Η, KOtBu, NaOtBu, TBAF, and NaH) in solvents such as thf and MeOH, at 〇. (: and nitrodecane (CANO2) at a temperature between the reflux temperature of the solvent to form a nitro-alcohol (XVII). The amino alcohol (X) is obtained by reducing a nitro group by a generally known method. , such as using a hydrogen source such as H2, cyclohexadiene or 45 200948790 NEUHCO2 'in the presence of Zn, in a solvent such as Me〇H&Et〇H, at a temperature between room temperature and solvent reflux temperature pd_ Catalytic hydrogenation. When a racemic and non-racemic mixture of the mirror image isomer is applied, a single image isomer can be isolated using known methods, such as for palm chromatography and recrystallization.

Ο (XIV) R2 person ^ household bonus 1 0 (XIII)

R2 R2 addition reduction HN^YAf1

OH R3 OH (XV) (XVI) (X) In a specific embodiment, the amine alcohol (X) wherein R 2 and R 3 are both -H' can be obtained from the α-haloke ketone (XIII) as shown in Scheme F )preparation. For the preparation of a non-pivotic amine-alcohol 'α-haloke ketone (ΧΠΙ), wherein Y = Br or Q, in a solvent such as DMF, THF, MeOH, EtOH or a mixture thereof at room temperature and solvent Treatment with sodium azide (NaN3) at a temperature between reflux temperatures provides the azide ketone (XIV). Azido-ketones are reduced by known methods, such as in solvents such as THF, MeOH and EtOH, at temperatures between 〇 ° C and room temperature, with borane complexes (BH3*THF and BH3). *DMS) or NaBH4, treated to provide azido-alcohol (χνΐ). Alternatively, the azido-alcohol (XVI) is produced by reduction of the a-halo ketone (oxime) to produce an a-halo-alcohol (XV) which is converted to an azido-alcohol (XVI) by the addition of NaN3. To form an amino group-alcohol (X) rich in mirror image isomers, α-haloke ketone (XIII) or azido-ketone (χΙν) 46 200948790 is attached to (S) or (R)-2-methyl - CBS oxazolidine borane (CBS) in the presence of a THF solution at a temperature between 0 ° C and room temperature, using a borane complex reduction. The azido-alcohol (XVI) is reduced by known methods, such as using a hydrogen source such as %, cyclohexadiene or NH4HC02 in the presence of Zn, in a solvent such as MeOH, EtOH or a mixture thereof at room temperature and Pd-catalyzed hydrogenation at a temperature between solvent reflux temperatures at a pressure of 0 to 50 psi provides the amine-alcohol (8). Further, the azido-alcohol (XVI) is NaBH4 in the presence of CuS04 «5H20 in a solvent such as EtH, MeOH or a mixture thereof at a temperature between 〇 ° C and the reflux temperature of the solvent. Reduction to the amino-alcohol (X) at temperature. Preferred 'α-functional ketone (XIII), wherein X = Br, is treated with NaN3 in EtOH at room temperature, followed by reduction with NaBH4 at 0 °C in EtOH to provide the azido-alcohol (XVI) It is then reduced with a mixture of NaBH4 and CuSCV5H2 in MeOH at a temperature between 0 °C and 80 °C to provide the amine alcohol (X). When a racemic and non-racemic mixture of the mirror image isomers is obtained, known methods (such as for palm chromatography and recrystallization) can be used to separate the single-mirror isomers. The compounds of formula (I), (I-A), (I-B) and (Ι-C) can be converted to their corresponding salts using the general techniques described in the technical art. For example, the compounds of formula (I), (I-A), and (I_C) can be used in solvents such as EtsO, (3⁄4⁄4, THF or

MeOH) is treated with trifluoroacetic acid, hydrazine alpha or citric acid to provide the corresponding salt form. The compounds prepared according to the above scheme can be synthesized as a single-mirror, non-mirromer by mirror image, non-mirrored or bit-specific synthesis or by l-isolation. Compounds prepared according to the above scheme: =; (l : Ο or non-racemic (non-1: Ο mixture or non-mirror... or a mixture of meta-isomers. When the isomerization of the mirror image isomer 200974890 and the non-racemic mixture, (4) _ Separation methods (such as for the palm layer to obtain Γ = = mirror image isomerization salt formation, derivatization into non-image material mixture biotransformation or enzymatic conversion) single-single-mirror isomers step description of the invention and various The following specific embodiments are provided in the following specific embodiments. [Embodiment] Example Chemistry: Ο When the characterization data described in the following examples are obtained, the following analytical methods are followed unless otherwise stated. The reaction mixture was stirred at room temperature (rt) under a nitrogen atmosphere. When the solution was concentrated, it was shaken under reduced pressure using a rotary evaporator. When the solution was dried, it was usually dried with a desiccant such as MgS. 〇4 or Na2S04 The microwave reaction is carried out at CEM Discover® or Biotage InitiatorTM Microwave at a specific temperature. 溥 The 溥 layer chromatography is pre-coated with Merck's 60 F254 2.5 cm X 7.5 cm 250 or 5.0 cm x 10.0 cm 250 ym. Prepared by a silica gel plate. Preparative thin-layer chromatography was performed using a EM Science Shijiao 60 F254 20 cm X 20 cm 0.5 mm pre-coated plate with a 20 cm x 4 cm concentration zone. Normal phase purification is generally performed by normal phase. Flash column chromatography (F CC) was performed using a RediSep® cartridge column with EtOAc/hexane or CH 2 Cl 2 /MeOH as 48 200948790 solvate (unless otherwise stated). Reverse Phase High Performance Liquid Chromatography (HPLC) is used below Execution under conditions: 1) Instrument, Shimadzu; column ' Phenomenex Gemini column 5 # m C18 (150 x 21.2 mm) or Waters Xterra RP18 OBD 5 from m (100 x 30 mm); gradient, 95: 5 to 0: 100 water (0.05% trifluoroacetic acid (TFA)) / CH3CN (0.05% TFA); flow rate '30-80 mL/min; detection, UV at λ = 220-254 nm. 2) Instrument, Gilson;

PhenomenexLUNA Column 5 // ηι(:18 (250 χ50πιιη;^ Waters XBridge Prep C18 OBD 5 /zm (30 X 150 mm); Gradient '95:5 to 0:100 water (0.05% D??)/(: 113〇^(0.05% butyl [eight]; flow rate, 30-80 mL/min; detection, UV at; l = 220-254 nm. Analytical versus palm HPLC is performed under the following conditions: static phase, 252€: 〇1^1卩&1<:eight 8 (250 parent 4.6 111111); mobile phase, 1 〇〇/0 containing 0.2% triethylamine in MeOH, 90% C02; flow rate, 2 mL/min; Back pressure, 150 bar. Preparative palmitic HPLC was performed under the following conditions: static phase, 〇1^^ plus 1<: into 8-118?匚250 乂21111111 (1^1.〇.); mobile phase , 1〇〇/^ Me0H with 0.2% triethylamine, 90% C02; flow rate, 31.5 mL/min; back pressure, 150 bar. Hydrochloride is HCl at rt (4 N in dioxane) Prepared by treating the corresponding free base with 2 Μ in Et20 or 1.25 N) in MeOH. The mixture is condensed to give the HCl salt or the solid formed by filtration. The trifluoroacetate is prepared by reverse phase. The crude reaction product was purified by HPLC to obtain a nuclear magnetic resonance (NMR) spectrum in the Bruker DRX type. Obtained on the spectrometer. The format of the following bNMR data is: the chemical shift represented by the tetramer decane reference material 49 200948790 pre-field ppm (multimodality, coupling constant j is represented by ^^, integral). Mass spectrometry is based on Agilent 1100 MSD series. Obtained, unless otherwise indicated 'otherwise using positive mode electrospray ionization (ESI). The calculated mass corresponds to the actual mass. The chemical name is using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp) Cambridge, ΜΑ) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada) produces 0 intermediate A · Amino-1-(4-chaotic-stupyl)-ethanol·hydrochloride

a mixture of OH (S)-(-)'l, r_bi-2-naphthalene ((S)-BINOL) (573 mg, 2.0 mmol) and lithium isopropoxide (132 mg, 2.0 mmol) with toluene (4 〇mL) treatment. After 40 min, 4-fluorobenzaldehyde (2.15 mL, 20.0 mmol) was added dropwise. The resulting yellow solution was placed in a dry ice/acrylonitrile bath. After 10 min, trimethylsulfonyl cyanide (TMSCN; 2.5 mL, 20.0 mmol) was added. After 75 min, the mixture formed by hydrazine was treated with a solution of HC1 methanol (1% by volume; 20 mL) and warmed to rt. The resulting mixture was poured onto a mixture of ethyl acetate (EtOAc) (200 mL) and water (200 mL). The aqueous phase was extracted with EtOAc (2 x 100 mL). The combined extracts were dried (MgS04) and concentrated to give a mixture of green oil and crystalline solid. The oil was decanted to yield 2.24 g of product (75%). This oil (1. g, 6.6 mmol) in EtOAc (EtOAc) (EtOAc) The resulting mixture was heated to reflux for 1 h' at rt for 16 h, then slowly added MeOH to 50: 50,387,490 (2.5 mL). The volatiles were removed in vacuo. The solution formed by the addition of Me 〇 H (3 mL) was treated with HCl (2IV [at Et20; 6 mL). Addition of Et20 (30 mL) gave a solid, which was taken and dried in vacuo to give title compound (564 mg, 45%).

- intermediate B · chloremidine-4-ylamine a VI-(4-gas benzene a V r, alcohol. (8)-2-amino-1-(4-fluoro-phenyl)-ethanol hydrochloride ( 500 mg, 2 61 mmol), 4,6-dichloropilot (353 mg, 2.37 mmol) and a suspension of NaHC03 (1.39 g, 16.6 mmol) in dioxane (i〇mL) in i〇〇〇c bath The mixture was heated for 19 h and cooled to rt. Water (1 mL) was added, and a mixture of solids was extracted with CH.sub.2 (3×10 mL). The combined organic extracts were dried (MgSO.sub.4) and concentrated. FCC) gave the title compound as a white solid ( 415 g, 59%), EtOAc (yield: </ RTI> </ RTI> </ RTI> <RTIgt;

_中中不别C : 2-Amino-1-(3.4-dioxin-stupyl)-Ethyl. 3,4-Dichlorobenzaldehyde (3.50 g, 20.2 mmol) and Znl2 (19 mg, 0.06 mmol) The mixture was added tmSCN (2.2 g, 2.2 mmol) in EtOAc. The reaction mixture was stirred at 0 °C for 1 min and then warmed to rt and stirred for an additional 1 h. The mixture was concentrated to give an orange brown oil. This oil was dissolved in THF (20 mL) at 0. (: BH3.THF (1 Μ in THF; 25 mL, 25 mmol) was added. The mixture was warmed to rt and stirred overnight. The mixture was cooled to 〇〇c, and MeOH (6 mL) was added under continuous stirring. After 2 h. After warming to rt, the mixture was concentrated. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The white solid formed was filtered and washed with EtOAc EtOAc (EtOAc (EtOAc) (td. Pyrimidine.

Add 4,6-dichloro-pyrimidine (3.63 g, 22.7 mmol) and Ph3P (840 mg, 2.2 mmol) to a solution of CH3CN and water (75: 25 mL) (which has been degassed by bubbling N2 into the solvent). ). Continue to degas for another 15 min, then add 3-chloro-4-trifluorodecylphenyl-acid (5 g, 22 mmol), Pd (OAc) 2 (250 mg, 1-11 mmol) and K3P04 (9.4 g, 44.3 mmol). The resulting mixture was stirred at rt for 2 h then diluted with water and EtOAc. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude residue was purified (FCC) to afford the title compound (2.3 g, 35%). Intermediate E: 2,2-difluoro-5-(4,4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3 Dioxazole

Add 5-bromo-2,2-difluorobenzo[1,3]dioxazole (2.0 g, 8.44 mmol), bis(pinacol) diboron (2.36 g, 9.28 mmol) to an 80 mL microwave vessel ), potassium acetate (1.66 g, 16.9 mmol), Pd(dppf)Cl2.CH2Cl2 52 200948790 (689 mg, 0.84 mmol) and 1,4-dioxane (25 mL). The vessel was ventilated with N2 and heated by microwave irradiation at 14 ° C for 45 min. The reaction mixture was diluted&apos; filtered through a pad of Celite, then filtered through a 0.45 μM nylon filter, and the residue palladium particles were removed, dried (Na2S 4) and concentrated. The crude product was purified (FCC) to give the title compound as a green oil (i. 4 i g, 59%). : 4,4,5,5-tetramethyl-2-(5-trifluoromethyl-stupidyl bl thiazol-2-

5-trifluoromethyl-stupid and rbl thiophene. 5-trifluoromethyl-benzo[b]thiophene-2-furic acid (2.00 g, 8.12 mmol) and 1,8-diazabicyclo[5.4. 0] A mixture of undecane-7-ene (DBU) (5.0 mL, 34 mmol) in MeOH (13 mL). The reaction was cooled to EtOAc (EtOAc (EtOAc)EtOAc. The organic layer was washed with water (10 mL), dried (EtOAc, The residue was dissolved in EtOAc (25 mL) and washed with water (25mL). The aqueous layer was extracted with Et20 (10 mL x 2). The combined EkO layer was dried (Na2S04) and concentrated. The crude was purified (FCC) toiel Step B. Add [Ir(OMe)(COD)]2 (19 mg, 0.03 mmol) and 4,4'-dibutyl-2,2,-bipyridine (dtbpy) in a 2-neck round bottom flask (15.0 Mg, 0.06 mmol) 'The flask was evacuated and refilled. The flask was charged with a solution of 5-trifluorodecyl-benzo[b]thiophene (380 mg, 1.88 mmol) in hexane (12 mL). The reaction mixture was stirred at rt for 4 h then diluted with CH.sub.2 C.sub.2 (20 53 2009487. The organic layer was dried (EtOAc EtOAc m. Intermediate G: 4_trifluoromethylsulfane a certain - clumsy.

Step A: 4,4,5,5-tetradecyl-2·(4-trifluoromethyl decane oxime-laughing V[l,3,21 dioxaborolane. The title compound is similar to intermediate E Prepared as follows. Step B. Add 4,4,5,5-tetradecyl-2-(4-trifluoromethylsulfanyl) to THF and water (4: 1,26 mL) in a round bottom flask. -Phenyl)^,3,2]dioxolane (960 mg, 3.16 mmol) and sodium sulphate (2.03 g, 9.48 mmol). The resulting suspension was stirred at rt for 30 min. HC1 (1 N aq , 2.21 mL) was added to the suspension' and the reaction mixture was stirred at rt for 18 h. The formed precipitate was removed by filtration and washed with hexane. The filtrate was diluted with water (25 mL) and

Extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjjj Isoxazole _6·facial acid·

Step Α: 1-(4ϋ:^-yl-phenyl)_:^2,2-trimethylacetone. Pre-cooled with 3-bromophenol (4.93 ml, 46.2 mmol) and di-hexane (185 mL) (〇〇c) Trifluoroacetic anhydride (9·3 mL, 67 mmol) was added to the solution at 1 Torr. Aluminum chloride (20.1 g, 150.7 mm 〇1) was then added in portions over 15 min. Reaction Mixing 54 200948790 The material was gradually warmed to rt at 2 h, then heated at 4 〇 γ for 19 h. The reaction mixture was cooled to rt and poured onto ice water. The resulting mixture was extracted with EtOAc (EtOAc) (EtOAc) Crude

The product was dissolved in Et20 (1 〇〇 mL;) and extracted with NaHC03 (10% aq., 1 〇〇 mL X 4). Combined with the aqueous extract? ]9 [by careful addition of hC1 (6n called) to 7 and the resulting mixture was extracted with Et 2 〇 (2 〇〇 mL). The section 2 layer was dried (NaJO4) and concentrated. Purification (FCC) of EtOAc (EtOAc): , Tong ^B: 1-(4-bromo-2-hydroxy-phenyl)-2,2,2-trifluoro-ethanone oxime. Add sodium acetate (9.46 g, 115 mmol) to a round bottom flask. The base amine hydrochloride (7.09, 102111111〇1) and ]^011 (1〇1^). Add 1_(4_bromo) to this mixture

• A solution of 2-amino-based)-2,2,2-difluoro-ethyl (2.5 g, 9.3 mmol) and MeOH (62 mL). The reaction vessel was heated at 64 for 7 h, then cooled to rt and the reaction mixture was poured into ice water (1 mL). The aqueous solution was then extracted with EtOAc (75 mL×2). &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&&& -3-trifluoromethyl- accompaniment dl is isoindole containing 1-(4-trans-2-phenyl-phenyl)-2,2,2-trifluoro-ethanone (2.64 g, 9.29 mmol) Acetic anhydride (14 mL) was added to the flask. The reaction mixture was stirred at rt for 18^. The reaction mixture was concentrated and dissolved in toluene and concentrated again to give a deuterated intermediate. This intermediate was dissolved in pyridine (15 mL) and triethylamine (3.2 mL). The reaction mixture was concentrated and the residue was crystallisjjjjjjjjjjjjj The layers were separated and the organic layer was washed with EtOAc (1 Naq·, 25mL). The combined aqueous layers were then extracted with EtOAc (25 mL EtOAc)EtOAc. The title compound (44 mg, 17%) was obtained. Step D. The title compound was prepared using a procedure analogous to Intermediate G. Intermediate, path 2: 3-trifluoromethyl-benzo[d]isoxazole heart-acid

Step A: Odor-2-gas-stupyl-2,2,2-tris-ethanol. 4-Dialdehyde-2-gas-benzofural (8.12 g, 40.0 mmol) and (trifluoromethyl) The mixture of hydrazine (7.50 mL, 48.0 mmol) in THF (40 mL) was cooled to EtOAc, then EtOAc (EtOAc &lt After 3 h, another TBAF (1 Μ in THF, 8.0 mL) was added. The resulting mixture was spoiled for 10 min, then HCl (1 N aq., 40 mL) was added and extracted with Et20 (4 mL). The Et20 layer was dried (MgSO4) and concentrated to give the title compound (10.7 g, 98%). Step 6: 1-(4->Smelly-2-chaotic-stupyl)-2,2,2-digas-B. Dess-Martin periodinane (16.57 g, 39.06 mmol) Adding to a solution of 1-(4-'; odor-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (10.66 g, 39.06 mmol) and DCM (100 mL) The mixture was given 1.5 h at rt. Add Na2S203 (10% aq" 100 mL), and the resulting mixture is extracted with CH2C12 (100 mL). The organic layer is Na2S203 (50 mL X 2), NaHC〇3 (satd. aq·, 100 mL x 2) and Brine (100 mL x 2) Washed in. 56 200948790 The organic layer was dried (NasSO4) and concentrated. The crude material was purified (FCC) to yield the title compound (3·20 g, 30%). Addition of hydroxylamine hydrochloride (4) to a solution consisting of M4_indol-2-fluoro-phenyl)_2,2,2_trimethyl-ethanone (3 12 g, u 5 face (4) and MeOH (50 mL) 〇〇g, 57=mmol) and sodium acetate (5_9〇g, 71 9 mm〇i). The resulting mixture was heated at 64 ° for 19 h, at which time additional hydroxylamine hydrochloride (24 〇g 345 leg 〇 1) and Sodium acetate (3.54 g, 431 Curry 1). The mixture was heated for 24 h. The mixture was cooled to 1 EtOAc. The mixture was filtered and evaporated. The filtrate was diluted with Et EtOAc (150 mL), washed with water (i5 〇mL), dried (NajA), and concentrated to give the title compound as a 70:30 ratio of E and Z oxime isomer (3.28 g, 1%). Pan invited P: 6-bromoisoxazole. By H4_漠_2_ Fluorine-stupyl-2,2,2-trifluoro-ethanone monthly loss (3 2g, u.2mm〇1)丄&amp;diazepine

^ Bicyclo [5.4. 〇] eleven carbon dilute (10) U) (1.1 mL, 7.4 〇〇 〇〇 and THF (42 mL) solution was heated at 150 τ for 3 〇 min via microwave irradiation.

The reaction mixture was diluted with CH.sub.2Cl.sub.2 (25 mL). The organic layer was dried (NaJCV), The title compound of the ancestor was prepared using a method similar to that described in Intermediate G. Intermediate 丨: 3 dioxo-4-trifluoromethoxy _ laughing _ xijin

F Γ 〇

OH

I

Cl fluoromethoxy step A: 4-side-2-oxo-upperfluoromethane 篡_1 from 3-chloro-4_57 200948790 base-aniline (2.12 g, 10.0 mmol) and HBr (48% aq, 50 mL The solution was added dropwise NaN02 (2 M aq., 917.7 mg, 13.3 mmol) at a rate at which the reaction temperature was kept below 5 ° C. After 1.75 h of mixing, urea (330 mg, 5.5 mmol) was added and the mixture was stirred for 20 min. A solution consisting of Cu(1)Br (2.96 g, 20.6 mmol) and HBr (48% aq" 13.1 mL) was then added at a temperature between 0 and 5 ° C. When fully added, the reaction mixture was heated to 85 ° C for 2.5 cycles. h After cooling to rt, the reaction mixture was poured with EtOAc EtOAc EtOAc (EtOAc) The title compound (806 mg, 29%) was obtained eluted eluted eluted elution elution elution elution elution elution elution elution elution Fluoroethyl-benzo[d]isoxazole-6-decanoic acid.

The title compound was prepared using a similar intermediate, as described in the path 2. Intermediate K: (1R&gt; 2-amino-1-(4-fluoro-phenyl)-ethanol hydrochloride.

Step A: nR)-2-Gas-1-(4-fluoro-cage-ethanol). From ΒΙ13·ΙΉΡ(1 M, 150 mL) and (R)-(+)-2-mercapto-CBS-oxazole Boron-fired (1 Μ in THF) (2.14 mL·) solution was added at rt for 1 h with σ from 2-chloro-4,-fluoro-ethylbenzene (37.0 g, 214 mmol) and THF (100) Ml) The second solution of the composition. 200948790 The colorless reaction mixture was stirred for 45 min and then quenched with MeOH (EtOAc) (EtOAc) (37 g, 100%) Step B: (1RV2-azide small (4-en) a brewing. Add sodium azide (41.8 g, 642 mmol) to (lR)- at rt a solution of 2-chloro-1-(4-fluoro-phenyl)-ethanol (37.4 g, 214 mmol) and DMF (214 mL). The reaction mixture was heated to 100 ° C for 3 h and diluted with water (500 (mL), and EtOAc (EtOAc) (EtOAc (EtOAc) Use (39 g, 100%). Disc waste (:: in (1 ft)-2-azido-1-(4-fluoro-phenyl)-ethanol (38. 8 g,

Add 5% Pd/C (60% water, 38 g) to a solution of 214. mmol) and EtOH (250 mL). The reaction mixture was subjected to 5 psi of hydrogen at rt for 1 h. • The reaction mixture produced a black filtrate through a 0.4 5 78 M nylon filter. HpLc analysis showed that the reaction was incomplete. Fresh Pd/C (38 g) was added and the reaction mixture was applied for another 2 h at 5 psi and rt. The reaction mixture was filtered through a 0.4578 M spurt to give a brown filtrate. Remove the solvent under vacuum and dissolve the residue

EtOH (215 mL). The glycolysis solution was then treated with HCl (2 Torr in Et2, 107 mL) followed by Et2 (250 mL). The title compound was precipitated by vacuum filtration (20.8 g, 51%). A solution consisting of dissolved (8)-(-)-2-amino-1-(4-fluorophenyl)-ethanol (22.3 g, 116 mmol) and ethanol (225 mL) was heated at 7 ° C to give a uniform sentence. Solution. Heptane (115 mL) was slowly added, and the solution was stirred for 1 Torr, after which the solution was slowly cooled to rt. Upon cooling, crystals are formed. After cooling to ^, the solution was placed at -20 °C for 18 h. The mother liquor in the flask was decanted and remained. 59 200948790 The crystals were washed twice with heptane (~50 ml) and dried under vacuum to leave compound (18.29 g, 81%). The recrystallized material and the crude product are determined according to the method for preparing [2-(4-fluorophenyl)-2-hydroxyl-ethyl]-aminophosphonium decanoate by a known method. HPLC conditions: OD-H column, 95% hexane/5% EtOH (0.1% Dea), 〇.8 ml/mil^fL. The ee of the crude and recrystallized materials was 94% and 97-98%, respectively. Day, day, day, night, night, amino group, small (4_fluoro_stupyl), ethanol

H OH

HO HO B

The title compound was prepared in a similar manner to that described in Step A of Example 1. HHiA2, 2-four i-Ι-Trifluoro-A-Λ美丄丄_酴

HO \

I

Hci

B

乙^bi^HL3,2H oxonium fluorene ring and 4.4·5·5 dimethyl group f~i· A mixture of the title compound was obtained by a method similar to that described in Intermediate F. The compound of the formula was prepared by the method described in the use of the hetero-intermediate g. Incision / Type 200948790 Intermediate Ο . 3-Difluoromethyl- benzo-benzoxene _6-yl-benzene

Step A: .. Ai, 5, 5, methyl fluoromethyl _ cage, which is called sulfonium j-based) - "lA? J ^ oxygen ^ ^ ring. The title compound was prepared using a method similar to that described in the intermediate. 6-Bromo-3-trifluoromethyl-benzo[b]thiophene is prepared as described in [0003], 2003, "7147." Step ^1_The title compound is described using a similar intermediate G. Prepared by the method. Example I: 1,4-aminoguanidino)-1-phenylethanol.

Step: A: (lR)-2_"(6_a pyrimidine-4-yl)amine oxime cage from (R)-(-)-2-amino-1-phenylethanol (4.80 g, A solution consisting of 35.0 mmol) and 1,4-dioxane (150 mL) was added dropwise at rt from 4,6-diox (5.21 g, 35.0 mmol) and 1,4-two-degree (75 mL) ) a solution of the composition. Upon complete addition, NaHC〇3 (17.6 g, 0.210 mol) was added and the mixture was heated to reflux (100 °C) for 17 h. The reaction mixture was cooled, diluted with water (6 mL) and pH was adjusted to π with 1 N NaOH (25 mL). The solution was extracted with (3⁄4⁄4⁄4 (75 mL) EtOAc (5 mL), EtOAc (EtOAc) (jjjjjjjjjjj °C to give a homogeneous solution. The solution was cooled to 61 200948790 rt and treated with a few drops of hexanes to give the title compound as a pale yellow solid (7.0 g, 81%). MS (ESI): Mass. Calculated C21H20F3N3O2, 403.2; m/z Found 404·2 [M+H]+. NMR (CD3OD): 8.44 (s, 1H), 8.15 (s, 1H), 8.09 (dd, 7 = 8.8, 2.2 Hz, 1H), 7.43 (d , J = 7.7 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.27-7.25 (m, 2H), 6.86 (s, 1H), 4.91-4.88 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.76-3.68 (m, 1H), 3.58 (dd, J = 13.7, 7.7 Hz, 1H), 1.45 (t, J = 7.1 Hz, 3H). [(6-Azapirin-4-yl)amino]-1-phenylethanol (62.4 mg, 0.25 mmol), 3· chloro-4-ethoxyphenylboronic acid (10 mg, 0.5 mmol), Pd(PPh3)4 (14.4 mg, 0.0125 mmol) and K3P04 (106 mg, 0.50 mmol) were placed in a two-neck round bottom flask and the flask was evacuated. The flask was backfilled with N2 and then loaded with DME (2.0 mL). Water (0.5 mL). Reaction The mixture was heated under reflux (85 ° C) for 17 h. then the mixture was evaporated EtOAc EtOAcjjjjjjjjjjjjjjjjjjjj Residue purification (FCC followed by reverse phase HPLC) to afford the desired product (90.1mg, 97%). MS (ESI): Mass. calc. C2 () H2() C1N302, 369.1; m/z, value: 370.2 [M +H]+.H NMR (CD3OD): 8.42 (s,1H), 7.94 (d,2.3 Hz, 1H), 7.81 (dd, J= 8.6, 2.3 Hz, 1H), 7.43 (d, /= 7.1 Hz, 2H), 7.36-7.32 (m, 2H), 7.27-7.24 (m, 1H), 7.14 (d, 7 = 8.6 Hz, 1H), 6.82 (s, 1H), 4.92-4.89 (m, 1H) , 4.19 (q, J = 6.8 Hz, 2H), 3.75-3.67 (m, 1H), 3.58 (dd, J = 13.9, 7.8 Hz, 1H), 1.46 (t, J = 6.8 Hz, 3H). The compounds of Examples 2 to 19 are prepared according to the method of Section 62 200948790 described in Example 1, using the mirror-isomerized pure or racemic amino alcohol in Step A, and substituting the appropriate acid or ester in Step B. And prepared. The final compound was purified by FCC.曰 blanket Example 2 ^2-{丨6-(4-氡Phenyl>Miha_4_基1amine Some MS (ESI): Mass spectrometry calculation C18H16C1N30, 325.1; m/z experimental value, 326.2 [M +H]+〇!HNMR (CD3OD): 8.45 (s, 1H), 7.88 (¢1,,=== 〇8.2 Hz, 2H), 7.48 (d, J= 8.7 Hz, 2H), 7.43 (d, J= 7.7 2H), 7.35-7.32 (m, 2H), 7.27-7.24 (m, 1H), 6.88 (s, 1H), 4.89 ((1(1,/= 7.7, 4.9 Hz, 1H), 3.77- 3.67 (m, 1H), 3.59 (10) j =13.7, 7.7 Hz, 1H). Example 3: 2-丨丨6-(4-Fluoryl)pyrimidin-4-one 1 M-Methyl B

ΟΗ ❹ MS (ESI): mass spectrometry calculation (: 811 811) 6 [1^3〇, 309.1; 111/2 experimental value, 310.2 [M+H]+. towel NMR (CD3OD): 8.45 (s, 1H), 7.94 (eg =8.8, 5.5 Hz, 2H), 7.42 (d, 7.1 Hz, 2H), 7.34 (t, J- 7 ?

Hz, 2H), 7.26 (t, J= 7.1 Hz, 1H), 7.22-7.19 (m, 2H), 6.86 (s 1H), 4.89 (dd, "/= 7.1, 4.9 Hz, 1H), 3.78-3.67 (m, 1H), 3.%' ((!(!,/= 13.7, 7.7 Hz, 1H). Example 4: 1_Stupyl-2-({6-"4-(2) ) Stupid 1. Dimidine-4-meryl) ethanol trifluoroacetate. 63 200948790

MS (ESI): mass calcd for C19 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; , 7.92 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 7.1 Hz, 2H), 7.37-7.34 (m, 2H), 7.29-7.27 (m, 1H), 7.04 (s, 1H), 4.94 (dd, J= 7.1, 4.9 Hz, 1H), 3.95-3.88 (m, 1H), 3.78 (dd, J =13.7, 7.7 Hz, 1H). Example 5: 2-丨丨6-(4-nitrophenyl)pyrimidin-4-yl 1 amine M-jatty ethanol trifluoroacetate.

MS (ESI): mass calcd for C18 </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 8.05 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 7.3 Hz, 2H), 7.38-7.34 (m, 2H), 7.30-7.26 (m, 1H), 7.06 (s, 1H), 4.96 -4.92 (m, 1H), 3.95-3.86 (m, 1H), 3.77 (dd, J = 13.6, 7.8 Hz, 1H).

Example 6: 2-U6-(4-ethyl pheno-V-Bitter _4-yl i-amino hydrazine-1 - benzyl _ MS (ESI): mass spectroscopy calculated 319.2; m/z experimental value, 320.2 [M+H]+°]H NMR (CD3OD): 8.44 (s, 1H), 7.80 (d, j = 200948790 8.3 Hz, 2H), 7.43 (d, &lt;/= 7.6 Hz, 2H), 7.37- 7.31 (m,4H), 7.28-7.24 (m, 1H), 6.86 (s, 1H), 4.91-4.90 (m,1H), 3.77-3.67 (m, 1H), 3.58 (dd, J= 13.9, 7.8 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.26 (t, /= 7.6 Hz, 3H). Example 7: 2-((6-"4-Π-methylethyl) A pyrimido-4-yl}amine, a VI-stupyl alcohol.

MS (ESI): m.p. NMR (CD3OD): 8.44 (s, 1H), 7.82-7.80 (m, 2H), 7.44-7.43 (m, 2H), 7.36-7.33 (m, 4H), 7.28-7.24 (m, 1H), 6.86 ( m, 1H), 4.91-4.90 (m, 1H), 3.76-3.68 (m, 1H), 3_58 (dd, 13.9, 7.8 Hz, 1H), 2.97 (seventh line, /= 6.8 Hz, 1H), 1.28 ( d, "/= 6.8 Hz, 6H).实施 Example 8: 2_U6-(3,4-dioxamethyl)pyrimidin-4-yl1amine M-Momo

MS (ESI): mass calc. calcd. bNMRCCDsOD) : 8·46 (s,1H), 8.09-8.08 (m, 1H), 7.82 (dd, J = 8.2, 2.2 Hz, 1H), 7.63 (d, J =8.2 Hz, 1H), 7.43 (d , 7.7 Hz, 2H), 7.35-7.32 (m, 2H), 7.27-7.24 (m, 1H), 6.89 (s, 1H), 4.89 (dd, J=7.1, 4.9 Hz, 65 200948790 1H), 3.78- 3.67 (m, 1H), 3.58 (dd, "/= 13.7, 7.7 Hz, 1H). Example 9: 2-U6-(3-Aza-phenyl)pyrimidin-4-yl 1 -amine M-phenylethanol.

MS (ESI): m.p. 4 NMR (CD3OD): 8.46 (s, 1H), 7.92 (s, 1H), 7.82-7.81 (m, 1H), 7.47-7.46 (m, 2H), 7.43 (d, 7 = 7.7 Hz, 2H), 7.34 (t, J = 1.1 Hz, 2H), 7.27-7.24 (m, 1H), 6.89 (s, 1H), 4.91-4.88 (m, 1H), 3.78-3.68 (m, 1H), 3.59 (dd, J = 13.7, 7.7 Hz, 1H). Example 10: 2-((6-"3-chloro-4-(trifluoromethyl)mosyl 1 pyrimidine-4-yl} fluorenyl)-1-methyl alcohol.

MS (ESI): m/z. bNMR (CD3OD): 8.50 (s, 1H), 8.16 (s, 1H), 8.00 (d, 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 7.26 (t, J = 7.1 Hz, 1H), 6.97 (s, 1H), 4.91-4.89 (m, 1H), 3.79-3.70 (m, 1H), 3.60 (dd, J = 13.7, 7.7 Hz, 1H). iMMn : 2-({6-丨4-(ethyl-based) molybdenum 1 pyridin-4-one} face 篡vu stupid base ethanol. 200948790

MS (ESI): mass calcd for C2 〇H2iN3 〇2, 335.2; m/z </ RTI>, 336.2 [M+H] + NMR (CD3OD): 8.41 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.43 (d, 7.7 Hz, 2H), 7.36-7.33 (m, 2H),

7.27-7.25 (m, 1H), 7.00 (d, J= 8.8 Hz, 2H), 6.81 (s, 1H), 4.91-4.88 (m, 1H), 4.09 (q, 7 = 7.1 Hz, 2H), 3.75 -3.67 (m, 1H), 3.57 (dd, J — 13.7, 7.7 Hz, 1H), 1.4j ^ j= η | fjz 3H). Example 12: phenylethyl 1 benzopyrimidine _4_yl)

MS (ESI): mass calcd for Cn,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ), 7.43 (d, /= 7.7 Hz, 2H), 7.34 (t, 7.7 Hz, 2H), 7.26 (t, J= 7.1 Hz, 1H), 6.98 (d, J= 8.8 Hz, 2H), 6.81 ( s, 1H), 4.89 (dd, J = 7.7, 4.4 Hz, 1H), 4.68 (seven lines, 6.0 Hz, 1H), 3.75-3.67 (m, 1H), 3.57 (dd, 13.7, 7.7 Hz, 1H) , 1.33 (d, J = 6.0 Hz, 6H). Example 13 · 1-Phenyl-2-(anthracene 6-"4-(stupyloxy)- benzylidene _4_ylamino)ethanol. 67 200948790

MS (ESI): mass spectrometer #C24H2iN302, 383.2; m/z, 384.2 [M+H]+ NMR (CD3OD): 8.43 (s, 1H), 7.90-7.88 (m, 2H), 7.44-7.38 (m, 4H), 736-7.32 (m, 2H), 7.27-7.24 (m, 1H), 7.19-7.15 (m, 1H), 7.07-7.03 (m, 4H), 6.85 (s, 1H), 4.91 -4.89 (m, 1H), 3.75-3.67 (m, 1H), 3.59 (dd, 13.9, 7.8 Hz, 1H). Example 14: 2-(丨6-『3-nitro-4彳乙氲) 策基1 pyrimidine_4-very} glare base)-1-phenyl alcohol.

MS (ESI): mass calcd for C12H12 C1N30, 249.1; m/z, </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> NMR (CD3OD): 8.21 (s, 1H), 7.40 (d, J = 7.1 Hz, 2H) , 7.35-7.32 (m, 2H), 7.27-7.24 (m, 1H), 6.52 (s, 1H), 4.84 (dd, J= 7.7, 4.9 Hz, 1H), 3.74-3.66 (m, 1H), 3.56 -3.54 (m, 1H). Example 15: (1R)-1-indolyl-2-anthracene-6-"4-indolyltrifluoromethyl]phenyl]pyrimidinyl]amino}ethanol).

MS (ESI): mass calcd for C19H: 6F3N30, 359.1; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 2H), 7.78 (d, J= 8.3 Hz, 2H), 7.43 (d, 7.3 Hz, 2H), 7.36-7.32 (m, 2H), 7.28-7.24 (m, 1H), 6.96 (s, 1H) , 4.92-4.90 (m, 1H), 3.80-3.70 (m, 1H), 3.61 (dd, /= 13.6, 7.8 Hz, 1H). Example 16: Πϊ〇-2-({6-"3_chloro-4-f-trimethyl)methyl sulphate 1 azopyrim-4-yl}amino)-1-methyl alcohol.

MS (ESI): mass calcd for C19H15C1F3N30, 393.1; m. ^NMRCCDsOD): 8·50 (s,1H), 8.16 (s, 1Η), 8.01-7.98 (m, 1H), 7.88 (ά, J = 8.3 Hz, 1H), 7.44 (d, J =7.3 Hz, 2H), 7.37-7.34 (m, 2H), 7.27-7.24 (m, 1H), 6.97(s, - 1H), 4.93-4.90 (m, 1H), 3.79-3.71 (m, 1H), 3.60 (dd , J = 13·6, 7.6 Hz, 1H).标题 The title compound was also prepared in a similar manner to Example 1 in the following steps: Steps A and B: 4,6-di-pyrimidine (50 g, 0.34 mol, 1.0 eq.) in CH3CN (1.2 L) NaHC〇3 (34 g, 0.40 mol, 1.2 eq.) and (and)-(-)-2-amino-1-phenyl-ethanol (48·3 g, 0.35 mol, 1.05 eq.) were added sequentially. The reaction mixture was stirred at reflux temperature for 3 hours at N2 then cooled to rt. The H p l C analysis of the crude reaction mixture showed that the reaction was completed to yield intermediate (li?)-2-[(6-apyrimidin-4-yl)amino] phenylethanol. In the same flask, without adding purification or processing, K3p〇4 (85g, 69 200948790 0.40 mol, 1.2 equivalents) in H20 (750 mL), 3-chloro-4_ ( Trifluoromethyl)phenyl-acid (79.4 g, 0.35 mol, 1.05 equivalent), Pd(dppf)Cl2·CH2CI2 (2.4 g, 2.9 mmol, 0.009 eq.) and Pd(OAc)2 (68 mg, 0.29 mmol, 0.0009) equivalent). The reaction solution was degassed with N 2 (3×), stirred at reflux temperature for 16 hours and then cooled to rt. The layers were separated and the CH3CN phase was dried (MgS04) and filtered. The filtrate solution was stirred at rt for 1 hour with Si-Thiol (8.8 g, 1.5 mmol/g loading, 4 equivalents of Pd). Si-Thiol is commercially available from SiliCycle (230-400 mesh '40-63 μιη). Si-Thiol was filtered off and washed with EtOAc. The organics were combined and concentrated under reduced pressure. The crude residue was recrystallized from EtOAc (EtOAc:EtOAc) The mother liquor was further concentrated, followed by a second self-heating of EtHH under recrystallization to provide another portion of the title compound (23 g). The combined recrystallization yield of the title compound was 80% (106 g, &gt; 99% ee). MS (ESI): mass spectrum Calculated CwHbClF3:^3. , 393.1 ; m/z experimental value, 394.1 [M+H]+. ]H NMR (CDCI3, 500 MHz): 8.69 (s, 1H), 8.12 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.52- 7.28 (m, 5H), 6.74 (s, 1H), 5.42 (br s, 1H), 5.10-4.98 (m, 1H), 3.92 (br s, 1H), 3.70-3.58 (m, 1H). Example 16A; (lR)-2_({6-"3-chloro-4-[trimethylpyridinium-1]pyrimidin-4-yl>amino)-1-phenylamine hydrochloride. 1H NMR (CD3OD): 8.72 (s, 1H), 8.11 (s, 1H), 8.04 ((1, / = 8.3, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.48-7.44 (m, 2H ), 7.37-7.34 (m, 2H), 7.30-7.27 (m, 1H), 7.11(s, 1H), 4.95 (dd, 4.1, 7.8, 1H), 3.94 (dd, y=4.2, 13.6 Hz, 1H ), 3.60 (dd, J =13.6, 7.6 Hz, 1H). 200948790 Example 17: l-|~4-(6-{|~(2R)-2-yl-2-yl-phenyl) Glyden-4-yl)phenyl 1-ethanone.

MS (ESI) ················································································ 2H), 8.02 (d, /= 8.8 Hz, 2H), 7.43 (d, 7.3 Hz, 2H), 7.36-7.32 (m5 2H), 7.27-7.24 (m, 1H), 6.96 (s, 1H), 4.92 -4.89 (m, 1H), 3.79-3.69 (m, 1H), 3.60 (dd, J = 13.6, 7.8 Hz, 1H), 2.64 (s, 3H). f Example 18: (lR)-2-((6-"4-n-methylethyl) methyl 1 pyrimidine-4- some} face base VI-stupyl alcohol.

MS (ESI): m.p. iHNMR (CD3OD) ·· 8.44 (s, 1H), 7.82-7.80 (m, 2H), 7.44-7.42 (m, 2H), 7.36-7.32 (m, 4H), 7.27-7.24 (m, 1H), 6.86 (s, 1H), 4.91-4.89 (m, 1H), 3.77-3.68 (m, 1H), 3.59 (dd, «/= 13.6, 7.6 Hz, 1H), 2.96 (seventh line, "/=6.8 Hz, 1H), 1.28 (^7 = 6.8 Hz, 6H). Example 19: ΠΙΟ-2-"(6-{3-argon-4-"Π-methylethyl) gas group 1 策一一素 71 200948790 pyridine-4-yl)amino hydrazine-jasmine ethanol.

MS (ESI): mass calcd for C21.21.21.咕NMR (CD3OD): 8.42 (s, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.6, 2.3 Hz, 1H), 7.44-7.42 (m, 2H), 7.36- 7.32 (m, 2H), 7.27-7.24 (m, 1H), 7.16 (d, J = 8·8 Hz, 1H), 6.82 (s, 1H), 4.91-4.89 (m, 1H), 4.73 (seven lines) , */= 6.1 Hz, 1H), 3.75-3.66 (m, 1H), 3.58 (dd, */= 13.6, 7.6 Hz, 1H), 1.37 (d, 6.1 Hz, 6H). Example 20: (lRV2-{"6-(3-fluoro-4-methyl-methyl) pyrimidin-4-yl 1 amine M-phenylethanol trifluoroacetate.

The title compound was also synthesized in a similar manner to Example 1, and the modification of Step B was as follows:

Step B. (lR)-2-[(6-Chloropyrimidin-4-yl)amino H-phenylethanol (62.4 mg, 0.3 mmol), 3-fluoro-4-mercapto-phenyl decanoic acid ( 42 mg, 0.30 mmol), Pd(PPh3)4 (2.9 mg, 0.0025 mmol) and K3P04 (106 mg, 0.50 mmol) were placed in a microwave vial and the vial was evacuated. The vial was then backfilled with N2 and loaded with DME (2.0 mL) and degassed water (0.5 mL). The reaction mixture was at 180 in the microwave. (The mixture was heated for 21 min. EtOAc EtOAc (EtOAc). : mass spectroscopy for C19Hi8FN30, 323.1; m/z calc., 324.2 [M+H]+. NMR (CD3OD): 8.62 (s, 1H), 7, 55-7.48 (m, 3H), 7.43 (d, J = 7.1 Hz, 2H), 7.37-7.34 (m, 2H), 7.29-7.27 (m, 1H), 6.98 (s, 1H), 4.95-4.92 (m, 1H), 3.93-3.87 (m, 1H), 3.79 (dd, /= 13.7, 7.7 Hz, 1H), 2.38 (s, 3H). The compounds of Examples 21 to 102 were prepared using a method similar to that described in Example 20, using the image-isomerization purity or elimination in Step A. The amino group and the appropriately substituted 4,6-dichloropyrimidine are prepared by substituting the appropriate acid or ester in step B. Example 21: (lR)-2-((6-丨4) - (hydroxymethyl) jasmine 1 pyrimidine-4- some} face base)-1-phenyl acetamidine.

MS (ESI): mass calcd for C19H19N302, 321.2; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 7.47 (d, J = 8.2 Hz, 2H), 7.43 (d, 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 7.27-7.24 (m, 1H), 6.88 (s, 1H), 4.90 (dd , J = 7.7, 4.4 Hz, 1H), 4.67 (s, 2Ή), 3.76-3.68 (m, 1H), 3.60 (dd, 13.7, 7.7 Hz, 1H). Example 22. 4-(6-{"(2R)-2-Phenyl-2-phenylethyl 1amino}0 milidine-4-yl)benzaldehyde.

MS (ESI): mass calcd for CI9 HI7N302, 319.1; m/z,,,,,,,,,,,,,,,,,, Towel NMR (CDC13): 10.09 (s, 1H), 8.70 (s, 1H), 8.12 (d, 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.43-7.42 (m, 2H) , 7.40-7.37 (m, 2H), 7.33-7.30 (m, 1H), 6.79 (s, 1H), 5.33 (br s, 1H), 5.01-4.99 (m, 1H), 3.94-3.87 (m, 1H) ), 3.65-3.60 (m, 1H). Example 23: 3-(6-{"(2RV2-hetero-2-methylethyl 1 oxapyrimidin-4-yl) oxazaldehyde.

MS (ESI): m.p. 4 NMR (CDC13): 10.10 (s, 1H), 8.69 (s, 1H), 8.45-8.44 (m, 1H), 8.20-8.25 (m, 1H), 7.99-7.97 (m, 1H), 7.66-7.63 (m, 1H), 7.44-7.37 (m, 4H), 7.34-7.30 (m, 1H), 6.80 (s, 1H), 5.33 (br s, 1H), 5.01 (dd, J= 7.3, 3.3Hz, 1H), 3.93-3.85 (m, 1H), 3.66-3.60 (m, 1H). Example 24: (lRVl-methyl-l-["(6-(4-indole(2,2,2-trifluoroethyl))yl 1 phenylpyridin-4-yl)amino 1 ethanol.

MS (ESI): mass calcd for C2 </RTI> &lt;RTI ID=0.0&gt; NMR (CD3OD): 8.43 (s, 1H), 7.90 (d, 8.8 Hz, 2H), 7.43 (d, 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 7.27-7.24 (m, 1H), 7.12 (d, J= 8.8 Hz, 2H), 6.84 (s, 1H), 200948790 4.91-4.87 (m, 1H), 4.61 (q, J= 8.2 Hz, 2H), 3.73-3.69 (m, 1H), 3.59 (dd, «/= 14.3 8.2 Hz, 1H). Example 25: (1RV1-mollyl-2-indole (6-{3-"(2?2-trioxazide) 1 styrylpyrimidine-4-one) amine 1 ethanol.

PCT 3): Mass spectrometry calculation: (201118?3^3〇2, 389.1; 111/2 experimental value, 390.2 [M+H]+. W NMR (CD3OD): 8.46 (s, 1H), 7.57-7.54 (m , 2H), 7.46-7.42 (m, 3H), 7.36-7.32 (m, 2H), 7.27-7.23 (m, 1H), 7.14-7.11 (m, 1H), 6.89 (s, 1H), 4.91-4.88 (m, 1H), 4.63-4.57 (m, 2H), 3.77-3.69 (m, 1H), 3.62-3.58 (m, 1H). Example 26: ΠΐΟ-2-{Γ6-(4-氦-3 -Methyl yl) pyrimidine-4- Ί Μ Μ 茉 - jasmine ethanol trifluoroacetate.

MS (ESI): m.p. H NMR (CD3OD): 8.64 (s, 1H), 7.74 (s, 1H), 7.61-7.59 (m, 2H), 7.45-7.44 (m, 2H), 7.37-7.34 (m, 2H), 7.29- 7.27 (m, 1H), 6.98 (s, 1H), 4.95-4.93 (m, 1H), 3.94-3.89 (m, 1H), 3.82-3.78 (m, 1H), 2.49 (s, 3H). Example 27: nRV2-{[6-(4-Ga-3-fluoromethyl)pyrimidine-4- Ί脍 75 75 200948790 Stupyl alcohol trifluoroacetate.

MS (ESI): mass calcd for C18H15C1FN30, 343.1 m/z, 344.1 [M+H]+. 4 NMR (CD3OD): 8.65 (s, 1H), 7.77-7.22 (m, 2H), 7.64-7.62 (m, 1H), 7.45-7.44 (m, 2H), 7.36-7.34 (m, 2H), 7.29 -7.28 (m, 1H), 7.01 (s, 1H), 4.95-4.93 (m, 1H), 3.93-3.90 (m, 1H), 3.79 (dd, y = 13.7, 8.2 Hz, 1H). Example 28: nRV2-((6-丨4-chloro-3-(trifluoromethyl)mosyl 1 pyrimidin-4-yl}amino)-1-phenylethanol trifluoroacetate.

MS (ESI): mass calcd for C] </RTI> &lt;RTI ID=0.0&gt;&gt; NMR (CD3OD): 8.65 (s, 1H), 8.24 (s, 1H), 8.04 (dd, J = 8.2, 2.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 7.1 Hz, 2H), 7.36 (t, 7.7 Hz, 2H), 7.29-7.26 (m, 1H), 7.03 (s, 1H), 4.95-4.93 (m, 1H), 3.93-3.87 (m, 1H) , 3.78 (dd, "/= 13.2, 7.7 Hz, 1H). Example 29: nRV2-((6-"3-Fluoro-4-(trifluoromethane)-methyl 1 pyrimidin-4-yl}amino)-1-phenylethanol tri-ethylene sulfonium salt. 200948790 MS (ESI): Mass spectroscopy for C19H15F4N302, 393.1; m/z </ </ s> </ s> </ RTI> </ RTI> [M+H]+. 4 NMR (CD3OD): 8.64 (s, 1H), 7.88-7.85 (m, 1H), 7.75-7.73 ( m,1H), 7.69-7.65 (m, 1H), 7.44 (d, J= 7.7 Hz, 2H), 7.36 (t, J= 1.1 Hz, 2H), 7.29-7.27 (m, 1H), 7.00 (s , 1H), 4.95-4.92 (m, 1H), 3.93-3.84 (m, 1H), 3.77 (dd, "/= 13.7, 7.7 Hz, 1H). Example 30: (110-2-(丨6- (4-Ethyl-3-fluoromethyl)pyrimidine-4-篡1 face base M-stupyl alcohol trifluoroacetate.

!^氓81): Mass spectrometry calculation &lt;:2()112(^1&lt;[302,353.2; 111/2 experimental value, 354.2 [M+H]+ °]H NMR (CD3OD): 8.60 (s, 1H), 7.63-7.59 (m, 2H), 7.45-7.43 (m, 2H), 7.37-7.34 (m, 2H), 7.33-7.27 (m, 2H), 6.94 (s, 1H), 4.94-4.92 (m, 1H) ), 4.23 (q, J= 7.1

Hz, 2H), 3.93-3.88 (m, 1H), 3.79 (dd, / = 13.7, 8.2 Hz, 1H), 1.47 (t, J = 7.1 Hz, 3H). Example 31: (1RV2-丨丨6-(4-acetamido-3-methylphenyl)pyrimidine-4-yl 1 amino-M-methylethanol trifluoroacetate.

MS (ESI): m.p. NMR (CD3OD): 8.58 (s, 1H), 7.64-7.62 (m, 1H), 7.60 (s, 1H), 7.44-7.43 (m, 2H), 7.37-7.34 (m, 2H), 77 200948790 7.30 - 7.27 (m,1H), 7.11-7.10 (m, 1H), 6.93 (s,1H), 4.94-4.92 (m, 1H), 4.17 (q,J= 7.1 Hz, 2H), 3.91 (άά, / = 13.2, 4.4 Hz, 1H), 3.79 (dd, 13.7, 7.7 Hz, 1H), 2.30 (s, 3H), 1.46 (t, /= 7.1 Hz, 3H). Example 32: (lR)-2-(丨6-丨4-(瑗propylmethyl) is a certain pyrimido-4-yl}amino)-1-phenylethanol trifluoroacetate.

❹ MS (ESI) · mass s § ten nose C22H23N3 〇 2, 361.2 ; m/z experimental value, 362.2 [M+H]+° !H NMR (CD3OD): 8.58 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.37-7.34 (m, 2H), 7.30 -7.26 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), " 4.94-4.92 (m, 1H), 3.95 (ά, J = 7.1 Hz, 2H), 3.91-3.87 (m, 1H), 3.80-3.76 (m, 1H), 1.32-1.26 (m, 1H), 0.67-0.63 (m, 2H), 0.40-0.37 (m, 2H). 'Pour 13 : (1R)·2-丨『6-(4-butoxy) 4_ its 18 &amp; ❹ }}-1- stupyl alcohol trifluoroacetate.

MS (ESI): m.p. ]H NMR (CD3OD): 8.59 (s, 1H), 7 63 7 % (m, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.37-7.34 (m, 2H), 7.31 (t J - 8.8 Hz, 1H), 7.29-7.28 (m, 1H), 6.93 (s, 1H), 4.94-4 92 78 200948790 (m, 1H), 4.17 (t, J = 6.6 Hz, 2H), 3.94-3.86 ( m, 1H), 3.78 (dd, 13.7, 7.7 Hz, 1H), 1.86-1.81 (m, 2H), 1.54 (six-wire, "/= 7·7 Hz, 2H), 1.01 (t, */= 7.7 Hz, 3H). Example 34: (110-2-indole "6-(4-butanyl)pyrimidin-4-yl 1 amine M-phenyl alcohol trifluoroacetate.

MS (ESI): mass calcd for C22H25N302, 363.2; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 7.45 (d, 7.7 Hz, 2H), 7.37-7.34 (m, 2H), 1.29-1.21 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 4.94- 4.92 (m, 1H), 4.10 (t, J= 6.6 Hz, 2H), 3.95-3.88 (m, 1H), 3.80-3.76 (m, 1H), 1.83-1.78 (m, 2H), 1.54 (six-weight Line, J = 7.7 Hz, 2H), 1.00 (t, /= 7.7 Hz, 3H). Example 35 · (lR)-2-{random-4-propoxyphenyl) benzoate 0--4-yl 1 amine M-phenylethanol trifluoroacetate.

MS (ESI): mass calcd for C21.21.21. WNMRCCDsOD): 8.61 (s, 1H), 7.63-7.59 (m, 2H), 7.45-7.43 (m, 2H), 7.37-7.26 (m, 4H), 6.94 (m, 1H), 4.94-4.92 (m, 1H), 4.13 (t, / = 6.6 Hz, 2H), 3.93-3.90 (m, 1H), 3.82-3.77 (m, 1H), 1.87 (six-wire, •/= 7.1 Hz, 2H), 79 200948790 1.08 (t, "/= 7.1 Hz, 3H). Example 36: (lR)-2-({6-"3·fluoro-4-(1-methylethoxy)phenyl 1 〇 喷 _4 yl}amino)-1-phenylethanol Trifluoroacetamidine

MS (ESI). Mass spectrum δ calc. C21. H22. NMR (CD3OD): 8.60 (s, 1H), 7.63-7.58 (m, 2H), 7.45-7.43 (m, 2H), 7.37-7.27 (m, 4H), 6.93 (s, 1H), 4.94-4.92 ( m, 1H), 4.81-4.74 (m, 1H), 3.94-3.88 (m, 1H), 3.81-3.77 (m, 1H), 1.39 (d' ό.Ο Hz, 0H). ,, _ Example 37: (lR)-2-({6-『4-(2-methylpropenyl)-pyridylpyrimidine_4_篡} Amino)-1-phenylethanol triterpenoid Acetic acid turns.

MS (ESI). mass spectrometer iso C22H25N3 〇 2, 363.2 ; m/z calc., 364.2 [M+H] + 〇]H NMR (CD3OD): 8.60 (s, iH), 7.74 (d, J = 8.8 Hz , 2H), 7.43 (d, 7.7 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.30-7.27 (m, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6 94 ( s 1H), 4.93 (dd, J — 8.2, 4.4 Hz, 1H), 3.94-3.90 (m, 1H), 3.86 (d, J= 6.6 Hz, 2H), 3·80 (dd, J= 13.7, 7 • 7 Hz, 1H), 2.11 (seventh line ' — 6.6 Hz, 1H), 1.05 (d, */ = 7.1 Hz, όΗ). 200948790 Aminopyrene-1-methylethanol ethanol trifluoroacetate.

MS (ESI): mass calcd for C20H21N3O2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 1H), 7.60-7.59 (m, 1H), 7.44 (d, 7.7 Hz,

2H), 7.36 (t, J= 7.1 Hz, 2H), 7.30-7.27 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 4.94-4.92 (m, 1H) ), 3.94 (s, 3H), 3.94-3.90 (m, 1H), 3.79 (dd, 13.7, 7.7 Hz, 1H), 2.29 (s, 3H). Example 39: Πΐ〇-2-Π6-[3-chloro-4-methylphenyl)pyrimidin-4-yl 1 amine M-jasmethanol trifluoroacetate.

MS (ESI): mass spectroscopy (: 1911) 8 &lt;: 30, 339.1; 111^ experimental value, 340.1 [M+H]+ NMR (CD3OD): 8.62 (s, 1H), 7.85-7.84 (m, 1H) , 7.63 (dd, J= 8.2, 1.7 Hz, 1H), 7.54 (d, 8.2 Hz, 1H), 7.44 (d, 7.1 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.98 (s, 1H), 4.95-4.92 (m, 1H), 3.94-3.89 (m, 1H), 3.80 (dd, 13.7, 7.7 Hz, 1H), 2.48 (s, 3H). 40 ·· nR)-2-{『6-(3,5-dimercapto- pheno-V-spray-4-yl l-fat-based M-jamone ethanol trifluoroacetate. 200948790

MS (ESI): m.p. bNMR (CD3OD): 8.61 (s, 1H), 7.45-7.43 (m, 2H), 7.39 (s, 2H), 7.38-7.33 (m, 3H), 7.30-7.27 (m, 1H), 6.96 (s, 1H), 4.95-4.93 (m, 1H), 3.94-3.91 (m, 1H), 3.80 (dd, «/= 13.2, 7.7 Hz, 1H), 2.42 (s, 6H). Example 41: (lR)-2-({6-"3-Fluoro-4-(tris-methyl)phenyl 1 pyrimidin-4-yl} oxime amino)-1-methylethanol ethanol trifluoroacetate.

MS (ESI): mass calcd for C19H15F4N30, 377.1; ^NMRCCDsOD): 8.63 (s,1H), 7.93-7.90 (m, 1H), 7.86-7.81 (m, 2H), 7.45-7.44 (m, 2H), 7.37-7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.04 (s, 1H), 4.95-4.92 (m, 1H), 3.90-3.83 (m, 1H), 3.78-3.73 (m, 1H). Example 42. (1 ft ') -2- ({6-"3- 乱-5-(dimethylmethyl) stupyl~|Bite-4-yl~{. Amino)-1-Methoxy Ethanol trifluoroacetate.

MS (ESI): m.p. 4 NMR (CD3OD): 8.64 (s, 1H), 8.01 (s, 82 200948790 1H), 7.93-7.91 (m, 1H), 7.76-7.74 (m, 1H), 7.44 (d, J = 7.1 Hz, 2H ), 7.36 (t, J = 7.7 Hz, 2H), 7.29-7.26 (m, 1H), 7.04 (s, 1H), 4.95-4.93 (m, 1H), 3.92-3.84 (m, 1H), 3.77 ( Dd, / = 13.7, 7.7 Hz, 1H). Example 43: gRV2-H6-(3-Gu.-5-indolyl)pyrimidin-4-yl 1amino}-h stupylethanol trifluoroacetate.

MS (ESI): mass calcd for C18H15C1FN30, 343.1; m/z. 4 NMR (CD3OD): 8.63 (s, 1H), 7.72 (s, 1H), 7.59-7.57 (m, 1H), 7.53-7.50 (m, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.37-7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.00 (s, 1H), 4.95-4.92 (m, 1H), 3.93-3.86 (m, 1H), 3.77 (dd, J = 13.7 , 7.7 Hz, 1H).实施 Example 44: (1RV1-Momo-2-pyrene-6-(4-propionylphenyl)pyrimidin-4-indole 1 amide acetonitrile trifluoroacetate.

MS (ESI): m.p. HNMR (CD3OD): 8.58 (s, 1H), 7.76-7.74 (m, 2H), 7.43 (d, 7.1 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.25 (m, 1H), 7.15-7.13 (m, 2H), 6.93 (s, 1H), 4.94-4.92 (m, 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.94-3.86 (m, 83 200948790 1H), 3.80- 3.75 (m, 1H), 1.88-1.81 (m, 2H), 1.07 (t, J = 7.7 Hz, 3H). f Example 45: (1RV2-丨丨6-(2.1,3-Mos oxadiazole _5-V. Cyclopyridin-4-yl 1 Amino M-stupylethanol triterpenoid salt.

MS (ESI): m.p. 4 NMR (CD3OD): 8.70 (s, 1H), 8.49-8, 48 (m, 1H), 8.14 (d, 9.3 Hz, 1H), 7.88 (dd, 9.3 Hz, 1.7

Hz, 1H), 7.45 (d, 7.7 Hz, 2H), 7.36 (t, J= 7.7 Hz, 2H), 7.30-7.27 (m, 1H), 7.13 (s, 1H), 4.97-4.94 (m, 1H) ), 3.96-3.90 (m, 1H), 3.79 (dd, 13.7, 8.2 Hz, 1H). Example 46: ΠΙ〇-2-α6-"3-indolyl-4-indole-methyl ethane (a) methyl 1 pyrimidine -4-ylindolyl)-1-phenylidene.

MS (ESI): mass calcd for C22H25N302, 363.2; 4 NMR (CD3OD): 8.40 (s, 1H), 7.70-7.69 (m, 2H), 7.42 (ά, J = 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 7.27-7.24 (m, 1H) ), 6.98 (d, J= 9.3 Hz, 1H), 6.80 (s, 1H), 4.91-4.88 (m, 1H), 4.68 (seventh line, 6.0 Hz, 1H), 3.74-3.68 (m, 1H), 3.57 (dd, 13.7, 7.7 Hz, 1H), 2.24 (s, 3H), 1.35 (d, J=6.0Hz, 6H). 200948790 Example 47: (lRV2-({6-"3-Ga-4-(trifluoromethyl)phenyl)1-5-fluorenylpyridin-4-ylindolyl)-1-phenylethyl Yeast two gas acetate.

MS (ESI): mass calcd for C20H17ClF3N3O, 407.1; m.咕NMR (CD3OD): 8.66 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.49 ◎ (d, J = 7.7 Hz, 2H), 7.37 (t, J = 1.1 Hz, 2H), 7.31-7.28 (m, 1H), 5.02 (dd, /= 7.7, 4.9 Hz, 1H), 3.97-3.88 (m, 2H) , 2.09 (s, 3H). - Example 48: Indole-2-({6-Γ3-fluoro-4-(trifluoromethyl)phenyl)1-5-decylpyrimidine. Aridin-4-ylindolyl VI-stupylethanol III Fluoroacetate.

Q MS (ESI): mass spectroscopy (: 201117 卩 &lt;^3〇, 391.1; 111/2: experimental value, 392.1 [M+H]+. NMR (CD3OD): 8.66 (s, 1H), 7.97 (t , J = 7.7 Hz, 1H), 7.65 (d, /= 10.4 Hz, 1H), 7.56 (d, /- 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 2H), 7.38-7.35 (m , 2H), 7.31-7.28 (m, 1H), 5.03-5.01 (m, 1H), 3.97-3.89 (m, 2H), 2.09 (s, 3H). Example 49: (lR)-2-(( 6-"4-(Difluoromethyl)3,5-difluorophenyl 1 pyrimidine 4-yl]·Yan'anji)-1-phenylethylidene dioxetane salt. 85 200948790

MS (ESI): mass calcd for C19H15F4N302, 393.1; 4 NMR (CD3OD): 8.65 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.37-7.34 (m, 2H), Ί30-1.26 ( m, 1H), 6.99 (t, JH.F = 72.0 Hz, 1H), 7.00 (s, 1H), 4.94-4.91 (m,1H), 3.92-3.85 (m,1H), 3.79-3.74 (m, 1H). Example 50: 2-"4-(6-{"(2R)-2-Phenyl-2-phenylethyl 1amino}^1 dimethyl 4-yl)phenyl 1-2-decylpropane Nitrile trifluoroacetate.

MS (ESI): m.p. 4 NMR (CD3OD): 8.67 (s, 1H), 7.86-7.84 (m, 2H), 7.81-7.79 (m, 2H), 7.43 (d, J = 7.1 Hz, 2H), 7.38-7.34 (m, 2H ), 7.31-7.27 (m, 1H), 7.02 (s, 1H), 4.93 (dd, 7.3, 4.3 Hz, 1H), 3.94 (dd, 13.6, 4.3 Hz, 1H), 3.80 (dd, «/= 13.9 , 7.8 Hz, 1H), 1.78 (s, 6H). Example 51: 1-Indole 2-fluoro-4-(6-U(2RV2-hydroxy-2-methylethyl 1amino)pyrimidin-4-yl)phenyl 1 ethyl ketone trifluoroacetate.

MS (ESI): mass spectroscopy (:20111 疋)^3〇2, 351.1; 111/2 experimental value, 86 200948790 352.2 [M+H]+. 々NMR (CD3OD): 8.69 (s, 1H), 8.07-8.04 ( m,1H), 7.76-7.73 (m, 1H), 7.72-7.71 (m,1H), 7.44 (d, J = 7.2 Hz, 2H), 7.36 (t, 7.2 Hz, 2H), 7.30-7.28 (m , 1H), 7.06 (s, 1H), 4.95-4.93 (m, 1H), 3.92 (dd, J= 13.5, 3.6 Hz, 1H), 3.79 (dd, y = 13.8, 7.9 Hz, 1H), 2.67 ( d, 4.3 Hz, 3H). Example 52: (lR)-2-({6-"3,5-Dimethyl-4-indole-methylethenyl)methyl 1 pyridin-4-ylindole Amino)-1-phenylethanol trifluoroacetate.

MS (ESI): mass calcd for C23H27N302, 377.2; m/z, &quot; 378.2 [M+H]+. 4 NMR (CD3OD): 8.60 (s, 1H), 7.48 (s, 2H), 7.43 (d, 7.2 Hz, 2H), 7.37-7.35 (m, 2H), 7.30-7.27 (m, 1H), 6.93 ( s, 1H), 4.94-4.92 (m,1H), 4·37 (seven lines, ·/ = 6.3 Hz, 1H), 3.91 (άά, J = 13.5, 4.3 Hz, 1H), 3.78 (dd, J- ❹ 13.8, 8.2 Hz, 1H), 2.36 (s, 6H), 1.31 (d, «/= 6.3 Hz, 6H). Example 53: Indole-2-indole-6-indole-indol-6-yl)pyrimidin-4-yl 1 amine M-stupylethanol trifluoroacetate.

MS (ESI): m.p. iNMR (CD3OD): 8.60 (s, 1H), 7.88 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.50 (d, /= 2.7 Hz, 1H), 87 200948790 7.46-7.44 (m , 2H), 7.43 (dd, J= 8.2, 1.7 Hz, 1H), 7.36 (t, J = 7.7 Hz, 2H), 7.30-7.27 (m, 1H), 7.03 (s, 1H), 6.59 (d, J = 3.3 Hz, 1H), 4.95-4.93 (m, 1H), 3.94-3.91 (m, 1H), 3.82-3.78 (m, 1H). Example 54 · (1R)-1 - stupid-2-("6-(3,4,5-trifluoro)) biting-4-yl 1 amine hydrazine ethanol trifluoroacetate.

MS (ESI): mass calcd for C18H14F3N30, 345.1; HNMR(CD3OD): 8.61 (s,1H), 7.70-7.68 (m, 2H), 7.43 (d, J= 7.7 Hz, 2H), 7.37-7.33 (m, 2H), 7.28-7.26 (m, 1H ), 6.97 (s, 1H), 4.94-4.92 (m, 1H), 3.91-3.83 (m, 1H), 3.77 (dd, 13.7, 7.7 Hz, 1H). Example 55: (lRV2-{"6-(1-Amethyl-1Η-° 哚-2-)pyrimidin-4-yl 1 Amino]•-l-stupylethanol three iL acetate.

MS (ESI): mass calcd for C21.::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: , 7.54 (d, 8.2 Hz, 1H), 7.45 (d, "/= 7.1 Hz, 2H), 7.41-7.35 (m, 3H), 7.31-7.28 (m, 1H), 7.20-7.17 (m, 1H) , 7.09 (s, 1H), 6.96 (s, 1H), 4.96-4.90 (m, 1H), 3.98-3.88 88 200948790 (m,1H), 3.91 (s,3H),3.83-3.77 (m,1H) . Example 56: (lRV2-i丨6-(5-methyl-1_mol #thiophen-2-yl)pyrimidine-4-yl 1 amine}_1-stupylethanol.

MS (ESI): mass calcd for C21.21.21. 4 NMR (CD3OD): 8.39 (s, 1H), 7.92 (s, 1H), 7.75 (d, 8.2 Hz, 1H), 7.66 (s, 1H), 7.43 (d, J= 7.1

Hz, 2H), 7.35 (t, J= 7.7 Hz, 2H), 7.27-7.23 (m, 2H), 6.94 (s, 1H), 4.92-4.89 (m, 1H), 3.76-3.71 (m, 1H) , 3.59 (dd, J = 13.7, 7.7 Hz, 1H), 2.46 (s, 3H). Example 57: f4-(6-丨丨(2RV2-hydroxy-2-methylethylamine A certain pyrimidin-4-yl) phenyl) ketone trifluoroacetate.

MS (ESI): mass calcd for C25H21N302, 395.2; NMR (CD3OD): 8.69 (s, 1H), 7.98-7.94 (m, 4H), 7.82-7.81 (m, 2H), 7.71-7.68 (m, 1H), 7.57 (t, J = 7.7 Hz, 2H) , 7.44 (d, 7- 7.1 Hz, 2H), 7.36 (t5 7.1 Hz, 2H), 7.30-7.27 (m, 1H), 7.08 (s, 1H), 4.96-4.94 (m, 1H), 3.96G. 90 (m, 1H), 3.82 (dd, ·/= 13.7, 8.2 Hz, 1H). 89 200948790 Example 58: (11〇-2-丨 "6-(3.5-di I. yl) pyrimidin-4-yl 1 amine M-phenylethanol trifluoroacetate.

MS (ESI): m.p. 4 NMR (CD3OD): 8.64 (s, 1H), 7.49-7.43 (m, 4H), 7.37-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.00 (s, 1H), 4.95-4.92 (m, 1H), 3.93-3.85 (m, 1H), 3.78 (dd, 13.7, 7.7 Hz, 1H). Example 59: (lR)-2-U6-(3,4-difluorobenzoquinone)pyrimidin-4-yl i-amino-p-propylethanol trifluoroacetate.

MS (ESI): m.p. A NMR (CD3OD): 8.64 (s, 1H), 7.82-7.78 (m, 1H), 7.67-7.63 (m, 1H), 7.56-7.51 (m, 1H), 7.43 (d, , / = 7.7 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.24 (m, 1H), 6.97 (s, 1H), 4.95-4.92 (m, 1H), 3.94-3.87 (m, 1H), 3.78 (dd, J — 13.7, 7.7 Hz, 1H). It is advisable to apply the formula 6: (11〇-2-({令二丨3-氡-4-(毛一甲)) 基1_2_(甲甲硫烧基)啸咬-4-基丨胺))- 1-stupyl alcohol two gas △ acid pound 200948790

MS (ESI): mass calcd for C20H17C1F3N3OS, 439.1; m. 4 NMR (CD3OD): 8.09 (s, 1H), 7.95 (d, 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.37-7.33 (m, 2H), 7.29-7.25 (m, 1H), 6.69 (s, 1H), 4.96-4.93 (m, 1H), 3.91-3.85 (m, 1H), 3.78-3.73 (m, 1H), 2.65 (s, 3H). Example 61: (110-2-(丨2-amino-6-indole-3-chloro-4-(trifluoromethyl)methyl 1 pyridin-4-yl]-amino)-1-benzene Ethyl alcohol

MS (ESI): mass calcd for C19H16 C1F3N40, 408.1; m. HNMR (CD3OD): 8.00-7.98 (m, 2H), 7.83-7.80 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.26 (m, 1H) , 6.44 (s, 1H), 4.92-4.89 (m, 1H), 3.84 (dd, 13.6, 4.5 Hz, 1H), 3.65 (dd, 13.6, 8.3 Hz, 1H). Example 62: at〇-2-({6-"3-Gas-4-(trifluoromethyl)phenyl 1 pyridin-4-yl} genomic phenyl)ethanol

MS (ESI): mass calcd for C19H14C1F4N30, 411.1; m/z. ^NMRCCDsOD): 8.50 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.88 (d, 8.1 Hz, 1H), 7.47-7.43 (m, 2H), 7.09 -7.04 (m, 2H), 6.97 (s, 1H), 4.92-4.89 (m, 1H), 3.76-3.70 (m, 1H), 3.63-3.57 (m, 1H). Example 63: (lR)-2-{"6-(6-Methylpyridin-3-yl-V-pyridine-4-yl 1 amine M-phenylethanol).

MS (ESI): m/z.咕NMR (CD3OD): 8.90-8.83 (m, 1H), 8.62 (s, 1H), 8.35 (dd, 2.5, 8.7 Hz, 1H), 7.65-7.57 (m, 2H), 7.55-7.49 (m, 2H ), 7.46-7.40 (m, 1H), 7.09-6.99 (m, 2H), 5.10-5.05 (m, 1H), 4.15 (s, 3H), 3.96-3.85 (m, 1H), 3.76 (dd, * /= 7.7, 13.7 Hz, 1H). Example 64: nRV2-(f6-(6-Ethylpyridin-3-yl)pyrimidin-4-yl 1 amine M-phenylethanol.

MS (ESI): mass calcd for C19H2 〇N402, 336.2; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ), 7.93 (dd, 2.5, 8.7 Hz, 1H), 7.23-7.17 (m, 2H), 7.14-7.08 (m, 2H), 7.05-6.99 (m, 1H), 6.64-6.59 (m, 2H), 4.68-4.65 (m, 1H), 4.15 (q, 7.1 Hz, 2H), 3.54-3.43 92 200948790 (m, 1H), 3.35 (dd, J= 7.7, 13.7 Hz, 1H), 1.17 (t, J= 7.1 Hz, 3H). Column 65: (lR)-2-a6-"4-(dimethylamine) jasmonyl 1 pyrimidine-4-yl}amino)-1-phenyl alcohol.

MS (ESI) · mass spectrometer Nasal C20H22N4O, 334.2; m/z, 335.2 [M+H]+ = NMR (CD3OD): 8.38 (s, 1H), 7.83-7.78 (m, 2H), 7.48-7.41 (m, 2H), 7.39-7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.85-6.79 (m, 2H), 6.79-6.76 (m, 1H), 4.95-4.87 (m , 1H), 3.78-3.65 (m, 1H), 3.58 (dd, 13.7, 7.6 Hz, 1H), 3.03 (s, 6H). The actual employment example is $6 (lR)-2-"6-r4-(methyl 醯 ))) 茉 定 ! ! 胺 胺 胺 胺 胺 胺 胺 ! ! ! !.

MS (ESI): mass reading for Ci9H19N3 〇3s, 369.1; m/z, 370.1 [M+H]+ 〇^NMR^OD): g.53 (s, 1H), 8.19-8.12 (m, 2H ), 8.10-8.04 (m, 2H), 7.52-7.39 (m, 2H), 7.39-7.30 (m, 2H), 7.30-7.23 (m, 1H), 7.03-6.95 (m, 1H), 4.98-4.87 (m, 1H), 3.87-3.68 (m, 1H), 3.68-3.58 (m, 1H), 3.18 (s, 3H). 93 200948790 Implementation &gt; Example 67 . lSf-玉莉propyl-4-(6-{|~(21〇-2_light-based-2-benylethyl January) Base) stupid Huang Yunyue.

MS (ESI): m.p. 4 NMR (CD3OD): 8.52 (s, 1H), 8.18-8.03 (m, 2H), 8.02-7.95 (m, 2H), 7.50-7.39 (m, 2H), 7.38-7.33 (m, 2H), 7.31 -7.24 (m, 1H), 7.03-6.93 (m, 1H), 4.97-4.86 (m, 1H), 3.86-3.67 (m, 1H), 3.63 (dd, 13.7, 7.7 Hz, 1H), ❹ 2.30- 2.12 (m, 1H), 0.63-0.41 (m, 4H). Example 68. (lR)-2-{『6-(3-Gas-4-Ethyl-Based-Blocky-4-yl 1-amine M-stupylethanol.

MS (ESI): mass calcd for C2 </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 4 NMR (CD3OD): 8.43 (s, 1H), 7.96 (d, Q 2.2 Hz, 1H), 7.83 (dd, 8.7, 2.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.38- 7.32 (m, 2H), 7.30-7.25 (m, 1H), 7.15 (d, J= 8.7 Hz, 1H), 6.83 (s, 1H), 4.96-4.86 (m, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.79-3.66 (m, 1H), 3.60 (dd, 13.8, 7.7 Hz, 1H), 1.47 (t, «/= 7.0 Hz, 3H). Example 69. (lR)-2-(~C-Arachidin-4-yl-4,5'-linked^^-6-yl)amine 1-1-phenylethanol. 94 200948790

MS (ESI): mass calcd for C2 〇H22N602, 378.2; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ), 7.51-7.38 (m, 2H), 7.38-7.32 (m, 2H), 7.30-7.24 (m, 1H), 6.86-6.75 (m, 1H), 4.90 (dd, J= 7.6, 4.7 Hz, 1H ), 3.95-3.83 (m, 4H), 3.79-3.73 (m, 4H), 3.74-3.69 (m, 1H), 3.60 (dd, */= 13.8, 7.7 Hz, 1H). Example 70: Πί〇-2-("6-(6-morpholin-4-ylpyridin-3-yl)pyrimidin-4-yl 1aminopurine-phenylethanol.

MS (ESI): m.p. 4 NMR (CD3OD): 8.74-8.64 (m, 1H), 8.42 ❹ (s, 1H), 8.09 (dd, 9.0, 2.5 Hz, 1H), 7.50-7.39 (m, 2H), 7.38-7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.93-6.85 (m, 1H), 6.83-6.80 (m, 1H), 4.94-4.87 (m, 1H), 3.86-3.76 (m, 4H), 3.76- 3.68 (m, 1H), 3.64-3.56 (m, 5H). Example 71: ΠΙ〇-2-·ί『6-(3-氤-4-Methane-based phenyl)pyrimidin-4-yl-1amino-M-phenylethanol. 200948790 MS (ESI): Mass spectrometry C19H18FN302 , 339.1; m/z experimental value, 340.2 [M+H]+. iHNMRCCDgOD): 8.33 (s,1H), 7.65-7.52 (m, 2H), 7.37-7.29 (m, 2H), 7.27-7.22 (m, 2H), 7.19-7.13 (m, 1H), 7.13-7.06 ( m, 1H), 6.73 (s,1H), 4.83-4.78 (m, 1H), 3.84 (s, 3H), 3.69-3.55 (m, 1H), 3.48 (dd, 7 = 13.8, 7.7 Hz, 1H) . Example 72: (110-2-丨 "6_(2,3-dihydro-1,4-benzodioxin-6-yl)pyrimidine _4_yl 1amino)-1-phenylethanol.

MS (ESI): mass spectroscopy (::::::::::::::::,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ), 7.42-7.37 (m, 1H), 7.37-7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.97-6.86 (m, 1H), 6.82-6.78 (m, 1H), 4.95-4.85 (m, 1H), 4.34-4.22 (m, 4H), 3.79-3.63 (m, 1H), 3.63-3.54 (m, 1H). f Example 73: (110-2-((6-丨3-Gao-4-(trifluoromethyl)phenyl)1-2-methylpyrimidin-4-ylindenyl)-1-phenylethanol .

]^8氓81): Mass spectrometry calculation (:20:«17&lt;:1?3:^3〇, 407.1; 111/2 experimental value, 408.1 [M+H]+. NMR (CD3OD): 8.15 (s, 1H), 8.00-7.94 (m, 1H), 7.89-7.85 (m, 1H), 7.48-7.39 (m, 2H), 96 200948790 7.39-7.32 (m, 2H), 7.29-7.24 (m, 1H), 6.81-6.70 (m, 1H), 4.97-4.85 (m, 1H), 3.87-3.67 (m, 1H), 3.66-3.58 (m, 1H), 2.52 (s, 3H). Example 74: benzyl- 1H-pyrazole-4_yl)pyrimidin-4-yl 1 Aminoguanidine-stupylethanol.

❹ MS (ESI): mass calcd for C22H21. NMR (CD3OD): 8.34 (s, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.45-7.41 (m, 2H), 7.40-7.22 (m, 8H), 6.68 (s, 1H) , 5.39 (s, 2H), 4.93-4.84 (m, 1H), 3.77-3.61 (m, 1H), 3.62-3.52 (m, 1H). Example 75. (1 R)-2-Ga-5-fluorenyl g ratio -3--3-hydrazin-4-yl 1

MS (ESI) · mass spectrometric calculation C18H17FN40, 324.1; m/z, 325·2 [M+H]+. 4 NMR (CD3OD): 8.48 (s, 1H), 8.12 (s, 1H), 7.50-7.39 (m, 2H), 7.38-7.32 (m, 2H), 7.30-7.24 (m, 1H), 7.07-7.01 (m, 1H), 6.60 (s, 1H), 5.04-4.84 (m, 1H), 3.86-3.67 (m, 1H), 3.67-3.56 (m, 1H), 2.43 (s, 3H). Example 76: 4-(6-U(2R)-2-hydroxy-2-phenylethyl 1 -aminopyrimidin-4-97 200948790 s)-N,N-dimethyl jasmonamine.

MS (ESI): mass calcd for C20H22N4O3S, 398.1; NMR (CD3OD): 8.57-8.46 (m,1H), 8.19-8.11 (m, 2H), 7.93-7.88 (m, 2H), 7.49-7.42 (m, 2H), 7.39-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.03-6.94 (m, 1H), 5.00-4.84 (m, 1H), 3.84-3.68 (m, 1H), 3.67-3.57 (m, 1H), 2.82-2.61 (m , 6H). Example 77: 5-(6-(丨(2RV2-hydroxy-2-malylethyl 1aminopyrimidinium)-pyridin-2-indene.

MS (ESI): m.p. 4 NMR (CD3OD): 9.32-9.12 (m, 1H), 8.60-8.43 (m, 2H), 8.04-7.93 (m, 1H), 7.49-7.41 (m, 2H), 7.39_7.33 (m, 2H ), 7.30-7.25 (m, 1H), 7.08-7.00 (m, ih), 5.00-4.84 (m, 1H), 3.86-3.68 (m, 1H), 3.68-3.58 (m, 1H). Example 78. (lR)-2-({6-"6-(Dimethylamino)0 to 0 -3--3-1 1 〇^_4 yl}amino)-1-phenylethanol. 200948790 MS (ESI)························ NMR (CD3OD): 8.78-8.67 (m,1Η), 8.52-8.46 (m, 1H), 8.14 (dd, J= 9.1, 2.5 Hz, 1H), 7.58-7.49 (m, 2H), 7.48-7.41 ( m, 2H), 7.40-7.33 (m, 1H), 6.94-6.77 (m, 2H), 4.94-4.86 (m, 1H), 3.92-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.25 (s, 6H). Example 79: Stupid-2-((6-"4-(piperidin-1-one sulfonate) V 篡1 pyrimidin-4-ylguanidino)ethanol.

MS (ESI): mass calcd for C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 7.85 (m, 2H), 7.48-7.41 (m, 2H), 7.39-7.33 (m, 2H), 7.30-7.23 (m, 1H), 7.02-6.93 (m, 1H), 5.04-4.87 (m, 1H) ), 3.87-3.66 (m, 1H), 3.66-3.59 (m, 1H), 3.10-2.96 ❹ (m, 4H), 1.72-1.53 (m, 4H), 1.53-1.40 (m, 2H). Example 80: (1R)-1-indolyl-2-((6-"4-(° ratio p bit-1-yl group, phenyl 1 pyridin-4-ylguanidino) .

MS (ESI): m.p. 4 NMR (CD3OD): 8,57-8.45 (m,1H), 8.19-8.07 (m, 2H), 7.98-7.91 (m, 2H), 7.49-7.39 (m, 2H), 99 200948790 7.39-7.32 ( m, 2H), 7.30-7.24 (m, 1H), 7.04-6.90 (m, 1H), 5.01-4.85 (m, 1H), 3.87-3.69 (m, 1H), 3.67-3.59 (m, 1H), 3.28-3.19 (m, 4H), 1.9M.61 (m, 4H). _ Example 81: 4-(6-(丨(2RV2-鼗 phenylethyl 1amine)} azulsulfonyl-4-yl) molybdenum amine.

MS (ESI): mass calcd for C18H18N4O3S, 370.1; bNMR^CDsOD): 8.33 (s, 1H), 7.93-7.86 (m, 2H), 7.85-7.82 (m, 2H), 7.32-7.22 (m, 2H), 7.22-7.14 (m, 2H), 7.13- 7.07 (m, 1H), 6.84-6.75 (m, 1H), 4.88-4.67 (m, 1H), 3.66-3.49 (m, 1H), 3.49-3.40 (m, 1H). Example 82. Qi policy a) mouth bite 4-yl 1 amino hydrazine-1-phenyl alcohol trifluoroacetate.

MS (ESI): mass calcd for C18H16FN30, 309.1; hNMR ((CD3)2CO): 8.89 (br hum, 4 H), 8.06 (br s, 2H), 7.49 (d, J = 7.0 Hz, 2H), 7.37-7.34 (m, 4H), 7.30-7.26 ( m, 2H), 5.05 (br s, 1H), 3.98 (br s, 1H), 3.75 (br s, 1H) 〇 Example 83: ΠΙΟ-2-丨丨6-(3-nitro-4-stupid a) pyridin-4-one 1 amino group M- 200948790 stupid ethanol trifluoroacetate.

MS (ESI): mass calcd for C18H15C1FN30, 343.1; m/z. iHNMRCCCD^CO) : 10.06 (br hum, 2H), 9.20-8.6 (br m, 2H), 8.13-7.98 (m, 2H), 7.51-7.47 (m, 2H), 7.36-7.33 (m, 2H), 7.28-7.25 (m,1H), 5.04 (br s, 1H), 3.96 (br s,1H), 3.73 (br s, 1H). Example 84: (lR)-2-((6-丨3-(methylsulfanyl)methyl 1 pyrimidin-4-yl}amino)-1-phenylethanol trifluoroacetate.

MS (ESI): m.p. hNMRGCD^CO) : 11.25 (br hum, 2H), 8.88 (s, 1H), 7.71 (s, 1H), 7.59 (br s, 1H), 7.48-7.45 (m, 4H), 7.36-7.32 (m, 3H), 7.27 (t, J = 6.5 Hz, 1H), 5.10-5.00 (br m, 1H), 4.00-3.68 (br m, 2H), 2.55 (s, 3H). Example 85: ni〇-2-H6-nH-indol-5-yl)pyrimidin-4-yl 1 amine M-stupylethanol trifluoroacetate.

MS (ESI): mass spectrometer, C20H18N4O, 330.2; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ), 8.68 (s, 1H), 8.10 (s, 1H), 7.55-7.50 (m, 5H), 7.35 (t, J = 7.0 Hz, 2H), 7.26 (t, J = 7.0 Hz, 1H), 6.56 (s, 1H), 5.10-5.01 (br m, 1H), 3.95-3.92 (m, 1H), 3.70-3.65 (m, 1H). Example 86: (1R)-1-indolyl-2-"(6-啥啦-3- 〇 〇^_4_yl)amino i

MS (ESI): mass calc. 342.2; m/z, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, , 8.26-8.14 (m5 2H), 8.00 (br s, 1H), 7.81 (br s, 1H), 7.57-7.48 (m, 2H), 7.36 (t, 7.5 Hz, 2H), 7.29-7.26 (br t , J = 7.0 Hz, 1H), 5.12-5.07 (br m, 1H), 4.04- 3.81 (brm, 2H). Example 87: (lR)-2-~{T6-(l-stupyl-p-phen-3-yl)p-densole-4-ylamine hydrazine-stupylethanol trifluoroacetate.

Ν Η MS (ESI): mass calc. for C20H17N3OS, 347.1; m/z. 】11Liuji (Yang 3) 2 (:0): 10.13 (br hum, 2H), 9.19 (br s, 1H), 8.81 (br s, 1H), 8.45 (s, 1H), 8.11 (s, 1H ), 8.04- 8.03 (dd, J= 1.5, 7.0 Hz, 1H), 7.51-7.46 (m, 4H), 7.36-7.32 (m, 3H), 7'27 (t, J= 7.0 Hz, 1H), 5.06 (br s,1H), 3.98 (br s,1H), 3.71 (br s,1H). 102 200948790 Example 88: 2-Fluoro-4-(6-([(2RV2-)-yl-2-ethyl-1-aminocarbazin-4-yl) carbonitrile trifluoroacetate.

MS (ESI): m.p. W NMR ((CD3)2CO): 8.34 (br s,1H), 8.03-8.00 (m, 2H), 7.73 (br riding peak, 3H), 7.47 (br s, 2H), 7.34 (t, */= 7.2 Hz, 2H), 7.27 (t, J = 7.8 Hz, 1H), 5·02 (br riding peak, 1H), 3.95-3.68 (brm, 2H). Example 89: 2-Fluoro-5-(6-claw 21〇-2-鼗-2-phenylethyl 1amino}pyrimidin-4-yl)mosanonitrile trifluoroacetate.

MS (ESI): m.p. ΗΝΜΙΙ((€ϋ3)2(:0) : 8.83 (br humm, 1H), 8.55-8.35 (br m, 3H), 7.76 (bm% » 2H), 7.62 (t, J= 9.0 Hz, 1H) , 7.47 (br s, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 5.02 (br hum, 1H), 3.95-3.68 (br m, 2H) Example 90: nRV2-(r6-n-methyl-1H-indol-5-yl)pyrimidin-4-yl 1 aminoguanidine-jasmonethanol trifluoroacetate.

MS (ESI): mass calc. calc. for C.sup..sup.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 1H), 8.04 (s, 1H), 7.54-7.44 (m, 4H), 7.36-7.33 (m, 4H), ' 7.27 (t, J- 7.2 Hz, 1H), 7.14 (s, 1H), 6.52 ( s, 1H), 5.10-4.99 (m, 1H), 3.92-3.61 (br m, 2H), 3.81 (s, 3H). It should be applied. Example M: _(1 R)_2-"(6_ {4-丨(1 -methylethyl)sulfane) ^^u}uu-4-yl)amine 1-1-stupyl ethanol Trigastric acid _ .

MS (ESI): mass calcd for C, s,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 7.80 (br d, J = 8.4 Hz, 2H), 7.47-7.41 (m, 4H), 7.33 (t, J = 7.8 Hz, 2H), 7.26 (br s, 2H), 5.09-5.02 (br m, 1H), 3.97-3.62 (br m, 3H), 1.32 (d, 6.6 Hz, 6H). Example 92: [4-(6-丨[(2RV2-hydroxy-2-pyanoethyl 1aminopyrimidin-4-yl)] phenyl 1 acetonitrile triterpenoid.

MS (ESI): m.p. hNMRCCCD^CO) : 9.30 (s, 1H), 8.88 (s, 1H), 7.92 (d, 8.6 Hz, 2H), 7.79 (br hum, 1H), 7.58 (d, «/ = 7.8 Hz, 2H), 7.49-7.46 (m, 2H), 7.35-7.25 (m, 4H), 5.10-5.02 (br m, 1H), 4.08 (s, 2H), 3.98-3.69 (m, 2H). 104 200948790 Example 93: ΠΙ〇-2-({6-『3-氦-4-(trifluoromethyl)phenyl1-2-(trifluoromethyl)

N person N

A pyrimidin-4-ylguanidino)-1-phenylethanol trifluoroacetate. cf3

N

H OH

MS (ESI): m.p. iHNMRCCCDACO) : 8.38-8.19 (brm, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.49-7.45 (m, 3H), 7.35 (t, J = 7.8 Hz, 2H), 7.26 (t, 7.2 Hz, 1H), 5.00 (br s, 1H), 3.97-3.54 (brm, 2H). Example 94: nRV2J "6-(3,4-dioxanyl)-2-mercaptopyrimidin-4-yl 1 amine .. base M-phenylethanol.

. CI

CI MS (ESI): mass spectroscopy for C19H17C12N30, 373.1; m/z </ RTI> </ RTI> value, 374.1 [M+H]+. 4 NMR (CD3OD): 8.06 (d, / = 2.1 Hz, 1H), 7.79 (dd, J=2.1, 8.4 Hz, 1H), 7.61 (d, /=8.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.37-7.30 (m, 2H), 7.28-7.22 (m, 1H), 6.67 (s, 1H), 4.91-4.88 (m, 1H), 3.80-3.67 (m, 1H), 3.59 (dd, J = 7.4, 13.8 Hz, 1H), 2.49 (s, 3H). Example 95: ΠΙ〇-2-{"6_α4-dioxamethyl)-pyrimidin-4-yl 1amino 11-phenylethanol. 105 200948790

MS (ESI): mass calcd for C18H15 C12N30, 359.1; 4 NMR (CD3OD): 8.46 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.1, 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H) , 7.45-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.28-7.23 (m, 1H), 6.90 (s, 1H), 4.92-4.88 (m, 1H), 3.80-3.67 (m, 1H), 3.59 (dd, J = 7.7, 13.7 Hz, 1H). Example 96. (lR)-2-(丨6-丨4-(ethylthioalkyl) phenyl 10 butyl-4-yl}amine Vi-phenyl alcohol.

MS (ESI): mass calcd for C20H21N3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -7.42 (m, 2H), 7.39 {&amp;, J = 8.8 Hz, 2H), Ί35-132 (m, 2H), 7.27-7.24 (m, 1H), 6.86 (s, 1H), 4.89 (dd, 7.7, 4.4 Hz, 1H), 3.75-3.69 (m, 1H), 3.58 (dd, 13.7, 7.7 Hz, 1H), 3.02 (q, /= 7.1 Hz, 2H), 1.33 (t, 7.1 Hz, 3H) . Example 97: Πί〇-2-·ί "6-(3-Ethyl-phenyl)pyrimidin-4-yl-1amino-M-phenylethanol. 200948790 MS (ESI): mass spectrometer #C20H21N3O2, 335.2; m/z experimental value, 336.2 [M+H]+. 4 NMR (CD3OD): 8.44 (s, 1H), 7.44_7.41 (m, 4H), 7.38-7.32 (m, 3H), 7.28-7.24 ( m, 1H), 7.01 (ddd, J = 8.1, 2.5, 1.3 Hz, 1H), 6.87 (s, 1H), 4.91-4.89 (m, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.76 -3.68 (m, 1H), 3.61-3.55 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H). Example 98: (1RM-stupyl-2-丨 "6-0-propane group Phenyl)pyrimidin-4-yl 1 amine oxime ethanol.

MS (ESI): m.p. 4 NMR (CD3OD): 8·44 (s, 1H), 7.44-7.41 (m, 4H), 7.38-7.32 (m, 3H), 7.28-7.24 (m, 1H), 7.03-7.00 (m, 1H) , 6.87 (s, 1H), 4.93-4.89 (m, 1H), 4.00 (t, J = 6.6 Hz, 2H), 3.76-3.68 (m, 1H), 3.61-3.55 (m, 1H), 1.87-1.78 (m, 2H), 1.07 (t, 7.3 Hz, 3H). Example 99: ΠΙΟ-2-·[丨6-Π-butanylphenyl)pyrimidin-4-yl 1amino M-stupylethanol.

MS (ESI): m.p. NMR (CD3OD): 8.44 (s, 1H), 7.44-7.40 (m, 4H), 7.38-7.32 (m, 3H), 7.28-7.24 (m, 1H), 7.02 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.87 (s, 1H), 4.91-4.89 (m, 1H), 4.05 107 200948790 (t, 7 = 6.6 Hz, 2H), 3.76-3.68 (m, 1H), 3.61-3.56 (m, 1H), 1.82-1.75 (m, 2H), 1.58-1.49 (m, 2H), 1.00 (t, 7 = 7.6 Hz, 3H). Example 100: nRV2-{丨6-(1- benzothiophen-5-yl)pyrimidin-4-yl 1 amine M-phenylethanol trifluoroacetate.

MS (ESI): mass calcd for C20H17N3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, d, J = 8.2 Hz, 1H), 7.79 (d, 5.5 Hz, 1H), 7.72 (dd, 7=8.2, 1.7 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.46-7.44 ( m, 2H), 7.38-7.35 (m, 2H), 7.30-7.28 (m, 1H), 7.07 (s, 1H), 4.97-4.94 (m, 1H), 3.97-3.91 (m, 1H), 3.82 ( Dd, 13.7, 7.7 Hz, 1H). Example 101: ΠΙ〇_2-[(6-"3-nitro-4·(三氤甲)) 1-2-[dimethylamino guanidine-4-ylguanidino)- 1-styl-ethyl yeast three-gas acetate.

1^8氓81): Mass spectrometry calculation: (211120 €1卩31^4〇, 436.1; 111/2 experimental value, 437.1 [M+Hn+^HNMRCCDsOD): 8.01 (s,1H), 7.95 (d, J= 8.2 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.43-7.41 (m, 2H), 7.36-7.33 (m, 2H), 7.29-7.26 (m, 1H), 6.32 (s, 1H) ), 4.94-4.93 (m, 1H), 3.85-3.81 (m, 1H), 3.71 (dd, 13.7, 7.7 200948790

Hz, 1H), 3.28 (s, 6H). Example 102: (lI〇-2-({6-"3-fluoro-4-(trifluoromethyl)methyl 1-2-(methylsulfenyl)pyrimidin-4-ylindenylamine VI - Stupid ethanol trifluoroacetate.

MS (ESI): mass calcd for C20H17F4N3OS, 423.1; m. bNMR (CD3〇D): 7.86-7.83 (m,3H), 7.43-7.42 (m, 2H), 7.36-7.33 (m, 2H), 7.28-7.25 (m, 1H), 6.68 (s, 1H), 4.95-4.92 (m, 1H), 3.87-3.78 (m, 1H), 3.73-3.69 (m, 1H), 2.62 (s, 3H). The compounds of Examples 10 to 10 4 were prepared in a similar manner to that described in Example 20, substituting the appropriate three tillages in Step A and substituting the appropriate acid in Step B. Example 103: (1RV1-methyltrifluoromethylhydrazine tritricin-2-ylindolyl)ethanol trifluoroacetate.

MS (ESI): mass calcd for EtOAc (m.). 4 NMR (CD3OD, TFA salt): 8.54 - 8.53 (m, 2H), 7.83-7.79 (m, 2H), 7.49-7.43 (m, 2H), 7.36-7.21 (m, 3H), 4.97-4.95 (m , 1H), 3.88-3.60 (m, 2H). 109 200948790 Implementation inverted 1〇_4”11尺)-2_({4-『3-气_4_-(Trifluoromethyl hydrazine 篡1_1.3.5-Trip well-2-yl guanylamino)-1- Stupid ethanol trifluoroethylene brewing,

MS (ESI): mass calcd for C18H14C1F3N40, 394.8; b NMR (CD3〇D, TFA salt): 8.53 (m, 1H), 8.44-8.41 (m, 1H), 7.93-7.90 (dd, J = 8.4, 12.0 Hz, 1H), 7.44 (t, 7 = 9.0 Hz, 2H), 7.36-7.20 (m, 3H), 4.96-4.94 (m, 1H), 3.87-3.62 (m, 2H). Example 105: Stupid-2-({6-Γ3-ΓTrifluoromethane)芏1 pyrimidin-4-yl}amino)ethanol.

The title compound was also prepared in a similar manner to that of Example 1 and the </ RTI> </ RTI> </ RTI> </ RTI> was modified as follows: 2-[(6-a) , 0.25 mmol), 3s fluoromethylphenyl face gman (71.2 mg, 0.38 mmol) &gt; K3PO4 (106.1 mg, 0.5 mmol) &gt; Pd(OAc)2 (8.4 mg, 0.013 mmol) and 1,1 '-Bis(di-tert-butylphosphino)-ferrocene (5.9 mg, 0.013 mmol). The flask was then evacuated, backfilled with N2 and charged with 1,4-dioxane (2.5 mL). The reaction mixture was heated with EtOAc EtOAc (EtOAc)EtOAc. The crude residue was purified (EtOAc EtOAc) MS (ESI): mass calcd for C19H16F3N3 s, 359.1; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; = 7.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (t, 7 = 7.8 Hz, 1H), 7.44 (d, J= 7.3 Hz, 2H), 7.37-7.33 (m, 2H ), 7.28-7.24 (m, 1H), 6.96 (s, 1H), 4.93-4.90 (m, 1H), 3.79-3.69 (m, 1H), 3.61 (dd, J = 13.6, 7.8 Hz, 1H). Example 106: Phenyl-2-indole (6-(4-"(trifluoromethyl))-based pyridyl-4-yl)aminoethanol.

Step A. 4-Ga-6-(4-trimethylmethoxy-phenyl)-feeding. 4,6-Dichloropyrimidine (2.18 g, 14.7 mmol) and 4-trifluoromethoxyphenyl_ K3P04 (6.24 g, 29.4 mmol) and Pd(PPh3)4 (0.51 g, 0.44 mmol) were added to a suspension of acid (3.32 g, 16.1 mmol) in DME (72 mL) and water (18 mL). The reaction mixture was heated at 85 ° C under N 2 for 16 h. The reaction mixture was cooled to rt and the organic layer was evaporated, evaporated The residue was purified (FCC) toield Step. Hui B. From 4-chloro-6-(4-trifluorodecyloxy)phenylindole (0.137 g, 0.5 mmol) and (R)-2-amino-1-phenylethanol (75 mg A solution consisting of 0.55 mmol) and one by one (2 mL) was added NaHC〇3 (252 mg, 3.0 mmol) at rt. The reaction mixture was heated under reflux for 18 h. The reaction mixture was cooled to rt and the precipitate was isolated by filtration. The precipitate was purified (FCC) to give a white solid (m. MS (ESI): mass calc. calcd. ^NMRCCDCl): 8.67 111 200948790 (s, 1H), 8.01-7.97 (m, 2H), 7.46-7.21 (m, 7H), 6.70 (s, 1H), 5.38-5.18 (m, 1H), 5.05- 4.95 (m, 1H), 4.00-3.77 (m, 1H), 3.68-3.54 (m, 1H). The compounds of Examples 107 to 130 were synthesized in a manner similar to that described in Example 1 〇6. Substituting the appropriate citric acid and ester in Step A and the amino alcohol in Step B (similar to Intermediate B or C) . Example 107: 1-(4-Nitrophenyl)-2-indole (6-(44(三氤甲)) 11 Benzyl 1 pyrimidin-4-yl)amine 1 ethanol.

^48 (Ugly 81). Mass spectrometer nose (1119^115?3 team 〇4,420.1; 111/2 experiment 421.1 [M+Hr^HNMR (CDC13): 8.71 (s, 1H), 8.32-8.14 (m, 2H ), 8.02-7.98 (m, 2H), 7.66-7.55 (m, 2H), 7.34-7.24 (m, 2H), 6.74 (d, J = 1.1 Hz, 1H), 5.30-4.94 (m, 2H), 4.05-3.89 (m, 1H), 3.74-3.56 (m, 1H). Example 108: 2-丨(6-丨4-丨(trifluoromethyl)yl 1 phenylhydrazine} _4_ base Amino 1-1-"4-(trifluoromethyl) yl 1 ethanol.

MS (ESI): mass calcd for C2 〇H </RTI> 5F6N302, 443.1; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 1.2 Hz, 1H), 5.20 (m, 112 200948790 1H), 5.13-5.04 (m, 1H), 4.03-3.79 (m, 1H), 3.74-3.56 (m, 1H).

Example 109: 1-(4-chloromethane)-2-f(6-(4-"(trifluoromethyl)oxyl芨U

]^氓81): Mass spectrometry calculation: (1911150^3]^3〇2, 409.1; 111/2 experimental ❹ value, 410.1 [M+Hr^HNMRCCDOb): 8.67 (s, 1H), 8.04-7.96 (m, 2H) , 7.35 (s, 4H), 7.31 (d, 7 = 8.0 Hz, 2H), 6.71 (d, J = 1.1 Hz, 1H), 5.25-5.16 (m, 1H), 5.05-4.93 (m, 1H), 4.05-3.78 (m, 1H), 3.68-3.50 (m, 1H). • Example _110: 4-{l-hydroxyl-2-indole (6-{4-indole (trifluoromethyl) gas group 1 jasmine}^ 唆-4-yl)amino 1 ethyl) .

MS (ESI): mass calcd for C19H16F3N303, 391.1; 4 NMR (CDC13): 8.66 (s, 1H), 8.07-7.89 (m, 2H), 7.34-7.27 (m, 4H), 6.91-6.76 (m, 2H), 6.70 (d, J = 1.1 Hz, 1H ), 5.37-5.19 (m, 1H), 5.08-4.85 (m, 2H), 3.90-3.74 (m, 1H), 3.66-3.51 (m, lH). Example 111: l-"4-(Methyl-based) Molybdenum 1-2-indole (6-{4-indole (trifluoromethyl hydrazine, chromophenyl 1 phenylpurine-pyrimidin-4-yl)amino group 1 ethanol. 113 200948790

^^氏81): Mass spectrometry calculation: (20111疋3]^3〇3,405.1; 111/2 experimental value ' 406.2 [M+H]+.咕NMR (CDC13): 8.66 (s,1H),8.03-7.96 ( m, 2H), 7.32 (m, 4H), 6.97-6.83 (m, 2H), 6.69 (d, 1.0

Hz, 1H), 5.43-5.12 (m, 1H), 5.00-4.83 (m, 1H), 3.93-3.73 (m, 4H), 3.66-3.53 (m, 1H). Example 112: 4-Π-hydroxy-2-indole (6-fluorenyl 4-fluorenyl (trifluoromethyl))-yl 1 yl} pyrimido-4-yl)amino 1 ethyl hydrazine-2-(methyl Gas based) phenol.

MS (ESI): mass spectroscopy (:201118?31\[3〇4, 421.1; m/z experimental value, 422.2 [M+Hr^HNMR CCDCh): 8.66 (s, 1H), 8.10-7.85 (m, 2H) , 7.31 (d, 8.2 Hz, 2H), 7.00-6.84 (m, 3H), 6.70 (s, 1H), 5.63 (s, 1H), 5.39-5.17 (m, 1H), 4.99-4.83 (m, 1H) ), 3.90 (s, 3H), 3.87-3.75 (m, 1H), 3.68-3.54 (m, 1H). Example 113: 1-(4-Fluoromethyl)-2-"(6-丨4-fluorenyltrifluoromethyl))yl 1 yl)} p-butyl-4-yl)amino 1 ethanol.

MS (ESI) · MS calcd for C19H15F4N302, 393.1; m/z, mp, 394.1 [M+HfJHNMR CCD Ch): 8.67 (s, 1H), 8.08-7.92 (m, 2H), 7.45-7.35 (m, 2H), 7.33-7.29 (m, 2H), 7.12-7.01 200948790 (m, 2H), 6.78-6.64 (m, 1H), 5.36-5.16 (m, 1H), 5.08-4.91 (m, 1H), 3.95-3.76 ( m, 1H), 3.67-3.52 (m, 1H). f. Example _1_1£.:..}_(3,4-_Dichloromethane V2_IT6-(4_"(trifluoromethyl) 氲1 phenyl hydrazine-hydrazin-4-yl)amine Base 1 ethanol.

MS (ESI): mass calcd for C19H14C12F3N302, 443.0; m/z. NMR (CDC13): 8.68 (s, 1H), 8.09-7.85 (m, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.31 (d, / = 8.0 Hz, 2H), 7.24 (d, 2.0 Hz, 1H), 6.73 (d, J = 1.1 Hz, 1H), 5.22-5.16 (m, 1H), 5.02-4.93 (m, 1H), 3.96-3.83 (m, 1H), 3.66_3.51 (m, 1H). Example 115: 1-(2-Chlorophenyl)-2-indole 6-{4-"(trifluoromethyl) phenoxy] oxapyridin-4-yl)amino 1 ethanol.

^^: Mass spectrometry calculation (: 191115 (: which 3〇2, 409.1; „ 1/2 experimental value, 410.1 [M+H]+JHNMR (CDCl3): 8.68 (s, 1H), 8.09-7.88 (m, 2H) , 7.65 (dd, J = 7.6, 1·7 Hz, 1H), 7.39-7.20 (m, 5H), 6.75 (s, 1H), 5.40-5.34 (m, 1H), 5.33-5.22 (m, 1H) , 3.98-3.84 (m, 1H), 3.77-3.62 (m, 1H).

Example 116: 1-(3-indolyl)-2-"(6-丨4-丨(trifluoromethyl, oxy.an i benzene I 115 200948790 pyrimidin-4-yl)amine 1 ethanol.

MS (ESI): mass calcd for C19H15C1F3N302, 409.1; m. 4 NMR (CDC13): 8.68 (s, 1H), 8.03-7.97 (m, 2H), 7.46-7.40 (m, 1H), 7.34-7.28 (m, 5H), 6.72 (d, J = 1.1 Hz, 1H ), 5.29-5.18 (m, 1H), 5.03-4.92 (m, 1H), 4.02-3.82 (m, 1H), 3.70-3.53 (m, 1H). Example 117: l-"3-(Methyl-based) phenyl 1-2-"(6-{4-"(trifluoromethyl)yl 1 lysylpyrimidin-4-yl)amino 1 ethanol.

MS (ESI): mass spectrometry 405.1; m/z, s.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 6.94 (m, 2H), 6.90-6.80 (m, 1H), 6.70 (d, J = 1.0 Hz, 1H), 5.36-5.17 (m, 1H), 5.04-4.92 (m, 1H), 3.96-3.76 ( m, 4H), 3.70-3.56 (m, 1H). Example 118: l-"2-(indolyl)-l-yl-l-"(6-{4-"(trifluoromethyl)ayl 1 lysylpyrimidin-4-yl)amino 1 ethanol.

MS (ESI): mass spectroscopy, C20H18F3N3O3, 405.13; m/z. 4 NMR (CDC13): 8.67 (s, 1H), 8.09-7.89 116 200948790 (m, 2H), 7.47 (dd, 7.5, 1.4 Hz, 1H), 7.35-7.29 (m, 3H), 7.01-6.98 (m , 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 5.50-5.30 (m, 1H), 5.26-5.18 (m, 1H), 3.97-3.81 (m, 4H), 3.73-3.58 (m, 1H). Example 119: (1R, 2SV 1-phenyl "(trifluoromethyl) gas II group > pyrimidine-4-yl) amine 1 propan-1-ol.

MS (ESI): mass calcd for C20H18F3N3O2, 389.1; m. NMR (CDC13): 8.60 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.38-7.35 (m, 4H), 7.32-7.27 (m, 3H), 6.65 (d, J = 1.0 Hz , 1H), 5.11 (br s, 1H), 4.93 (d, 7=2.8 Hz, 1H), 4.67 (br s, 1H), 4.43 (br s, 1H), 1.13 (d, J= 7.1 Hz, 3H ). Example 120: (lR, 2RV2-r-methyl (6-i4-indole (trifluoromethyl) gas group 1 jamo} pyrimidin-4-yl)amino 1-1-mercaptopropan-1-ol.

MS (ESI): mass calcd for C21. H. NMR (CDC13): 8.70 (s, 1H), 8.05-7.99 (m, 2H), 7.45-7.29 (m, 7H), 6.77 (s, 1H), 4.97-4.81 (m, 1H), 4-78- 4.70 (m, 2H), 2.98 (s, 3H), 1.18 (d, "/= 7.2 Hz, 3H). f Example 121: (lR, 2S)_2-r methyl (6-{4-"trifluoromethyl) gas group 1 Mo Mo} 117 200948790 口密0定-4_基)月安基1· 1 - Stupid propan-1 - alcohol.

MS (ESI): mass spectrometer, C2iH2 〇F3N302, 403.2; m/z. 4 NMR (CDC13): 8.67 (d, 1.0 Hz, 1H), 8.10-7.88 (m, 2H), 7.41-7.27 (m, 7H), 6.70 (d, 1.1

Hz, 1H), 4.99-4.84 (m, 3H), 2.74 (s, 3H), 1.33 (d, J = 7.1 Hz, 3H). Example 122. 1-(2,2-disorder-1,3-stupred 2° pentyl-5-yl)-2-"(6-(4-indole(trifluoromethyl))yl 1 }pyrimidin-4-yl)amino 1 ethanol.

]\48出81): Mass spectrometry calculation 0:20111/5:^3〇4,455.1; 111/2 experimental value, 456.1 [M+Hr^HNMRCCDCh): 8.68 (s, 1H), 8.09-7.91 (m, 2H) , 7.37-7.00 (m, 5H), 6.73 (s, 1H), 5.30-5.18 (m, 1H), 5.06-4.93 (m, 1H), 3.93-3.79 (m, 1H), 3.68-3.48 (m, 1H). Example 123: 1-pyridin-2-yl-2-indole (6-(4-"(trifluoromethyl))yl 1 phenyl] thiophenycyl-4-yl)amino 1 ethanol.

MS (ESI): mass calcd for C18H15F3N402, 376.1; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 2H), 7.75-7.71 (m, 1H), 7.51-7.44 118 200948790 (m, 1H), 7.34-7.20 (m, 3H), 6.70 (d, J = 1.1 Hz, 1H), 5.48-5.37 (m, 1H), 5.04-5.00 (m, 1H), 4.15-3.95 (m, 1H)K 3.80-3.60 (m, 1H). Example 124: 1-Pyridin-3-one_2-"(6-(44(trifluoromethyl))yl)benzoyl-4-yl)amino 1ethanol.

MS (ESI): mass calcd for C18H15F3N402, 376.1; NMR (CDC13): 8.71-8.50 (m, 3H), 8.11-7.91 (m, 2H), 7.82-7.75 (m, 1H), 7.35-7.28 (m, 3H), 6.73 (s, 1H), 5.49- 5.36 (m, 1H), 5.11-5.00 (m, 1H), 3.99-3.85 (m, 1H), 3.73-3.56 (m, 1H). Example 125: 1-pyridin-4-yl-2-ίΤ6-ί4-indole (trifluoromethyl) hydrazine 1 hydrazine} pyrimidin-4-yl)amino 1 ethanol.

MS (ESI): mass calcd for C18H:5F3N402, 376.1; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 7.28 (m, 4H), 6.73 (s, 1H), 5.46-5.35 (m, 1H), 5.08-4.92 (m, 1H), 4.02-3.90 (m, 1H), 3.70-3.53 (m, 1H). Example 126 · l-(3,5-dioxaphenyl)-2-"(6-{4-"(difluoromethyl)oxyl 119 200948790 jasmonium-pyrimidin-4-yl)amino group 1 ethanol.

MS (ESI): mass calcd for C19H14C12F3N302, 443.0; m/z. 4 NMR (CDC13): 8.69 (s, 1H), 8.04-7.97 (m, 2H), 7.35-7.28 (m, 5H), 6.74 (d, 1.1 Hz, 1H), 5.25-5.18 (m, 1H), 5.00-4.92 (m, 1H), 3.96-3.82 (m, 1H), 3.66-3.53 (m, 1H). Example 127: 1-Π.3-Mos dioxin-5-yl V2-"(6-(4-"(trifluoromethyl))yl 1 lysylpyrimidin-4-yl)amino 1 ethanol.

MS (ESI): mass spectroscopy for C2 〇H16F3N304, 419.1; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, (m, 2H), 6.93 (d, 7 = 1.6 Hz, 1H), 6.86 (dd, 7 = 8.0, 1.3 Hz, 1H), 6.80 (d, J= 7.9 Hz, 1H), 6.71 (d, J = 1.1 Hz, 1H), 5.96 (s, 2H), 5.28-5.21 (m, 1H), 4.98-4.86 (m, 1H), 3.87-3.75 (m, 1H), 3.65-3.52 (m, 1H). Example 128: nSV2-((6-"3-Aza-4-(trifluoromethyl)phenyl)pyrimidin-4-yl}amino)-1-phenylethanol.

MS (ESI): mass calcd for C19H15C1F3N30, 393.1; m/z. 4 NMR (CD3OD): 8.50 (s, 1H), 8.16 (s, 1H), 8.01-7.98 (m, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.37-7.34 (m, 2H), 7.27-7.24 (m, 1H), 6.97 (s, 1H), 4.93-4.90 (m, 1H), 3.79-3.71 (m, 1H), 3.60 (dd, J = 13.6, 7.6 Hz, 1H). Base}amino)-1-phenylethanol III I.

From 1·[2·Fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl]ethyl] (46.5 mg, 0.10 mmol A solution of ethanol (1 mL) was added NaBH4 (5.7 mg, 0.15 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred for 10 min. Additional NaBH4 (5.7 mg, 0.15 mmol) was added and the mixture was stirred 15 min. An additional amount of NaBHU (5.7 mg, 0.15 mmol) was added and stirring was continued for another hour at rt. The reaction mixture was then diluted with water (2 mL) and extracted with CH2 C12 (10 mL). The organic extract was dried (Na2S 4) and concentrated. The crude was purified by EtOAc (EtOAc) MS (ESI): mass calculus 匚 2.112 (^1^302, 353.2; 11 1/2 experimental value, 354.2|&gt;1+11]+.1111^11 (CD3OD): 8.66 (s, 1H), 7.80 (t , 7.8 Hz, 1H), 7.64 (dd, J = 8.1, 1.8 Hz, 1H), 7.55 (m, 1H), 7.43 (d, J = 7.1 Hz, 2H), 7.38-7.34 (m, 2H), 7.30 -7.27 (m, 1H), 5.18 (q, J = 6.6 Hz, 1H), 4.95-4.92 (m, 1H), 3.92 (dd, 13.6, 4.3 Hz, 1H), 3.80 (dd, 13.6, 7.6 Hz, 1H), 1.48 (d, 6.6 Hz, 3H). 121 200948790

Implementation of the inverted _no: 2- ({6_『3_ 曱 ) ) 茉 ] ] ] ] ] ] ] ] ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ( ( ( ( ( ( ( ( ( Salt. Step A: 2_Amino-1-(3,4-^^_ _ a v ethanol. From 3,4-difluorobenzidine (3.85 g, 27.1 mmol), 峨J匕Zinc (1〇 A solution of 4 9 mg, 0.329 mmol) and THF (5 mL) was added to a mixture of mTMSCN (4.60 mL, 33.9 mmol) D under nitrogen for 35 h, then the cannula was fed to LiAlH4 ( 1.41 g, 67.7 mmol) of 〇°c suspension in THF (80 mL). The resulting mixture was slowly warmed to rt over 21 h. The reaction mixture was then cooled to (rc and carefully water (2.57) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; CH2C l2 / MeOH / NH3) gave the desired product. Step </ RTI> </ RTI> </ RTI> </ RTI> 4- -6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidine (59.9 mg, 0.204 mmol), 2 -Amino-1-(3-trifluorodecyloxy-phenyl)-ethyl alcohol (72.4 mg, 0.327 mmol), "_BuOH (2 mL) and DIPEA (0.15 mL, 0.86 mmol) vial N2 Rinse, rinsing and heating at 100 °: 20 h. The reaction mixture was purified by reverse phase HPLC. MS (ESI): mass calc. 02.1114 (^6)^3〇2, 477.8; 111/2 experimental value, 334.1 []^ +1^]+.111 NMR((CD3)2CO) : 10.06 (br riding peak, 2H), 8.92-8.77 (m, 1H), 8.35-8.23 (m, 1H), 8.10-8.00 (m, 2H) , 7.67-7.34 (m, 4H), 7.24 (d, 7 = 6.6 Hz, 1H), 5.20-5.01 (br m, 1H), 4.29-3.82 (br 122 200948790 m, 2H). Examples 131 to 135 The compound was prepared in a similar manner to that described in Example 130, using the appropriate aldehyde in Step A. Example 131: 2_({6-『3·Gas-4_(Χ氲methyl)Mosyl 1 Pyrimidine_4_ Aminoguanidine-(3-fluorophenyl)ethanol trifluoroacetic acid^

〇 MS (ESI): mass calc. for C19H14C1F4N30, 411.8; m/z. 4 NMR((CD3)2CO) : 10.52 (br hum, 2H), 8.95-8.81 (m, 1H), 8.34-8.21 (m, 1H), 8.07-8.03 (m, 1H), 7.44-7.25 (m, 3H), 7.05-7.02 (m, 1H), 5.15-4.98 (br m, ·_ 1H), 4.05_3.53 (brm, 2H). Example 132: 2-f6-(3-Gas-4-trifluoromethyl-methyl)-pyrimidine-4-ylamino 1-1-1-(3,4-di-p-phenyl)-ethyl 3- Gas acetate. n today n

Ν-γΑΛρ

H OH MS (ESI): mass calc. for C19H13C1F5N30, 429.8; m/z. bNMRCCCDACO): 9.65 (br hum, 2H), 8.92-8.71 (m, 1H), 8.36-8.22 (m 1H), 8.08-8.03 (m, 1H), 7.44-7.19 (m, 3H), 5.13-4.96 ( Br m, 1H), 4.01-3.53 (br m, 2H). Example 133: 1-(4-Nitro-3_氤)-2-丨6-Π-nitro-4-trisole A-袈123 200948790 base)-pyrimidin-4-ylamino 1-ethanol Trifluoroacetate.

MS (ESI): mass calcd for C19H13C12F4N30, 446.2; m. hNMRGCDACO) : 10.06 (br hum, 2H), 8.91-8.62 (m, 1H), 8.34-8.02 (m, 2H), 7.66-7.34 (m, 3H), 5.15-5.10 (br m, 1H), 4.01- 3.80 (br m, 2H). Example 134: 1-(3-nitro-4-fluoromethyl chloride-4-(trifluoromethyl)phenylpyrimidin-4-ylindolyl)ethanol trifluoroacetate.

MS (ESI): mass calcd for C19H13C12F4N30, 446.2; m. ^NMRCCCD^CO) : 10.14 (br hum, 2H), 8.92-8.80 (m, 1H), 8.34-8.20 (m, 1H), 8.07-7.99 (m, 1H), 7.67-7.57 (m, 1H), 7.48-7.41 (m, 1H), 7.29-7.21 (m, 1H), 5.14-4.96 (br m, 1H), 4.01-3.55 (br m, 2H). Example 135: 2-({6-[3-Galy-4-(dioxamethyl) phenyl 1 propyl-4-yl}amino)-143-(trifluoromethyl)phenyl 1 ethanol Trifluoroacetate.

]^8(£81): Mass spectrometry calculation: (2〇1114(:1?6&gt;130,461.8; 111/2 experimental value, 462.1 [M+H]+.]HNMR((CD3)2CO): 10.35 (br hum , 2H), 8.92-8.81 (m, 1H), 8.34-8.21 (m, 1H), 8.09-8.02 (m, 124 200948790 1H), 7.84-7.72 (m, 2H), 7.65-7.20 (m? 2h) , 5.25-5.08 (br m 1H), 4.07-3.59 (br m, 2H). 'Example, 丨36 : (1 ft) -2-{[2^^^3,4_Dinitromethane ^^ base 1 amine M-phenyl b.

Add cyclopropyl formamidine hydrochloride (140 mg) to a solution of 3-(3,4-chlorophenyl)-3-oxo-propionylethyl ester (252 mg, 〇.%? mmol) and MeOH. , 1.16 mmol) and third butanol (266 mg, 2 37 _ 〇 1) 〇·- The reaction mixture was stirred overnight and then concentrated. Water and CH2Cl2 were added and the mixture was adjusted to pH 7 with glacial acetic acid. The layers were separated and the aqueous phase was extracted with EtOAc. The organics were combined, dried (NajO4) and concentrated. The crude residue was purified (EtOAc EtOAc)步 step logic B._4-gas-2-cyclopropyl-6-(3,4-dioxo-loaded a zhaha 2-cyclopropyl-6-(3,4-di-phenyl-phenyl)- shout P0C13 (0.13 mL, 1.42 mmol) was added to a suspension of octa-4-ol (131 mg, 0.467 mmol) in acetonitrile. The reaction mixture was heated at 80 ° C for 105 min, cooled to rt, and then quenched with saturated aqueous NaHCI3. The title compound (113 mg, 81%) was obtained. 3,4-·-Wind_Phenyl)-α·Sigma (108 mg, 0.364 mmol), (R)_(-)-2-Amino-1-phenylethanol (67.2 mg, 125 200948790 0.490 mm A mixture of 〇1^NaHC〇3 (190.1 mg, 2.26 1^〇1) and 14_diterone was refluxed for 48 h. The mixture was poured into water and extracted with Ch2ci2. The organic layer was dried (NajO4) and concentrated. Residue Purification (FCC) gave the title compound as a white solid (11. <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; : 8.13-8.05 (m, 1H), 7 85_7 79 (m, 1Η), 7.64-7.58 (m, 1H), 7.45-7.31 (m, 4H), 7 3〇_7 23 (m,1H), 6.68-6.59 (m,1H),4.93-4.85 (m,iH): 3 81_3 65 (m,1H),3.56-3.48 (m,1H),2.16-2.01 (m,m ), 1161 〇9 (m, 2H), 1.02-0.94 (m, 2H). ' · ❹ Re-dust - Example 137 : (lR)-2H (3,4--- chlorophenyl, A certain 、, Pain 4-based 1 amine M-phenylethanol.

The title compound was prepared in a similar manner as Example 136. MS (ESI): mass calcd. for C21.21.21.21. 1H NMR (CD3OD): 8.14-8.08 (m, 1H), 7.87-7.80 (m, 1H), 7.63-7.57 (m, 1H), 7.44-7.38 (m, 2H), 7.36-7.29 (m, 2H), 7.27-7.22 (m, 1H), 6.71-6.64 (m, 1H), 4.96-4.90 (m, 1H), 3.84-3.70 (m, 1H), 3.61-3.53 (m, 1H), 3.06-2.95 (m , 1H), 1.36-1.27 (m, 6H). Example 138: Indole-2-({6-"3-nitro-4-(trifluoromethyl)methyl 1-2-(methyl oxime)pyrimidin-4-ylguanidino)-1- Molybdenum ethanol. 126 200948790

From (1R)-2-({6-[3_chloro_4_(trifluoromethyl)phenyl]_2-(methylsulfanyl)&gt; dimethyl-4-yl}amino) phenylethanol ( Slowly add 3_chloroperoxybenzoic acid (45 mg, 0.20 mmol) to a solution of 55 4ing, 0 1〇mm〇l) and CH^Cl2 (2 mL). The reaction mixture is stirred at rt 3 and then called

Na2S03 (4 mL X 2) was washed with satd. aq· NaHC03 (5 mL X 2).分层 Layered and extracted with aCH.sub.2Cl.sub.2 (15 mL) &apos; dried (Na.sub.2) and concentrated. The crude material was purified by reverse phase chromatography to give the final product (2 mg, 43%). MS (ESI): mass calcd for C2 〇Hl7C1F3N3 〇3S, 471"; m/z, 472.1 [M+H] + 〇!H NMR (CD3OD): 8.30 (s, 1H), 8.14 (d, J = - 8.2 Hz, 1H), 7.90 (d, 8.2 Hz, 1H), 7.45-7.44 (m, 2H), — 7.36-7.32 (m, 2H), 7.27-7.21 (m, 1H), 7.15 (s, 1H ), 4.95-4.91 (m, 1H), 3.87-3.80 (m, 1H), 3.70-3.65 (m, 1H), 3.34 (s, 3H).实 Example 139: (lR)-2-a6-"3-Chloro-4-(trifluoromethyl) fluorenyl 1-2-(methylsulfinyl)pyrimidin-4-yl^face VI - Stupid ethanol.

The title compound was prepared in a similar manner to Example 138 using 1 m.s. of 3-chloro peroxybenzoic acid. MS (ESI): mass calcd for C20H] &lt;RTI ID=0.0&gt;&gt; WNMR^CDsOD): 8.35 127 200948790 (s,1H), 8.13 (d, J= 8.8 Hz, 1H), 7.89 (d, 8.2 Hz, 1H), 7.44-7.43 (m, 2H), 7.35-7.32 (m , 2H), 7.26-7.23 (m, 1H), 7.05 (s, 1H), 4.92-4.90 (m, 1H), 3.87-3.79 (m, 1H), 3.74-3.67 (m, 1H), 2.94 (s , 0.34H), 2.93 (s, 0.66H). Example 140: m〇-2-(r6-(3-methyl-1H-indole)pyrimidine·4_an i-based 丨-1-benzene-ethanol trifluoroacetate.

From 1_[2_fluoro-4-(6-{[(2R)-2-yl-2-phenylethyl]amino}carcin-4-yl)phenyl]acetamidine (68 mg, 0.15 mmol The solution consisting of a single hydrated σ well (1.5 mL) was heated to reflux in a sealed tube for 10 h. The reaction mixture was poured onto ice, and the precipitate was filtered and washed with hexane (15 mL). Reverse phase chromatography gave the title compound (19 mg, 29%). MS (ESI): mass calcd for C2 </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; WNMR (CD3OD): 8.65 (s, 1H), 7.96-7.93 (m, 2H), 7.48-7.44 (m, 3H), 7.38-7.35 (m, 2H), 7.30-7.26 (m, 1H), 7.06 ( s, 1H), 4.96-4.94 (m, 1H), 3.96-3.91 (m, 1H), 3.83-3.79 (m, 1H), 2.61 (s, 3H). Example 141: (lR)-2-({6_丨fluoromethyl)竿, its IK methyl abdomen, shame, l), acetophenone-4-ylaminoamine,-1-phenylidene acetate, HN^

128 200948790 From (lR)-2_({6-[3_[3-(4-(trifluoromethyl)phenyl]-2](nonylsulfonyl)) butyl-4-yl}amino)phenyl A solution of ethanol (47.2 mg, 0.10 mmol) and N. triterpenoid (1 mL) was added to a tight tube of decylamine (0.2 th; 0,15 mL in thF). The reaction mixture was at 13 Torr. (: Heated for 18 h. The crude material was filtered through a syringe tip filter, lysed in hexanes, and then purified by reverse phase chromatography to give the final product (36 mg, 67%). MS (ESI): mass calcd for C2 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Hz, 1H), 7.44-7.43 (m, 2H), 7.37-7.34 (m, 2H), 7.29-7.26 (m, 1H), 6.39 (s, 1H), 4.96-4.94 (m, 1H), 3.89- 3.85 (m, 1H), 3.75-3.70 (m, 1H), 3.05 (s, 3H) 〇M142: (lR)-2-("6-(4-Iodophenyl)pyrimidin-4-yl 1amine Some M-moat

Step A: 丨4-(6-Aza-piperidin-4-yl)-lamalin V-aminoglycolic acid tert-butylamine The title compound was obtained in a procedure similar to the procedure of Example B Step B. Step B: 4-(6-Gas-pyrimidin-4-yl)-Moum's face. [4-(6-Chloro-pyrimidin-4-yl)-phenyl]-amino decanoic acid tert-butyl g A mixture of (9l8 mg, 3.00 mmol), CH.sub.2C.sub.2 (30 mL) and HCl (4 N; 3.80 mL) was stirred overnight at rt and filtered to isolate the solid. The solid formed is dissolved in water, treated with saturated NaHC〇3 and extracted with (:3⁄43⁄4. The extract is dried, filtered, and concentrated. The material is used directly in step C. Step C: 4_gas-6_(4- Broken-Benzene)-disc spray. A solution consisting of 4-(6-chlorine bite_4-129 200948790 base)-phenylamine (399 mg, 1.94 mmol) and CH3CN (40 mL) was cooled to 〇 under A °c and treated with tributyl nitrite (〇39mL, 3 24mm〇l) to produce a dark brown mixture. After 30 min, add Cul (1.50 g, 7.88 mmol). After 30 min, the mixture was heated. To 75 after 3〇111丨11. The mixture is cooled to 1^' to £1; 〇人(:diluted, and watered by satd. aq. NaHC〇3 Washed. Organic layer dried (MgS〇4), filtered The residue was purified by FCC (CH2C12 / hexanes) to yield 218.1 mg (36%) of pure product MS (ESI): mass spectrometer #CI0H6C1IN2, 315.93; m/z experimental value, 317.0 [M+H] +.bNMRCCCD^CO) : 9.04 (br s, 1H), 8.18 (d, J= 1.2 Hz, 1H), 8.08-8.06 (m, 2H), ❹ 7·98_7.97 (m, 2H) 〇盘丽The title compound was prepared in a similar manner to that described in Example 1, Step A. MS (ESI). Mass. 6IN3〇, 417.3 ; m/z experimental value, 418 [M+H]+ 〇Ή NMR ((CD3)2CO): 8.53 (s, 1H), 7.84 (s, &quot; 4H), 7.46 (d, J= 7.8 Hz, 2H), 7.35-7.33 (m, 2H), 7.27-7.24 (m, 1H), 6.81 (br s, 1H), 5.05 (br s, 1H), 4.97 (br t, 7= 3.6 Hz, 1H), 3.84 (br s, 1H), 3.56-3.52 (m, 1H) ° 实施 Example 14 The compounds of 3 to 14 6 were prepared using methods analogous to those described in the previous examples. Example Trifluoromethyl Benzene Its pyrimidine _ amine 1-1-(3,4-difluoro-cage) _ ;?

Oh.

H OH The analytical analysis obtained from this compound is advantageously compared with the one obtained by the egg 2 130 200948790. Fluorine A - laugh a certain lion ^ amine Η: (3,4-difluoro-cage a Wj ^

OH

N^N work; F 匕车 f* compound paid analysis data and the results obtained in Example 132 Ο

Base)-2-"6彳3_氦冰三 U-based-phenyl-ion -4-aminoamine

F OH comparison The analysis data of this compound is obtained from Wei and Example 丨33. ❹, Γ6-(3-氪-4-triyl-phenyl-per propyl-4-ylamine

OH Comparison The analytical data for this &amp;&lt;RTIID=0.0&gt;&gt;&gt;&gt;&lt;&gt;&gt; 131 200948790 Example 147: 2-((6-丨4-(methyl-methyl)mosyl 1 pyrimidin-4-yl}amine 1) &lt; * —— 芏 乙醇 ethanol.

MS (ESI): mass calcd for C19H19N302, 321.2; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 7.43 (d, 7.7 Hz, 2H), 7.35 (t, 7.7 Hz, 2H), 7.28-7.25 (m, 1H), 7.02 (d, 7 = 8.8 Hz, 2H), 6.82 (s, 1H), 4.91 -4.88 (m, 1H), 3.85 (s, 3H), 3.76-3.67 (m, 1H),

3.57 (dd, J= 13.7, 7·7 Hz, 1H). O Example 148: 2-丨[6-(3-曱基笨基) 唆-4-美iamine Benzene on the alcohol.

MS (ESI). Mass spectrometer is different ^!!!9!^3. , 305.2 ; m/z experimental value, 306.2 [M+H]+. NMR (CD3OD): 8.45 (s, 1H), 7.70 (s, 1H), 7.65 (d, J - 7.6 Hz, 1H), 7.44-7.43 (m5 2H), 7.37-7 33 〇(m, 3H), 7.30-7.24 (m, 2H), 6.86 (s, 1H), 4.92-4.90 (m, 1H) 3.77-3.66 (m, 1H), 3.58 (dd, 13.9, 7.8 Hz, 1H) 2 42 (s 3H) ° 5 Example HU: Phenyl-2:J (6-{3-"(trifluoro-)-amino-p-hydroxyl-4-yl)amino 1 ethanol. 132 200948790

N^N

MS (ESI): mass spectroscopy calculated ^!!#:^3. 2, 375 J; m/z experimental value, 376.2 [M+H]+. H NMR (CD3OD): 8.48 (s, m), 7.91-7.89 (m, 1H), 7.84 (s, 1H), 7.59 〇8 l Hz, m), 7.44 (d, J = 7.1 Hz, 2H) , 7.40-7.38 (m, 1H), 7 36_7 33 (m 2H), 7.28-7.24 (m, 1H), 6.93 (s, 1H), 4.93-4, 90 (m, 1H), ' 3.79-3.68 ( m, 1H), 3·59 (dd, J = 13.6, 7.6 Hz, 1H). Example 150. (1S, 2R)-1-phenyl-2-(6-{4-"('^: far^methyl) gas group [phenyl] group] Amino 1 propan-1 - leaven. Ν^Ν F3C, XJ^ "Η MS (ESI): mass spectroscopy for C20H18F3N3O2, 389.1; m/z, mp. 390.2 [M+H]+.咕NMR (CDC13): 8.58 (s,1H),7 93 (d /= 8.8 Hz, 2H), 7.35-7.34 (m,4H),7.32-7.26 (m,3H) 6 63 (d,J= 1.0 Hz, 1H), 5.20 (br s, 1H), 4.92 (d, 2.5 Hz 1H) 4.86 (br s, 1H), 4.41 (br s, 1H), 1.12 (d, 7 i hz 3H). ❹

实施 Example 151 · (1S)-1-phenyl-2-(6-{4-IT dioxin κ 1 · γ·竹1 pyrimidin-4-yl)amine 1 ethanol.

Ν^Ν : f3c, 〇/^ h oh MS (ESI): mass spectrometry calculation C 9H16F3N302, 375.1 ; m/z experimental value, 376.2 [M+H]+. h NMR (CDC13): 8.62 (s, 1H), 7 97 (d 133 200948790 J = 8.8 Hz, 2H), 7.43-7.36 (m, 4H), 7.33-7.28 (m, 3H), 6.67 (d, J = 1.0 Hz, 1H), 5.41 (br s, 1H), 4.99-4.96 (m, 1H), 4.25 (br s, 1H), 3.89-3.83 (m, 1H), 3.62-3.55 (m, 1H). Example 152: ΠΙ〇-2-(ί6-『2,4-bis(trifluoromethyl)mosyl 1 pyrimidin-4-yl}amino)-1-phenylethanol trifluoroacetate.

MS (ESI): m.p. Towel NMR (CD3OD): 8.67 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.87-7.85 (m, 1H), 7.44-7.43 (m, 2H), 7.37-7.34 (m, 2H), 7.30-7.27 (m, 1H), 6.80 (s, 1H), 4.95_4.94 (m, 1H), 3.94-3.90 (m, 1H), 3.83-3.79 (m, 1H). Example 153: aR)-2-({6-"2-Methane-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]·月安基)-1-phenyl Yeast two chaotic acetate.

MS (ESI): mass calcd for C20H18F3N3O3, 405.1; m. hNMRCCDsOD): 8.63 (s,1H), 7.66-7.63 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.28 (m, 1H), 7.16 (s, (H, 1H) 7.7 Hz, 1H). 134 200948790 Example 154 . nR)-2-{"6-(4·Ethoxy-2-indenyl stupid V-bite-4-even 1

Amino 丨-1-phenylethanol trifluoroacetate. n^n

MS (ESI): mass calcd for C.sub.sup.sup.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 7.38-7.31 (m, 3H), 7.30-7.27 (m, 1H), 6.95 (s, 1H), 6.92 (dd, J= 8.8, 2.2 Hz, 1H), 6.71 (s, 1H), 4.94 (dd, J = 7.7, 4.4 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.95-3.91 (m, 1H), 3.81 (dd, J = 13.7, 7.7 Hz, 1H), 2.36 (s, 3H) ), 1.41 (t, J = 7.1 Hz, 3H). The compounds of Examples 155 to 156 were prepared in a manner similar to that described in Example 136. Example 155: nRV2-{"6-(3,4-dioxin) V2-methylpyrimidin-4-yl 1

MS (ESI): mass calcd for C19H17 C12N30, 373.07; HNMR (CD3OD): 8.06 (d, ·/= 2.1 Hz, 1H), 7.79 (dd, J = 2.1, 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.45-7.39 (m , 2H), 7.37-7.30 (m, 2H), 7.28-7.22 (m, 1H), 6.67 (s, 1H), 4.91-4.88 (m, 1H), 3.80-3.67 (m, 1H), 3.59 (dd , / = 7.4, 13.8 Hz, 1H), 2.49 (s, 3H). 135 200948790 Paste Example 156: ΠRV^2-·ί "6-α4-dihydromolyme&gt;l.pyrimidin-4-yllamine}}-l-jasmonethanol.

MS (ESI): mass calcd for C18H15C12N30, 359.06; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 7.83 (dd, 7 = 2.1, 8.4 Hz, 1H), 7.63 (d,7= 8.4 Hz, 1H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.28-7.23 (m , 1H), 6.90 (s, 1H), 4.92-4.88 (m, 1H), 3.80-3.67 (m, 1H), 3.59 (dd, J = 7.7, 13.7 Hz, 1H). The compounds prepared in Examples 157 to 162 were prepared in a manner similar to that described in Example 141. Example 157: (110-2-({2-"[2-Aminoethyl)amine 1-6-Γ3-azin-4-(trifluoromethyl)benzene 1-pyrimidin-4-ylguanamine Base)-1-phenyl alcohol trifluoroacetate.

H2N-NH

MS (ESI): mass calcd for C, s,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 7.86 (d, 9.3 Hz, 1H), 7.45-7.43 (m, 2H), 7.38-7.35 (m, 2H), 7.30-7.27 (m, 1H), 6.46 (s, 1H), 4.93-4.90 (m, 1H), 3.81-3.76 (m, 4H), 3.26-3.23 (m, 2H). 200948790 EXAMPLE-U8- : (lR)-2-"(6-"3-Gas-4-Γ三事甲其,苇其ι_2_Κ2-(didecylamino)ethyl 1 Amino}pyrimidine-4 - A certain amine, a small jasmine r" 醢 trifluoroacetate.

N person N

OH MS (ESI): mass calcd for C23H25C1F3N50, 479.17; m/z. ^NMR (CD3OD): 8.02 (s,1H), 7.96 (d,J = 8.1 Hz, 1H), 7.85 (d, 8.8 Hz, 1H), 7.44 (d, /= 7.8 Hz, 2H), 7.39-7.35 (m, 2H), 7.31-7.27 (m, 1H), 6.47 (s, 1H), 4.93-4.90 (m, 1H), 3.92-3.87 (m, 2H), 3.82-3.77 (m, 2H), 3.49-3.44 (m, 2H), 2.97 (s, 6H). Example 159: (!RV2-({6-f3-f.-4-(三气甲)Methyl 1-2-(ethylamino)) -4-merylamino)-1- Stupid ethanol three gas acetate.

N Η MS (ESI): mass calc. for C21. H.s. W NMR (CD3OD): 7.99-7.97 (m, 2H), 7.80 (d, 8.6 Hz, 1H), 7.44-7.42 (m, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H) ), 6.39 (s, 1H), 4.96-4.92 (m, 1H), 3.88-3.82 (m, 1H), 3.71 (dd, 7 = 13.4, 7.6 Hz, 1H), 3.53 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.3 Hz, 3H). 137 200948790 Example 160: (lR)-2-({6-"3-chloromethyl, 1 yl·μ2_吖2_mercaptoethyl)amine 1 pyridyl-4-ylguanidino)- 1- stupid a _di-fluoroacetate hov^nh one

MS (ESI): mass calcd for C2iH20ClF3N4 〇2, 452.12; m/z </ RTI>, 453.1 [M+H]+ °]H NMR (CD3OD): 8.00-7.98 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.43 (d, J= 7.6 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.42 (s, 1H), 4.95-4.92 (m, 1H) , 3.86-3.81 (m, 1H), 3.78-3.69 (m, 3H), 3.64-3.62 (m, 2H). Example 161: (lR)-2-({2-azetidin-1-one-6-indole-3-chloro-4-(trimethyl)methyl stearyl-4-ylamino group )-1-phenyl alcohol trifluoroacetate.

MS (ESI): mass calcd for C22H20ClF3N4O, 448.13; m/z, </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR (CD3OD): 7.98 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H) , 7.78-7.76 (m, 1H), 7.43-7.41 (m, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.29 (s, 1H), 4.93 (dd, J= 8.1, 4.5 Hz, 1H), 4.35 (t, J = 7.8 Hz, 4H), 3.80 (dd, J = 13.6, 4.3 Hz, 1H), 3.64 (dd, 13.6, 7.8 Hz, 1H), 2.50 (pentet, ·/= 7·8 Hz, 2H) 〇138 200948790 Example 162: (lR)-2-({6-『3-gas-4-(three-digit 甲一里1 1-2 amine) feeding-4 -hydrazinyl)-1-phenylethyltrifluoroacetate

NH N^N

OH MS (ESI): mass spectroscopy for C22H20C1F3N4 〇, 448.13; m/ζ μ μ,, a like, 449.1 [Μ+Η]+. ! Η NMR (CD3OD): 7.99-7.98 (m, 2m called, 7.8〇)

(d, J = 8·1 Hz, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.37-7, 33 2H), 7.30-7.26 (m, 1H), 6.41 (s, 1H), 4.98 -4.92 (br·干峰功' 1H), 3.91-3.84 (m,1H), 3.72-3.67 (m,1H),2.88-2.80 (br, peak, 1H), 0.92 (d,·/= 5.8 Hz , 2H), 0.74-0.68 (br hum, ^ 匕 Example 163: (lR)-2-"(6-r3-gas-4-(three 1. formazan H篡[2^2 ylamino) Amino-based acetophenone-4-yl)amino-1-n-phenylethanolate

OH Step A. (lR)-{2-"4-(3-Aza-4_trimethyl-methyl-ethylphenyl-ethylamino)-pyrimidin-2-amine A 1-B The amino-aminotributyl ester. The title compound was prepared using a procedure similar to that of Example 141. Step B: from (lR)-{2-[4-(3·chloro-4-trifluoromethyl)-phenyl - 6-(2-Hydroxyphenyl-ethylamino)-pyrimidin-2-ylamino]-ethyl}-fluorenyl-amino decanoic acid tert-butyl ester (40 mg, 0.06 mmol) and CH2C12 HCl (2 M in Et20, 0.15 mL) was added to a solution of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The compound (18 mg, 63%). MS (ESI): ESI (ESIESIESIESIESIESIESIESIESIESIESIESIESIESIESIESIESI 8.01 (br s, 1H), 7.85-7.80 (m, 1H), 7.53-7.44 (m, 5H), 6.46 (br s, 1H), 5.11-5.08 (m, 1H), 4.05-3.92 (m, 2H ), 3.90-3.87 (m, 2H), 3.39 (t, 5.8 Hz, 2H), 2.83 (s, 3H). Example 164: (lR)-2-({6-丨3-气-4-( Trifluoromethyl)mos 1-2-methane pyrimidine-4-ylguanidino)-1-phenylethanol Mince acetate salt.

From (lR)-2_({6-[3_ gas-4-(trifluoromethyl)phenyl]_2_(indolyl)methyl) dimethyl -4-yl}amino)-1-benzene A solution of the base ethanol (50.0 mg, 0.11 mmol) and NaOMe (25%, 0.75 mL) was evaporated in EtOAc EtOAc EtOAc. The filtrate was concentrated and purified by EtOAc EtOAc EtOAc (EtOAc). ) : 8.06 (s, 1H),

7.95 (d, 8.6 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.37-7.33 (m, 2H), 7.29-2.26 (m, 1H) ), 6.67 (s, 1H), 4.96-4.93 (m, 1H), 4.11 (s, 3H), 3.90-3.82 (m, 1H), 3.78-3.73 (m, 1H). 200948790 Example 165: (lR)-2-{『6-(gj _h2_笑其I oxazole_6_) pyrimidine-4-yl 1 amine M-stupylethanol.

Base)-phenyl]ethanone (88 mg, 0.25 mm 〇1), hydroxylamine hydrochloride (41 mg, 0.60 mmol), KOH (85./〇aq, 〇 158 mL), isopropanol (〇 5 mL) A mixture of water and water (0.5 mL) was placed in a sealed tube at 9 Torr. c Heat 丨〇 h. An additional amount of KOH (85% aq·, 2.38 mm Gl) was added and the temperature was increased to 12 Q〇C for an additional 21 h. The reaction mixture was diluted with water (5 mL) and extracted with DcM (5 mL×3). The combined extracts were dried (Na2qq. MS): Mass spectrum calculation C2GH18N402, 346.14; m/z experimental value, 347 2 [M+H]+. lH NMR (CDCl3): 8·70 (U = 0.8 Hz, 1H), 8.13 (dd, J = 1.3, 0.8 Hz, lH), 7.93 (dd &gt; J = 835 l3H2 &gt; 1HX77 〇 (ddjJ = 8.3, 0.8 Hz, (H, 1H) , 3.94-3.87 (m, 1H), 3.67-3.60 (m, 1H), 2.62 (s, 3H) ° ί^Μ_166: 定冰冰基)-2-裟一丙-2-醢.

The title compound was prepared using a procedure similar to that described in Example 106. MS 141 200948790

(ESI): Mass spectroscopy for C2 〇H17C1F3N30, 407.10; m/z. NMR (CD3OD): 8.45 (br s,1H), 8.14 (s,1H), 7.96 (d, 8.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.53 (d, J =7.7 Hz , 2H), 7.31 (d, J= 7.7 Hz, 2H), 7.20 (t, /= 6.6 Hz, 1H), 6.96 (br s, 1H), 3.88-3.80 (m, 1H), 3.73-3.70 (m , 1H), 1.58 (s, 3H). Example 167: 2-({6-"3·氪-4-(三氤甲) 策一一pyrimidin-4-yl}amine νΐ-Γ4- (Methylsulfanyl) Mothium 1 ethyl hydrazine.

Step A: 2-azido-1-(4-methyldecane-methylethyl ketone. From 2-bromo-1-(4-methylsulfanyl-phenyl)-ethanone (2.00 g The solution consisting of 8.16 mmol) and DMF (7 mL) was cooled to 15 ° C and treated with sodium azide (583 mg, 8.98 mmol) in portions. Once the addition was complete, the reaction mixture was stirred for 3 h at slowly rt. The reaction mixture was then diluted with EtOAc (20 mL) EtOAc (EtOAc (EtOAc)EtOAc. The title compound (1.69 g, 100%). Childhood B: 2·azido-1-(4·甲甲葙,院基_笨基)_Ethanol. From 2-azido-1-(4_ A solution consisting of methylthiol phenyl)-ethanone (1 69 g, g IS mm〇l) and THf (8.15 mL) was cooled to 0 °c, then BHfTHF (1.0) was slowly added with 1 〇 〇 Μ solution, 8.15 ml). The resulting solution was stirred for 2 h. EtOAc was evaporated from EtOAc EtOAc EtOAc EtOAc 200948790 Step C: 2-Face-based 1-ί4-methylthioalkyl-stupyl V ethanol. From 2-azido-1-(4-methylsulfanyl-benzene Stirring rt suspension consisting of acetonitrile (316 mg, 〇 4.6 mg, 0.50 mmol), 1 〇〇 /0 Pd/C (100 mg, 0.10 mmol) and MeOH (25 mL) 5.0 mmol). The resulting mixture was heated at 64 ° C for 2 h. After cooling to rt, the catalyst was filtered through a pad of Celite, and the pad was washed with MeOH. The filtrate was concentrated and purified (FCC) The title compound (66 mg, <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; +H]+.WNMRCCDsOD): 8.49 (s,1H), 8.16 (s,1H), 7.99 (d, 7.7 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.25-7.23 (m, 2H), 6.96 (br s, 1H), .- 3.75-3.67 (m, 1H), 3.60 (dd, J = 13.7, 7.7 Hz, 1H), 2.43 (s, one 3H). The compounds of Examples 168 to 169 were prepared by a method similar to that described in Example 167. Example 168: 2-α6-"3-Gas-4-(三翁甲篡,笑一一pyrimidin-4-yl}amine)-1-°Sep-3-yl-ethyl drunk.

]\^氓31): Mass spectrometry calculation: (1711] 3 (: positive 31 &lt;[3〇8,399.04; 111/2 experimental value, 400.1 [Μ+Η]+. NMR (CD3〇D): 8.50 (s, 1Η) ), 8.17 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.88 (ά, J = 8.3 Hz, 1H), 7.38 143 200948790 (dd, y = 5.1, 3.0 Hz, 1H), 7.35 -7.34 (m, 1H), 7.18 (dd, J = 4.8, 1.3 Hz, 1H), 6.98 (s, 1H), 4.99 (dd, J= 7.6, 4.8 Hz, 1H), 3.84-3.76 (m, 1H) ), 3.65 (dd, 13.9, 7.6 Hz, 1H). Example 169: 2-({6-"3-indole-4-(trifluoromethyl)methyl 1 pyrimidin-4-yl}amine) - 1-(1,3-thiazole-2-some, 匕醢.

H OH MS (ESI): Mass calc. for C16H12ClF3N4OS, 400.04; iHNMRCCDClJ : 8.68 (d, J = 1.0 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 7.92 (dq, J = 8.1, 0.8 Hz, 1H), 7.78 (d, J = 3.3 Hz, 1H ), 7.77 (d, J = 8.3 Hz, 1H), 7.32 (d, /= 3.3 Hz, 1H), 6.78 (d, /= 1.3 Hz, 1H), 5.49-5.44 (m, 1H), 5.27-5.24 (m, 1H), 4.20-4.14 (m, 1H), 4.0 3.95 (m, 1H).

Examples 170 to 172 were synthesized using a method similar to that described in Example 20. f Example 170: (1RV1-1 its -2- Γ6- porphyrin-6-pyrimidine ethanol.

OH MS (ESI): mass spectrometry for c2iH18N40, 342.15; m/z, 343.2

[M+H]+° ]H NMR (CD3OD): 8.90 (dd, J=4.4, 1.6 Hz, 1H), 8.53 (d, 7 = 2.2 Hz, 2H), 8.49 (d, 8.2 Hz, 1H), 8.29 (dd, J = 8.8, 2.2 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.62-7.59 (m, 144 200948790 1H), 7.44 (d, J = 1.1 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.26 (t, 7.1 Hz, 1H), 7.06 (s, 1H), 4.94-4.91 (m, 1H), 3.79-3.71 (m, 1H), 3.63 (dd, 13.7, 7.7 Hz, 1H). Example 171: N-Tertibutyl-4-(6-("(2R)-2-hydroxy-2-ylethylethyl 1 -aminopyrimidin-4-yl) oxasulfonamide.

HN-b- (Γ〇MS (ESI): mass calc. for C22H26N403S, 426.17; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 2H), 7.73-7.68 (m, 2H), 7.21-7.13 (m, 2H), 7.11-7.04 (m, 2H), 7.03-6.94 (m, 1H), 6.73-6.62 (m, 1H), 4.67 -4.61 (m, 1H), 3.56-3.42 (m, 1H), 3.34 (dd, 13.7, 7.6 Hz, 1H), 0.94 (s, 9H). Example 172: (1RM-phenyl-2-(( 6-"4-(thiomorpholin-4-ylsulfonyl) phenyl 1 pyrimidin-4-ylguanidino) ethanol.

]^18佴81): Mass spectrometry calculation (:221124&gt;&lt;[40382,456.13; 111々 experimental value, 457.4 [M+H]+.bNMRCCDsOD): 8.69-8.36 (m,1H), 8.18-8.09 (m , 2,,,,, , 4.76-4.51 (m, 2H), 3.88-3.70 (m, 1H), 3.62 (dd, J = 145 200948790 13.7, 7·8 Hz, 1Η), 3.41-3.33 (m, 4H), 2.76-2.68 ( m, 4H). The compounds prepared in Examples 173 to 182 were prepared in a manner similar to that described in Example 20. Example 173: ΠΙΟ-Μ4-fluorophenyl)-2-({6_"3-fluoro-4-(trifluoromethyl)phenylpyrimidin-4-ylindenyl)ethanol.

MS (ESI): mass calcd for C19H14F5N30, 395.咕NMR (CDC13): 8.68 (d, 0.8 Hz, 1H), 7.85-7.81 (m, 2H), 7.71-7.67 (m, 1H), 7.40 (d, 8.3 Hz, 1H), 7.39 (d, J= 8.3 Hz, 1H), 7.07 (d, 8.6 Hz, 1H), 7.06 (d, J= 8.8 Hz, 1H), 6.74 (d, 1.3 Hz, 1H), 5.35-5.30 (m, 1H), 5.01-4.98 (m, 1H), 3.91-3.85 (m, 1H), 3.62-3.56 (m, 1H). Example 174: Indole-1-(4-fluorophenyl)-2-({6-"3-fluoro-4-(trifluoromethyl)phenyl)pyrimidin-4-ylindenylamino)ethanol Trifluoroacetate.

氓8氓81): Mass spectrometry calculation: (1911141^&gt;13〇2,411.10; 111/2 experimental value, 412.1 [M+H]+ ° 1H NMR (CD3OD): 8.65 (s, 1H), 7.89-7.86 (m, 1H), 7.76-7.66 (m, 2H), 7.48-7.45 (m, 2H), 7.10-7.02 146 200948790 (m, 3H), 4.95-4.92 (m, 1H), 3.91-3.86 (m, 1H), 3.79-3.74 (m, 1H). Example 175: ΠΙΟ-2-((6-丨3-气-4-(trifluoromethyl)methyl 1 sulf- a &gt; amino)-1-( 4-fluorophenyl)ethanol triterpenoid acetate.

MS (ESI): m.p. 4 NMR (CD3OD): 8.67 (s, 1H), 8.09 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.48-7.44 (m, 2H), 7.10-7.06 (m, 2H), 7.01 (s, 1H), 4.95-4.93 (m, 1H), 3.93-3.87 (m, 1H), 3.81-3.75 (m, 1H). Example 176: (1RV1彳4-fluoromethane篡ν2-Γί6-Γ3-(pentafluoroethyl V1.2-maleisoxazole-6-yl 1 pyrimidine-4-one guanamine) acetamidine Acetate.

The title compound was prepared using a procedure similar to that of Example 20. MS (ESI): mass calcd for C2, H,,,,,,,,,,,,,,,,,,, ^NMRCCDsOD): 8.75 (s, 1H), 8.36 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 5.5, 8.3 Hz, 2H), 7.15 (s, 1H), 7.09 (t, /= 8.7Hz, 2H), 4.97-4.95 (m, 1H), 3.95-3.91 (m, 1H), 3.85-3.80 (m, 1H ). 147 200948790 Example 177: (11〇-1-(4-gas 1 stupyl)-2-({6-『3-(&quot;:?-fluoromethyl early)_1,2_stuppyloxazole- 6-yl 1 pyrimidin-4-ylguanidino)ethanol triterpenoid

F MS (ESI): mass calcd for C20H14F4N4O2, 418. 4 NMR (CD3OD): 8.69 (br s,1H) 8 36 (s 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.49-7.45 (m, 2H), 7.13-7.07 (m, 3H), 4.97-4.94 (m, 1H), 3.92-3.86 (br hum, 1H), 3.80-3.75 (m, 1H). Example 178 : (1ΐ〇-2-((6-Γ3-Fluoropyrimidin-4-ylindenyl)-1-ylylethanol trifluoroacetate).

MS (ESI): mass spectrometer, C20H17F4N3O2, 407.13; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 1H), 7.66-7.63 (m, 1H), 7.45-7.41 (m, 3H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.96 (s, 1H), 4.94 (dd , J = 7.1, 5.1 Hz, 1H), 4.75 (q, J = 8.3 Hz, 2H), 3.95-3.90 (m, 1H), 3.79 (dd, 13.6, 7.6 Hz, 1H). Example 179: (1 ft. 28)-2-(76-"3-chloro-4-(trifluoromethyl)methyl sulphate 1 pyridin-4-yl}amino)-1-methyl propyl-1 -醢. 200948790

MS (ESI): mass spectr. </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 4 NMR (CDC13): 8.69 (s, 1H), 8.12 (s, 1H) 7.93 (d, J = 8.3 Hz, 1H), 7.78 (d, 7 = 8.3 Hz, 1H), 7.37-7.36 (m, 4H) ), 7.33-7.28 (m, 1H), 6.72 (s, 1H), 5.02-4.97 (m, 2H) 4.56-4.47 (br hum, 1H), 1.17 (d, 6.8 Hz, 3H).实施 Example 180: Stupid-2- "(6-{4-"(difluoromethyl) sulphide | a 1 yl} ρ 密-4-yl) amine 1 ethanol.

MS (ESI): mass calcd for C19H16F3N3, 391. NMR (CDC13): 8.66 (s, 1H), 8.00 (d, = 8.5 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.43-7.42 (m, 2H), 7.40-7.37 (m, 2H), 7.34-7.31 (m, 1H), 6.77 (s, 1H), 0 5.03-5.01 (m, 1H), 3.91-3.80 (br hum, 1H), 3.65-3.59 (m, 1H). Example 181: (ΊΙΟ-2-((6-Γ3-gas-4-(trifluoromethane)H篡1 pyridin-4-yl}amine VI-stupylethanol.

MS (ESI): mass calcd for C19H:5C1F3N302, 409.08; m/z, 410.4 [M+H]+ 〇^NMRCCDCls): 8.66 (s, 1H), 8.11 (d, J = 149 200948790 1.9 Hz, 1H ), 7.88 (dd, J= 8.5, 2.2 Hz, 1H), 7.43-7.37 (m, 5H), 7.34-7.31 (m, 1H), 6.68 (s, 1H), 5.36-5.30 (brema peak, 1H), 5.01-4.99 (m, 1H), 3.92_3.85 (br hum, 1 Η), 3.64-3.59 (m, 1H). Example 182: (1RV1-methyl-l-({6-"K-trifluoromethyl, its m-isoxazole-6-yl 1 pyrimidine-4-decylamine) acetamidine.

MS (ESI): mass spectrometer, C20H15F3N4O2, 400.11; m/z, </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; J = 8.2, 1.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.44-7.42 (m, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 1H), 6.81 (s, 1H), 5.53-5.43 (br Junfeng ' 1H), 5.01 (dd, /= 7.4, 3.3 Hz, 1H), 3.95-3.87 (br dry peak, 1H), 3.65-3.60 (m, 1H) .例例例183 : (1RV2"『6-(2,2-Difluoro-1·3-莫#二恶茂_5-某V密定定-4-基一胺基丨-1-笨某r▲ alcohol.

The title compound was synthesized using a method similar to that described in Example 20, and the modification of Step B was as follows: Free B (2R)-2-[(6-a)- (75 mg, 0.30 mmol), 2,2-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[ 1,3]dioxazole (85 mg, 0.30 mmol), Pd(OAc) 2 150 200948790 (1.3 mg, 0.006 mmol, 2 mol 〇/〇), 2-dicyclohexylphosphino-2', 6'-di Methoxy-1,1'-biphenyl (S-Phos) (4.9 mg, 0.012 mmol, 4 mol%) and K3P04 (191 mg, 0.900 mmol) were dissolved in dioxin (1.0 mL) by making N2 The effervescent enters the solvent and water (0.1 mL) in the sealed tube and is degassed. The tube was rinsed with N2, heated at 100 °C for 16 h, then cooled to rt and filtered through a pad of Celite. The celite was washed with CH2C12 (5 mL) and the filtrate was concentrated to dry. The crude was purified by EtOAc (EtOAc) MS (ESI): mass calcd for C19H15F2N303, 371.11; m/z. NMR (CDC13): 8.64 (s, 1H), 7.73-7.71 (m, 2H), 7.43-7.37 (m, 4H), 7.34-7.30 (m, 1H), 7.14-7.12 (m, 1H), 6.65 (d, J = 1.1 Hz, 1H), 5.31-5.25 (br|S peak, 1H), 5.01-4.99 (m, 1H), 3.91-3.85 (br hum, 1H), 3.64-3.59 (m, 1H) . Example 18 4 to 18 7 was prepared using a method similar to that described in Example 18 3 . Example 184: (ΠΟ-1-裟-2-(76-Γ5-(trifluoromethyl VI-pyridin-2-yl 1 pyrimidin-4-yl decylamine) ethanol triterpenoid acetate.

]^(1): Mass spectrometry calculation: (211116?3]^3〇8,415.10; 111/2: experimental value, 416.4 [M+H]+ ° 1HNMR(CD3OD): 8.61 (s, 1H), 8.31 (s , 1H), 8.22, (s, 1H), 8.20 (d, J= 8.5 Hz, 1H), 7.75 (d, /= 8.5 Hz, 1H), 7.45 (d, J= 8.0 Hz, 2H), 7.38- 7.35 (m, 2H), 151 200948790 7.30-7.27 (m,1H),7.08 (s,1H), 4.96-4.93 (m,1H), 3.92-3.86 (m, 1H), 3.78-3.74 (m, 1H Example 185: Phenyl-2-({6-"5-(trifluoromethyl)-1-benzoin-2-yl-1pyrimidin-4-ylindenyl)ethanol trifluoroacetic acid salt.

MS (ESI): mass calcd for C21.m. 4 NMR (CD3OD): 8.57 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.46-7.41 (m, 3H), 7.38- 7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.05 (s, 1H), 4.95-4.92 (m, 1H), 3.90-3.83 (m, 1H), 3.78-3.72 (m, 1H). Example 186: (1RV1-Mucto-2-((6•丨6-(trifluoromethyl)-1-)#thiophen-2-yl 1pyrimidin-4-ylguanidino)ethanol trifluoroacetate .

珥8珥81): Mass spectrometry calculation: (21111疋3]^3〇8,415.10; 111/2 experimental value, 416.4 [M+H]+°^NMR (CD3OD): 8.56 (s, 1H), 8.37 (d, J = 0.8 Hz, 1H), 8.17 (s, 1H), 8.12 (d, 8.3 Hz, 1H), 7.71 (dd, J= 8.3, 1.5 Hz, 1H), 7.45 (d, J= 7.3 Hz, 2H) , 7.38-7.34 (m, 2H), 7.29-7.25 (m, 1H), 7.08 (s, 1H), 4.95-4.92 (m, 1H), 3.90-3.80 (m, 1H), 3.73 (dd, ·/ = 13.6, 7.6 Hz, 1H). 200948790 Example 187: (lRV2-U6-d._l-mosa thiophene-2-yl)pyrimidine _4-yl 1 amide 丨-1- stupid 匕 匕ν

Ο ❹ MS (ESI): mass spectroscopy for C2 〇H16FN3OS, 365.10; m/z, 366.4 [M+H] + 〇!H NMR (CDC13): 8.62 (s, 1H), 7.85 (s, 1H), 7.79 (dd, J= 8.8, 4.7 Hz, 1H), 7.47 (dd, 9.3, 2.5 Hz, 1H), 7.44-7.38 (m, 4H), 7.34-7.31 (m, 1H), 7.14 (td, J= 8.8, 2.5 Hz, 1H), 6.74 (d, J = 1.1 Hz, 1H), 5.36-5.31 (br dry peak, 1H), 5.02-4.99 (m, 1H), 3.91-3.86 (m, 1H), 3.64 -3.59 (m, 1H). Example 188: (lR)-2-({6-"3-(pentafluoroethyl Vl, 2-mole #isoxanthene-6.yl 1 gu -4-ylindolyl)-1- Stupid ethanol three I acetate.

MS (ESI). Mass Spectrum </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> C21H15F5N4O2, 450.11; m/z experimental value, 451.2 [M+H]+. Ill NMR (CD3OD): 8.74 (s, 1H), 8.36 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.94 (dd, J= 0.8, 8.4 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H), 7.36 (t, /= 7.3 Hz, 2H), 7.28 (t, 7 = 7.1 Hz, 1H), 7.14 (s, 1H), 4.97-4.95 (m, 1H), 3.96- 3.93 (m, 1H), 3.84-3.80 (m, 1H). Example 189: 2-({6-"3_Chloro_4_(trifluoromethyl) jasmine i a pyrimidine _4_摹} fluorenyl)-1-"2-(difluoromethoxy) mos 1乙醢. 153 200948790

The title compound was prepared using a procedure similar to that described in Example 130. MS (ESI): mass calcd for C2 〇H15C1F5N302, 459. 〇8; m/z </ RTI>, 46 〇] [M+H]+° NMR ((CD3)2CO): 8.53-8.48 (m, 1H), 8.28-8.18 (m, 1H), 8.11-8.03 (m, 1H), 8.00 (d, g.2 Hz, 1H), 7.73-7.56 (m, 2H), 7.41-7.30 (m, 1H), 7.28- 7.24 (m, 1H), 7.16-7.12 (m, 2H), 5.65 (d, 3.5 Hz, 1H), 5.14-5.08 (m, 1H), 3.76-3.56 (m, 1H), 3.57-3.45 (m, 1H).实城你丨190 : 2-({6-"3-Gas-4-(Trifluoromethyl) 哺-4--4-] face its VW4-Fluoro-based) ethanol.

The title compound was synthesized using a procedure analogous to that described in Example 130. The modification of Step A was as follows: Step A: 2-Amino-1-(4-A-phenyl-V-ethanol. From 2-Amino-1-(4) To a solution of fluoro-p-phenyl)-ethanone I (150 mg, 0.9 mmol) and MeOH (5 mL), EtOAc (EtOAc) Diluted with EtOAc and washed with a sat. NH4CI solution, then dried (Na.sub.2). Rabbits B. MS (ESI): Mass calc. for C19H14C1F4N30, 411.08; m/z </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR (CDC13): 8.70 (s, 1H), 8.17-8.10 (m, 1H) , 7.95 (d, J = 8.2 Hz, 1H), 7.80 (d, 8.2 154 200948790

Hz, 1H), 7.44-7.37 (m, 2H), 7.15-7.03 (m, 2H), 6.92-6.58 (m, 1H), 5.44-5.27 (m, 1H), 5.07-4.94 (m, 1H), 3.98-3.81 (m, 2H), 3.61 (ddd, 14.0, 7.5, 5, 2 Hz, 1H). Example 191: 4-"2-((6-|~3-Chloro-_4:(trifluoromethyl)phenyl)-pyrimidinyl VI-hydroxyethyl 1 jasmononitrile.

The title compound was synthesized using a method similar to that described in Example 130, and the modification of Step A was as follows: Step Α. 4-Γ2-Amino-1-hydroxy-ethyl-yl)-Baojia remained. 4-(2- A solution of bromo-ethenyl)-benzonitrile (1 g, 4·5 mmol) and THF (17 mL) was added &lt;RTIgt;&lt;/RTI&gt; The solution was warmed to rt at 1 h. MeOH (4 mL) was slowly added to the reaction vessel and the mixture was stirred for another 30 min. The reaction mixture was dried with EtOAc (EtOAc)EtOAc. The mixture was stirred at rt 12 for 12 h and then concentrated. The residue was dissolved in water and extracted with EtOAc. The organic layer was dried (Na 2 S 4) and concentrated. The crude residue was purified (EtOAc) eluting MS (ESI): mass spectrometer, C20H14ClF3N4O, 418.08; m/z. 4 NMR((CD3)2CO): 8.69-8.39 (m, 2H), 8.29-8.19 (m, 1H), 8.14-8.05 (m, 1H), 8.00 (d, 8.3

Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.71-7.55 (m, 2H), 7.19-7.06 (m, 1H), 5.94-5.75 (m, 1H), 4.98-4.76 (m, 1H), 3.77-3.55 (m, 1H), 3.54-3.44 (m, 1H). 155 200948790 Example 192: 2-((6-丨3-nitro-4-(trifluoromethyl)phenyl) 1 pyridin-4-one} face group)-1-naphthalen-2-ylethanol.

The title compound was synthesized using a procedure similar to that described in Example 191. MS (ESI): m.p. 'HNMR (CD3OD): 8.58-8.44 (m,1H), 8.22-8.07 (m, 1H), 8.05-7.73 (m, 6H), 7.60 (dd, J=8.5, 1.66 Hz, 1H), 7.49-7.41 (m, 2H), 7.04-6.89 (m, 1H), 5.20-4.97 (m, 1H), 3.95-3.79 (m, 1H), 3.74 (dd, 13.8, 7.4 Hz, 1H). Example 193: 2_({6-Γ3-氱-4-[trifluoromethyl)phenyl 1 pyridin-4-yl} face group)-1-(4-pyridine-2-one cage) .

Step A: 2-Nitropyridin-2-yl-lamyl Vethanol. Due to 4-pyridin-2-yl-benzaldehyde (346 mg, 1.9 mmol) and N02CH3 (0.3 mL) in THF (5 mL) Add ΚΟΗ (2·5 M, 1.13 mL) to the cooled (〇°C) solution of (2.5 mL). The reaction mixture was stirred at 〇 ° C for 30 min and then quenched with saturated NH 4 C 1 solution. The aqueous mixture was extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude residue was purified (EtOAc EtOAc) Step B: 2-Amino-1-(4-pyrimidin-2-indole-V-ethanol. From 2-nitroso 200948790 -1-(4-pyridine-2-yl-phenyl)-ethanol (275 mg NEUC1 (900 mg, 16.9 mmol), Zn powder (hl〇g, 16.9 mmol) and water (1 mL) were added to a solution of 丨"mm〇1) and acetone (5 mL). The reaction mixture was stirred at rt 2 The filtrate was washed with EtOAc EtOAc (EtOAc)EtOAc. The title compound was triturated using a method similar to that described in Example 130. MS (ESI): Mass calc. for C24H18C1F3N40, 470.11; m/z experimental enthalpy, 471.5 [M+H]+. NMR (CDC13): 8.70-8.69 (m,1H), 8.12 (s, 1 Η), 8.01 (d, J =8.3 Hz, 2 H), 7.92 (d, J =8.5 Hz, 1 H), 7.78-7.70 (m, 3 H), 7.53 (d, J = 8.3 Hz, 2H), 7.26-7.22 (m, 2H), 6.73 (s, 1 H), 5.36-5.26 (m, 1H), 5.11-5.06 (m, 1H), 4.02-3.93 (m,1H), 3.70-3.64 (m,1H). Example 194: 2-((6-丨3-Ga-4-(Trifluoromethyl)-M-I pyrimidine-4-臬1amino)-1-(4-purine-2-methyl)ethanol

The title compound was synthesized using a procedure similar to that described in Example 193. MS (ESI): mass calcd for C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 8.6 Hz, 1H), 7.79 (d, 8.3 Hz, 1H), 7.66-7.62 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.32 (ddd, J= 6.2, 4.3, 1.1 Hz , 2H), 7.11 (dd, 5.1, 3.6 Hz, 1H), 6.75 (s, 1H), 5.14-4.96 (m, 1H), 3.73-3.58 (m, 1H), 3.53-3.49 (m, 1H). 157 200948790 Example 195: 1-Linked 4-yl-&gt;({6_"3-disorder-4-(three-stringed methyl, benzodiazepine-4-ylguanidino)ethanol.

The title compound was synthesized using a procedure similar to that described in Example 130. The modification of Step A was as follows: Step A. 2-Amino-1-Lino-4-yl-ethanol. From 1-Benzene-4-yl-2 - 淳 _ solution of ethyl ketone (412 mg, 1.5 mmol) and EtOH (6 mL) was added to Nasdaq and NaN3 (107 mg, 1.6 mmol). The mixture was stirred at rt for 2 h and then cooled to 0 °C. NaBH4 (61 mg, 1.6 mmol) was added and the mixture was stirred for 45 min. A mixture of CuS04.5H20 (37 mg) / NaBH4 (28 mg) in MeOH (2 mL) (br.) was prepared from EtOAc EtOAc EtOAc EtOAc . This slurry was poured into the reaction mixture. Allow the reaction vessel to slowly warm to the surface. After the addition of the slurry, 3 paws were added to the additional amount of NaBH4 (28 mg). The reaction was stirred at rt for 2 h. The mixture was filtered through a pad of Celite, adhered to silica gel (7_8 g) and purified (FCC) to give the title compound (256 mg, 8 〇%). Step Dyes MS (ESD: Mass Spectrometry C25Hi9aF3N3〇, 469 12 ; m/z Experimental value, 470.2 [Μ + ΗΓ. iH NMR (CDCl3): 8 69 (s, m), 8.15-8.08 (m, 1H), 7.92 (d, J = 8 lHz, m), 7 77 (dj=8 2

Hz, 1H), 7.61 (d, J= 8.0 Hz, 2H), 7.58 (d, 7 = 7.9 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 7.45 (t, 7.7 Hz, 2H) , 7.39-7.33 (m, 1H), 6.74 (s, 1H), 5.52-5.29 (m, 1H), 5.11-4.96 (m, 1H), 4.03-3.82 (m, 1H), 3.70-3.63 (m, 1H) 〇158 200948790 Examples 196 to 218 were prepared in a manner similar to that described in Example 195. 1 _(1_表开)-2-({6_"3-乱- 4-(dimethylmethyl) jasmonyl 1 pyrimidin-4-ylindenyl)ethanol.

〇MS (ESI): mass spectroscopy for C21H15ClF3N3OS, 449.06; m/z, 450.1 [M+H]+°]H NMR (CDC13): 8.70 (s, 1H), 8.11 (s, 1H), 7.93-7.90 (m, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.77 (d, 8.3

Hz, 1H), 7.75-7.72 (m, 1H), 7.40-7.27 (m, 3H), 6.76 (d, J = 0.9 Hz, 1H), 5.45-5.16 (m, 2H), 4.20-3.91 (m, 1H), 3.86-3.75 (m, 1H). Example 197: 2-(丨6-|~3-Ga-4-(trifluoromethyl)phenylpyrimidin-4-yliamine Fluoro-4-(trifluoromethyl)phenyl 1ethanol.

MS (ESI): m.p. 4 NMR (CDC13): 8.72 (s, 1H), 8.13 (d, J = 0.7 Hz, 1H), 7.94 (dd, /- 8.3, 0.8 Hz, 1H), 7.79 (d, 8.2

Hz, 1H), 7.61 (t, J= 7.6 Hz, 1H), 7.33-7.27 (m, 2H), 6.78 (d, J= 1.1 Hz, 1H), 5.43-5.16 (m, 1H), 5.12-5.04 (m, 1H), 4.05-3.86 (m, 1H), 3.62 (ddd, */= 14.6, 6.8, 5.8 Hz, 1H). 159 200948790 Example 198: 2-((643-Aza-4-(trifluoromethyl)methyl 1 pyrimidin-4-yl}amino)-1-(3-"(trifluoromethyl)sulfanyl 1 stupid base} ethanol.

MS (ESI): m.p. 4 NMR (CDC13): 8.69 (d, 0.7 Hz, 1H), 8.11 (s, 1H), 7.92 (dd, 8.2, 0.8 Hz, 1H), 7.78 (d, 8.3

Hz, 1H), 7.72-7.69 (m, 1H), 7.63-7.57 (m, 1H), 7.56-7.52 (m, 1H), 7.44 (t, J= 7.7 Hz, 1H), 6.74 (d, /= 1.1 Hz, 1H), 5.42-5.19 (m, 1H), 5.04 (dd, 7.2, 2.9 Hz, 1H), 4.02-3.81 (m, 1H), 3.62 (ddd, 14.3, 7.2, 5.4 Hz, 1H). Example 199: 2-({6_"3-Gas-4-(trifluoromethyl)phenyl 1 pyrimidin-4-yl}amino)-1-(2,3-dihydro-1,4-benzene And dioxo-6-yl)ethanol.

MS (ESI): m.p. 4 NMR (CDC13): 8.67 (s, 1H), 8.12 (s, 1H), 7.93 (d, 7.9 Hz, 1H), 7.78 (d, 8.2 Hz, 1H), 6.96-6.89 (m, 1H), 6.88 -6.86 (m, 2H), 6.73-6.70 (m, 1H), 5.42-5.28 (m, 1H), 4.90-4.87 (m, 1H), 4.35-4.18 (m, 4H), 3.92-3.76 (m, 1H), 3.62-3.54 (m, 1H). Example 200: 2-(丨6-"3-Gas-4-(trifluoromethyl)methyl 1 pyrimidin-4-yl}amine imidazol-1-yl)phenyl 1 ethanol. 160 200948790

]^): Mass spectrometry calculation: (221117(^3]^50,459.11; 111/2 experimental value, 460.1 [M+HfJHNMRCCDCb): 8.71 (s,1H), 8.12 (s,1H), 7.94 (d, J= 8.5 Hz, 1H), 7.84 (s, 1H), Ί.19 (d, J= 8.3 Hz, 1H), 7.55 (d, 8.3 Hz, 2H), 7.41 (d, J= 8.5 Hz, 2H), 7.29 -7.27 (m, 1H), 7.23-7.20 (m, 1H), 6.78-6.77 (m, 1H), 5.47-5.31 (m, 1H), 5.10-5.07 (m, 1H), 4.12-3.81 (m, 1H), 3.74-3.55 (m, 1H). Example 201: 1-Π-Momothiophene-3-V-((6-"3-indol-4-(trifluoromethyl)phenyl)pyrimidine -4-ylaminoamine)ethanol.

MS (ESI): mass calcd for C.sub.sup.sup.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss = 8.1 Hz, 1H), 7.90-7.82 (m, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.52-7.47 (m, 1H), 7.46-7.35 (m, 2H), 6.68 (s, 1H), 5.47-5.34 (m, 2H), 4.21-4.01 (m, 1H), 3.77 (ddd, /= 14.3, 7.0, 5.4 Hz, 1H). Example 202: 2-((6-"3-Aza-4-(trifluoromethyl)methyl 1 pyridin-4-yl}amino)-1-(3,4-dimethoxyphenyl) Ethanol. 161 200948790

MS (ESI): mass calcd for C21.21.21.21.21. Towel NMR (CDC13): 8.82-8.54 (m,1H), 8.17-8.08 (m,1H), 7.93 (d,8·4 Hz,1H),7.81-7.75 (m, 1H), 7.28-7.26 (m , 1H), 6.99-6.84 (m, 2H), 6.75-6.70 (m, 1H), 5.48-5.30 (m, 1H), 5.00-4.90 (m, 1H), 3.94-3.79 (m, 7H), 3.67 -3.57 (m, 1H). o Example 203: 1-(3-Athene-4-oxime oxime)-2-[(6-Γ3-氦-4-Γ三翁.methyl) phenyl 1 pyrimidin-4-yl)amine Some) B. leaven.

MS (ESI): mass calcd for C2 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; H NMR (CDC13): 8.68 (d, / = 0.8 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 7.93 (ddd, *7 = 8.1, 1.5, 0.7 Hz, 1H), 7.78 ( d, J = 8.3 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 2.2, 0.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.74 ( d, J = 1.1 Hz, 1H), 5.45-5.17 (m, 1H), 4.97-4.87 (m, 1H), 3.90 (s, 3H), 3·87-3.82 (m, 1H), 3.59 (ddd, 14.1, 7.4, 5.3 Hz, 1H). Example 204: 2-({6-"3-chloro-4-(trifluoromethyl)-based thiol-pyrimidin-4-yl}-yl)-1-(3,4-dihydro-2H-1 , 5-benzodiazepine heterocyclic therapy 埤-7_ a) diol 162 200948790

MS (ESI): m.p. 4 NMR (CDC13): 8.67 (d, 0.5 Hz, 1H), 8.12 (s, 1H), 7.92 (dd, 8.3, 0.7 Hz, 1H), 7.77 (d, J^ 8.3 Hz, 1H), 7.06-7.01 (m, 1H), 6.98-6.95 (m, 2H), 6.72-6.70 (m, 1H), 5.50-5.11 (m, 1H), 4.92-4.87 (m, 1H), 4.28-4.10 (m, 4H) , 3.91-3.78 (m, 1H), 3.58 (ddd, 13.9, 7.5, 5.3 Hz, 1H), 2.23-2.16 (m, 2H). Example 205: 2-(丨6-『3-Ga-4-(trifluoromethyl)phenyl1pyrimidin-4-yl}amino)-1-"2-fluoro-5-(trifluoromethyl) ) Stupid 1 ethanol.

MS (ESI): mass calcd for C20H13ClF7N3O, 479.06; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, m, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.60-7.53 (m, 1H), 7.17 (t, J = 9.3 Hz, 1H), 6.79 (d, J = 1.1 Hz, 1H), 5.42-5.16 (m, 3H), 4.02-3.84 (m, 1H), 3.80-3.71 (m, 1H). Example 206: 3-"2-({6-f3-Aza-4-(trifluoromethyl)phenyl)pyrimidin-4-yl} geminyl)-1-lightylethyl 1 bromoonitrile.

163 200948790 MS (ESI): mass calcd for C20H14ClF3N4O, 418.08; m/z. iHNMRCCDCl): 8.76-8.66 (m, 1H), 8.15-8.10 (m, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.79 (d, 8.2

Hz, 1H), 7.76-7.74 (m, 1H), 7.67 ((1,/= 7.8 Hz, 1H), 7.62-7.59 (m, 1H), 7.52-7.47 (m, 1H), 6.78 (d, / = 1.0 Hz, 1H), 5.40-5.17 (m, 1H), 5.09-5.04 (m, 1H), 4.03-3.83 (m, 1H), 3.63 (ddd, J = 14.5, 7.0, 5.7 Hz, 1H). Example 207: 2-((6-"3-Chloro-4-(trifluoromethyl)methyl 1 pyrimidin-4-yl}amine

Base)-M3-stylisoxazole-5-yl)ethanol. ▲

OH MS (ESI): mass calcd. for C22H16C1F3N402, 460.09; m/z, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

8.12 (d, J = 0.8 Hz, 1H), 7.91 (dd, J = 8.2, 0.9 Hz, 1H), 7.80-7.75 (m, 3H), 7.48-7.39 (m, 3H), 6.79 (d, J = 1.2 Hz, 1H), 6.63 (d, 0.9 Hz, 1H), 5.44-5.30 (m, 1H), 5.23-5.13 (m, 2H), 4.19-4.11 (m, 1H), 3.98-3.89 (m, 1H) ). Example 208: 2-((6-"3-Chloro-4-(trifluoromethyl)phenyl)pyrimidin-4-yl}amino)-1-(4-pyrrolidin-1-ylphenyl) Ethanol.

MS (ESI): mass calcd for C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, D5 J = 7.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.25-7.24 (m, 2H), 6.75-6.62 (m, 1H), 6.56 (d, J = 8.6 Hz, 2H) , 5.45-5.37 (m, 1H), 4.93-4.78 (m, 1H), 3.89-3.70 (m, 1H), 3.65-3.57 (m, 1H), 3.31-3.22 (m, 4H), 2.07-1.85 ( m, 4H). Example 209: 2_((6-"3-chloro-4-(trifluoromethyl) fluorenyl 1 pyrimidine-4-some>amino)-1_(5-0 ratio bit-2-yl porphin- 2_base)ethanol·

MS (ESI): mass calcd for C22H16ClF3N4OS, 476.07; m/z, s, 477.1 [M+H]+. W NMR (CDC13): 8.68 (d, 0.7 Hz, 1H), 8.55 (ddd, 4.9, 1.7, 1.0 Hz, 1H), 8.14-8.10 (m,1 Η), 7.92 (dd, 8.2, 0.8 Hz, 1H) , 7.75 (d, 8.2 Hz, 1H), 7.71-7.66 (m, 1H), 7.63-7.60 (m, 1H), 7.45 (d, J = 3.7 Hz, 1H), 7.15 Q (ddd, 7.3, 4.9, 1.2 Hz, 1H), 7.05 (dd, 3.7, 0.8 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 5.50-5.34 (m, 1H), 5.29-5.21 (m, 1H), 4.15- 3.93 (m, 1H), 3.77 (ddd, 14.2, 6.4, 5.8 Hz, 1H). Example 210 · 5-"2-({6-"3-Gas-4-(trismethyl)) 某 咬-4-yl] · Cavity)-1-hydroxyethyl 1-2- Fluorobenzonitrile.

165 200948790 MS (ESI): mass calcd for C20H13C1F4N4O, 436.07; m/z. NMR (CD3OD): 8.52 (s, 1H), 8.22-8.16 (m, 1H), 8.02 (d, 8.3 Hz, 1H), 7.9 (d, J= 8.3

Hz, 1H), 7.86-7.76 (m, 2H), 7.35 (t, 7 = 8.9 Hz, 1H), 7.00 (d, /=1.1 Hz, 1H), 5.00-4.95 (m, 1H), 4.95-4.91 (m, 1H), 3.86-3.69 (m, 1H), 3.64 (dd, J = 13.9, 7.2 Hz, 1H). Example 211. 2-(丨6-[~3- gas-4-(trimethylsulfonyl) stupid milha_4_m}amino)-1-(2,6-di-phenyl)ethanol ·

〇MS (ESI): mass calcd for C19H13C1F5N30, 429.07; m/z,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, J = 8.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.30-7.26 (m, 1H), 6.92 (t, J = 8.2 Hz, 2H), 6.80-6.78 (m, 1H), 5.50-5.40 (m, 1H), 5.33 (dt, y = 7.7, 3.6 Hz, 1H), 4.08-3.93 (m, 1H), 3.90-3.81 (m, 1H). Example 212: 2-({6-丨3-Ga-4-(trifluoromethyl)phenyl 1 leucoyl-4-yl]amino)-1-(2-indolyl)ethanol.

MS (ESI): m.p. iHNMR(CDCl3): 8.13 (S,1H), 7.93 (d,J = 8.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.57 (dt, /= 7.3, 1.4 166 200948790

Hz, 1H), 7.34-7.28 (m, 2H), 7.21-7.14 (m, 1H), 7.10-7.02 (m, 1H), 6.82-6.71 (m, 1H), 5.44-5.33 (m, 1H), 5.33-5.27 (m, 1H), 4.05-3.82 (m, 1H), 3.77-3.66 (m, 1H). Example 213: 2-"6-Γ3-Gas-4·•Trifluoromethyl-phenyl"-pyrimidin-4-ylamino-1-1-1-3-(3,4-difluorene-mounted V Isoxazole-5-ylyl--ethyl yeast.

❹ MS (ESI): mass calcd for C22H14C13F3N402, 528. 々NMRCCDCb): 8.71 (s,1H), 8.12 (s, 1H), 7.92 (dd, J = 8.3, 0.7 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.78 (d, J= 8.3 Hz, 1H), 7.62 (dd, 8.3, 2.0 Hz, 1H), 7.52 (d, J '' =8.4 Hz, 1H), 6.81 (d, J= 1.1 Hz, 1H), 6.62 (d, 0.9 Hz , - 1H), 5.43-5.29 (m, 1H), 5.23-5.15 (m, 1H), 4.15 (ddd, J = 14.8, 5.6, 2.3 Hz, 1H), 3.94 (td, /= 14.8, 6.0 Hz, 1H).实施 Example 214: 1-丨3-(4-氪-phenyl)-isoxazole-5-an l-2-"6-(3-nitro-4-trifluoromethyl-phenyl)-pyrimidine 4-A certain amine 1-ethyl hydrazine.

MS (ESI): mass calcd for C22H15Cl2F3N4O2, 494.05; m/z, m, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, 1H), 7.91 (dd, /= 8.2, 0.68 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.74-7.71 (m, 2H), 7.46-7.38 (m, 2H), 6.80 (d , J = 1.1 Hz, 1H), 6.62 (d, J = 0.9 Hz, 1H), 5.44-5.31 (m, 167 200948790 1H), 5.21-5.15 (m, 1H), 4.18-4.11 (m, 1H), 3.99-3.88 (m, 1H).

f run-example 215 : 2-『6·^Α_4-three gas methyl 篡- laughing group V pyrimidin-4-ylamino dichloro-j-iso isomer 4 _5_ its ι_ Λ _ MS (ESI): mass spectrometry calculation c22H14C13F3N402 , 528.01 ; m/z experimental value, 531 [M+H]+. 4 NMR (CDC13): 8.75-8.64 (m, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.50 (d, J=2A Hz, 1H), 7.34 (άά, J = 8.4, 2.1 Hz, 1H), 6.81 (d, 1.1 Hz, 1H), 6.76 (d, 0.8

Hz, 1H), 5.46-5.32 (m, 1H), 5.24-5.18 (m, 1H), 4.20-4.07 (m, 1H), 4.02-3.92 (m, 1H). Example 216: 1- benzothiazol-2-yl-246-(3- gas-4-trifluoromethyl-mosyl)-pyrimidin-4-ylamino 1-ethanol.

MS (ESI): mass spectroscopy for C2 〇H14ClF3N4OS, 450.05; m/z, 451.1 [M+H]+°^NMR CCDCls): 8.71 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.49 (ddd, 8.3, 7.3, 1.2 Hz, 1H), 7.42-7.37 (m , 1H), 6.77 (d, 1.1 Hz, 1H), 5.54-5.40 (m, 1H), 5.35 (dt, 5.3, 2.6 Hz, 1H), 4.37-4.19 (m, 1H), 4.09 200948790 (td5l/= 14.6, 5.8, Hz, 1H). Example 217: M3,5-bis(trifluoromethyl)methyl 1-2-(丨6-"3-gas-4-(trifluoromethyl)phenyl 1 pyrimidin-4-ylguanidino) Ethanol.

MS (ESI): mass calcd for C21.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss m, 3H), 7.83-7.77 (m, 2H), 6.87-6.73 (m, 1H), 5.35-5.23 (m, 1H), 5.19-5.13 (m, 1H), 4.05-3.85 (m, 1H), 3.77-3.64 (m, 1H). Example 218: 1-(5-Bromo-1-mosathiophen-2-yl)-2-((6-"3- gas-4-(trifluoromethyl)phenyl)pyrimidin-4-yl} Amino) ethanol.

MS (ESI): mass calcd for C21.sub.d. 4 NMR (CDC13): 8.86-8.62 (m, 1H), 8.19-8.09 (m, 2H), 7.97-7.87 (m, 1H), 7.83-7.70 (m, 2H), 7.60-7.45 (m, 2H) , 6.84-6.62 (m, 1H), 5.67-5.22 (m, 2H), 4.26-4.02 (m, 1H), 3.81-3.68 (m, 1H). Examples 219 to 221 were prepared using a method similar to that described in Example 20. 169 200948790 Example 219: (1RV ylyl-2-{6-"4-(l,2,2,2-tetrafluoro-1_trifluoromethyl)ethyl V. stupid 1-pyrimidine-4- Aminoguanidine-ethanol

MS (ESI+) ····················· ^NMR (CD3OD): 8.50 (s, 1H), 8.24 (s, 1H), 8.14-8.09 (m, 1H), 7.77-7.69 (m, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.34 (t, 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 4.92-4.90 (m, 1H), 3.74 (br s, 1H), 3.62-3.58 ( m, 1H). Example 220: (1RV mazyl-2_{6-"3-indole, 2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-stupyl~l-mouth dense _4_ Amino group}-ethyl yeast _

MS (ESI+): calcd for C21.sub.sup.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.71 (t, 7.5

Hz, 1H), 7.43 (d, 7.5 Hz, 2H), 7.34 (t, 7.5 Hz, 2H), 7.25 (t, 7.5 Hz, 1H), 4.92-4.89 (m, 1H), 3.74 (br s, 1H ), 3.62-3.58 (m, 1H). Example 221: (1R)-p-styl-2-indole-6-(3-tri-indenyl-stupidyl b~|p-sept-6-yl)-°-densified_4_ethanol·170 200948790

MS (ESI): m.p. 4 NMR (CD3OD): 8.70 (s, 1H), 8.52-8.51 (m, 2H), 8.13 (d, 8.4 Hz, 1H), 7.90 (dd, J = 1.7, 8.6 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.30-7.26 (m, 1H), 7.12 (s, 1H), 4.98-4.95 (m, 1H), 3.95 (dd, 4.2 , 14 Hz, 1H), 3.85-3.80 (m, 1H). Example 222 can be prepared using a method similar to that described in Example 1. Example 222: 4-(3-Chloro-4-trifluoromethyl-phenyl-hydroxyl-_2_smiling ethylamino)-bite--2- bet.

The compounds of the following Examples 223 to 245 are the treasury compounds obtained by our employer from the third group, and therefore we consider that the shackles have found that these compounds have sputum-modulating activity, and therefore A = the therapeutic composition and method of the present invention It has a purpose and is reflected by the test result of the compound shown by 41. ' 171 200948790 Example 223 · 2-·}Τ6-(3,4-Dimethyl phenyl-butan-4-yl January Anki!-1 - stupyl ethanol.

Example 224: 2-({6-丨4-(1,1-Dimercaptoethyl)phenyl 1 pyrimidin-4-yl}amine

Example 225: 2-丨6-(4-mercaptothioalkyl-phenyl)- ̄3⁄411 -4-aminoamine 1-1-phenyl-ethanol.

Example 226 · 4-{6-f(2-peryl-2-phenylethyl)amine 1 密口口-4-yl! Stupid carbonitrile.

Example 227: 2-(6-Bist and 丨bl thiophen-2-yl-pyrimidin-4-ylamino M-styl-ethanol.

172 200948790 Example 228.1-(4-{6-[~(2-peryl-2-phenylethyl)amino group 1. lyophil-4-yl} phenyl) ethyl ketone.

Example 229: 2-f6-(3,4-dimethyl-phenyl-pyrimidin-4-ylamino-1-phenyl-ethanol.

Example 230: 2-U6-(4-methyl-phenyl)pyrimidin-4-yl-1-amino-M-methylethanol.

Example 231: 1-Phenyl-2-f(6-(4-IT trifluoromethyl) fluorenyl 1 phenyl pyridin-4-yl)amino 1 ethanol trifluoroacetate.

Example 232: 2-(6-Benzo"1,31 dioxazol-5-yl-pyrimidin-4-ylamino)-1-phenyl-ethanol.

173 200948790 Example 233 · 2- "6-(3-曱乳- stupid)&quot; 口密口定-4_基月安基1·1·phenyl_ethanol.

Example 234 · 2-"6·(3-石基基基)- 口密口定-4-基月安基1,1·本基乙醇.

Example 235: 24(6-naphthalen-2-ylpyrimidin-4-yl)amino 1-1-phenylethanol,

施 Example 236 · 1 -{5-"6-(2-transyl-2-phenylaminoethyl)- thiophene-4-ylthiophen-2-ylindole-ethanone.

Example 237 · 2_『6·(2,6_二乱-笨基) 口密口定,4·ylamino 1_1-stupyl-ethanol.

Example 238 · 4-『6·(2-carbazhen-2-yl-ethylamino)- 口密口定-4-基1-验· 174 200948790

OH Example 239: 246-(3,5-bis-trifluoromethyl-methyl)-pyrimidin-4-amine

F Example 240. 2-"6-(3-Amino-p-butyryl-4-ylamino-1-yl-phenyl-ethanol.

Example 241: 2-"6-(4-Hydroxymethyl-jaspyrimidin-4-ylamino-1-yl-methyl-ethanol.

Example 242: N-(3-"6-(2-Hydroxy-2-methyl-ethylamino)-pyrimidin-4-yl 1-phenylindole-acetamide.

Example 243. 1-Phenyl-2-(6-stupyl-0 dimethyl-4-ylamino)-ethanol. 175 200948790

OH Example 244 · 1 -styl-2-(6-°cephen-2-yl-.dimethylamino)-ethyl yeast

Example fe 245 · 1 - Stupid base ^-2- (6-ported mouth part 3-base: mouth 唆-4-ylamino group)-By yeast

Comparative Example The compounds of Comparative Examples 1 to 8 below are also the treasury compounds obtained by our employer from the third group, and therefore we consider compounds known per se. The control results of these compounds are shown in Table 2. _ Comparative Example 1 · 2-f6-(2,6-bis-dioxanyl-styl)-mouth g-1,4-ylureanyl 1 phenyl-ethanol.

Control, 4歹! 12 . Ν·经基·2_笨;^-·乙月安嘲咬-4-基1· Stupid 丨-acetamide ·

176 200948790 For 'as usual 3 · 1 _ stupid · 2- (6- stupid &quot; mouth secret _4 · ylamine V ethanol. Ν ^ Ν

OH Comparative Example 4: 2-"6-(2,6-Difluoro-mosyl V pyrimidin-4-ylamino 1-1-stupyl-B

Comparative Example 5 · 1 _Like-2·(6-port cymbal·2_base mouth 密口定_4·基月安基) 乙酉罕·

Control you]6 · yl-2-phenylethylamino)-pain _4·基纷·

Comparative Example 7 · 1 _ Stupid-Base-Body-Bite · 4_Aminoethanol

Comparative Example 8 · 2_"6-(3-月安基-笨基) 口密口定-4·基月安基1 Stupid-ethanol·η2ν, 11

OH Ν^Ν Biological test: 177 200948790 Test method 1

A. Cell transfection of human FAAH The l〇_cm tissue culture dish with confluent monolayer SK-N-MC cells was split for two days prior to transfection (d). Using sterile techniques, the medium is removed and the cells are detached from the culture dish by the addition of chymotrypsin. Place one-fifth of the cells on a new 10-cm culture dish. The cells are at 37. (The incubator was cultured in 5% c〇2 in the minimum essential medium Eaglet containing 10% fetal bovine serum. After 2 ,, the cells were about 80% confluent. These cells were removed from the culture dish using TGase and centrifuged in the clinic. The pellets were prepared in the machine. The pellets were resuspended in 4 〇〇 complete medium and moved to a gap of 0.4 crn between the electrodes. Superspira® human FAAH cDNA (1 μg) was added to the cells and mixed. The voltage for conductance is set at 0.25 kV' and the capacitance is set at 960 pF. After the conductance, the cells are diluted to complete medium (10 mL) and seeded on four i〇_cm dishes. Multiple variability can be inoculated with four different concentrations of cells. The ratios used are 1 ·· 20, 1: 10 and 1: 5, and the remaining cell lines are added to the fourth culture dish. The cells are repaired for 24 h, then added. Medium (complete medium containing 600 g/^mL G418). One day later, the viable cell colonies of the culture dishes were analyzed. Culture dishes containing completely isolated colonies were used. Cells from individual colonies were isolated and tested. Peanut tetraacetate Hydrolysis Measurement of FAAH activity maximum display set falls into for performing - Step B. FAAH Detection Study

T84 cold-twisted cell pellet or transfected SK-N-MC cells (content of 1 X 15 cm culture dish) in 50 mL FAAH detection buffer (125 mM

Tris' ImMEDTA'0.2% glycerol, 0.02% Triton X-1 〇〇, 0.4 mM

Homogenization in Hepes 'pH 9). The assay mixture consisted of 5 〇 cell homogenization 178 200948790, 10 pL test compound and 40 pL arachidonic acid ethanolamine [1-3H-ethanolamine] (3H-AEA, Perkin-Elmer, 10.3 Cj/mmol) (final addition, final Composition with a tracer concentration of 80 nM). The reaction mixture was incubated for 1 h at rt. During incubation, 96-well Multiscreen filters, plates (catalog number MAFCNOB50; Millipore, Bedford, MA, USA) were loaded with 25 pL of activated carbon (Multiscreen column loader, catalog number MACL09625, Millipore) and washed once with 100 pL MeOH . During the incubation period, the 96-well DYNEX # Lite board (catalog number NL510410) is also loaded with 100 // L ❹ MicroScint40 (catalog number 6013641, Packard Bioscience,

Meriden, CT, USA). After 1 h of incubation, the 60/L reaction mixture was transferred to a carbon plate which was then assembled on a DYNEX plate using Centrifuge Alignment Frames (MAF09604, Millipore). Unbound labeled ethanolamine was centrifuged to the bottom plate (at 2000 rpm for 5 min), which was pre-loaded with scintillation counters as previously described. The plates were sealed and left at rt for 1 h before counting on a Hewlett Packard TopCount. Detection method 2 ❹ A. Cell transfection of murine FAAH-1 The l〇-cm tissue culture dish with confluent monolayer SK-N-MC cells was split for two days before transfection (d). Using sterile techniques, the medium is removed and the cells are detached from the culture dish by the addition of trypsin. One-fifth of the cells were placed on a new l-cm dish. The cells were cultured in a 37 °C incubator at 5% C〇2 in the minimum essential medium Eagle containing iO% fetal bovine serum. After 2 days, the cells reached approximately 80% confluence. These cells were removed from the culture dish using trypsin and pelletized in a clinical centrifuge. The pellet was resuspended in a 4 〇〇 pL complete culture. The 'moved to the conductance photodetector' had a gap of 0.4 cm between the electrodes. Supercoiled murine FAAH cDNA (1 μg) was added to the cells and mixed. Electricity for Conduction 179 200948790 The pressure system is set at 0.25 kV and the capacitance is set at 960 gF. After the conductance, the cells were diluted into complete medium (1 〇 mL) and plated on four l〇-cm culture dishes. Because of the variability in conductivity, four different concentrations of cells can be inoculated. The ratios used were 1: 20, 1: 10 and 1: 5, and the remaining cell lines were added to the fourth culture dish. The cells were repaired for 24 h, after which a selection medium (complete medium containing 600 g/pm LG418) was added. After 10 days, the viable cell colonies of the culture dishes were analyzed. Use a culture dish containing completely isolated colonies. Individual cells from individual colonies were isolated and tested. Colonies showing the greatest FAAH activity were measured by arachidonic acid ethanolamine hydrolysis for further study. 〇 B. Detection of rodent FAAH-1

T84 frozen cell pellet or transfected SK-N-MC cells (content of 1 X 15 cm culture dish) in 50 mL FAAH detection buffer (125 mM

Tris, ImM EDTA, 0.2% glycerol, 0.02% Triton X-100, 0.4 mM

Homogeneous in Hepes, pH 9). The assay mixture consisted of 50 pL of cell homogenate, 10 pL of test compound and 40 pL of arachidonic acid ethanolamine [1-3H-ethanolamine] (3H-AEA, Perkin-Elmer, 10.3 Cj/mmol) (final addition, final indication The composition of the tracer concentration is 80 nM). The reaction mixture was incubated for 1 h at rt.期间 During the incubation period, the 96-well Multiscreen plate (catalog number MAFCNOB50; Millipore, Bedford, MA, USA) was loaded with 25 pL of activated carbon (Multiscreen column loader, catalog number MACL09625, Millipore) and washed once with 100 pL MeOH . During incubation, the 96-well DYNEX // Lite plate (catalog number NL510410) was also loaded with 100 μL MicroScint40 (catalog number 6013641, Packard Bio?cience, Meriden, CT, USA). After 1 h of incubation, the 60 μL reaction mixture was transferred to a carbon plate, which was then subjected to Centrifuge Alignment Frames.

ISO 200948790 No. MACF09604, Millipore) is assembled on the DYNEX board. Unbound labeled ethanolamine was centrifuged to the bottom plate (at 2000 rpm for 5 min), which was preloaded with scintillation counters as previously described. The plates were sealed and left at rt for 1 h' and counted on a Hewlett Packard TopCount. The results of the example compounds tested in this test are presented in Table 1. The results of the control compounds tested in this assay are presented in Table 2. When the activity table is not greater than (&gt;) a specific value, the value is the solubility limit of the compound in the test medium or the highest concentration tested by the test. The term "NT" in the table indicates that the compound has not been tested.

181 200948790 13 0.035 0.250 134 0.027 0.019 14 0.006 0.013 135 0.100 0.016 15 0.026 0.068 136 0.084 0.340 16 0.004 0.005 137 0.920 5.000 16A 0.0057 0.0076 138 0.371 10.000 17 0.012 0.010 139 2.000 10.000 18 0.005 0.097 140 0.127 0.265 19 0.020 0.012 141 0.012 0.005 20 0.032 0.181 142 0.009 0.060 21 0.340 1.500 143 6.00 4.00 22 0.081 0.270 144 0.015 0.003 23 5.000 10.000 145 7.00 2.00 24 0.013 0.208 146 0.026 0.004 25 0.390 10.000 147 0.205 1.600 26 0.052 0.163 148 3.000 &gt;10 27 0.024 0.120 149 0.412 10.000 28 0.025 0.064 150 1.500 5.000 29 0.008 0.026 151 10.000 10.000 30 0.007 0.034 152 4.000 &gt;10 31 0.003 0.021 153 0.303 10.000 32 0.092 1.000 154 0.065 1.200 33 0.270 2.000 155 0.060 0.270 34 0.500 10.000 156 0.018 0.066 35 0.043 0.180 157 2.000 4.000 36 0.008 0.020 158 3.464 0.110 182 200948790 37 0.400 8.000 159 0.020 0.007 38 0.027 0.260 160 0.150 0.290 39 0.018 0.060 161 10.000 0.580 40 0.766 &gt;10 162 0.570 0.130 41 0 .005 0.010 163 2.000 2.000 42 0.206 0.793 164 0.015 0.014 43 0.088 0.446 165 0.004 0.019 44 0.050 0.600 166 3.000 10.000 45 0.150 0.600 167 0.060 0.020 46 0.013 0.026 168 0.066 0.042 47 0.026 0.510 169 6.001 8.000 48 0.105 1.500 170 0.081 4.000 49 0.002 0.009 171 1.600 &gt;10 50 0.092 0.985 172 8.000 1.500 51 0.004 0.007 173 0.002 0.011 52 1.400 10.000 174 0.002 0.005 53 0.765 &gt;10 175 0.002 0.003 54 0.277 0.443 176 0.009 0.010 55 0.020 1.700 177 0.003 0.003 56 0.002 0.040 178 0.008 0.070 57 0.029 0.535 179 0.009 0.040 58 0.104 0.470 180 0.001 0.011 59 0.307 1.000 181 0.007 0.020 60 0.006 0.028 182 0.010 0.004 61 0.006 0.028 183 0.036 0.089 183 200948790 62 0.002 0.003 184 0.031 0.160 63 0.450 2.000 185 0.020 0.090 64 0.050 0.220 186 7.071 &gt ;10 65 0.038 6.001 187 0.020 0.400 66 0.073 0.140 188 0.024 0.035 67 0.020 1.200 189 0.170 0.150 68 0.001 0.003 190 0.007 0.012 69 0.900 &gt;10 191 0.019 0.007 70 0.800 &gt;10 192 0.047 0 .006 71 0.014 0.076 193 0.040 0.850 72 0.013 0.188 194 0.011 0.210 73 0.020 0.040 195 0.010 0.400 74 0.101 10.000 196 0.108 0.043 75 10.000 &gt;10 197 0.100 0.034 76 0.014 0.126 198 0.092 0.025 77 1.000 2.200 199 0.500 0.120 78 0.633 &gt; 10 200 0.165 1.600 79 0.542 0.530 201 0.170 0.170 80 0.068 0.665 202 0.225 0.100 81 0.110 0.492 203 0.270 0.200 82 2.000 10.000 204 0.548 0.082 83 0.210 0.654 205 0.080 0.014 84 0.044 0.965 206 0.025 0.015 85 0.018 5.000 207 0.067 0.111 86 0.095 1.200 208 0.028 0.500 184 200948790 87 0.042 1.400 209 0.012 0.036 88 0.065 0.033 210 0.020 0.020 89 1.600 1.400 211 0.056 0.050 90 0.004 0.675 212 0.065 0.039 91 0.003 0.057 213 0.022 0.400 92 0.110 0.850 214 0.036 0.160 93 0.183 0.152 215 0.240 1.000 94 0.060 0.270 216 &gt;10 &gt;10 95 0.018 0.066 217 &gt;10 8.000 96 0.001 0.014 218 &gt;10 1.000 97 0.580 8.000 219 2 &gt;10 98 0.850 8.000 220 0.042 0.69 99 10.000 10.000 221 0.019 0.48 100 0.043 1.400 2 23 0.144 0.707 101 0.032 0.080 224 0.028 0.538 102 0.017 0.050 225 0.011 0.128 103 0.305 0.350 226 0.341 0.663 104 0.130 0.058 227 0.033 0.216 105 0.190 1.000 228 0.026 0.066 106 0.016 0.041 229 0.408 10.00 107 0.240 0.320 230 0.575 3.464 108 0.110 0.150 231 0.031 0.201 109 0.150 0.042 232 0.150 1.00 110 5.000 10.000 233 2.00 NT 111 0.122 0.220 234 &gt;10 &gt;10 185 200948790 112 0.524 0.760 235 0.021 0.324 113 0.018 0.041 236 0.700 4.00 114 0.046 0.043 237 &gt;10 &gt;10 115 0.140 0.205 238 7 &gt;10 116 0.090 0.110 239 &gt;10 &gt;10 117 0.032 0.022 240 &gt;10 &gt;10 118 0.093 &gt;10 241 NT NT 119 0.017 0.055 242 &gt;10 &gt;10 120 &gt;10 &gt;10 243 &gt;10 &gt;10 121 0.580 3.000 244 &gt;10 &gt;10 245 &gt;10 &gt;10

Table 2. Ex. Detection 1 IC5 0 (β Μ) Detection 2 IC5 0 (β Μ) Ex. Detection 1 IC5〇(β Μ) Detection 2 IC50 (β Μ) CE1 &gt;10 &gt;10 CE5 &gt;10 &gt ;10 CE2 &gt;10 &gt;10 CE6 7.00 &gt;10 CE3 &gt;10 &gt;10 CE7 &gt;10 &gt;10 CE4 &gt;10 &gt;10 CE8 &gt;10 &gt;10

While the invention has been described by way of illustrative and preferred embodiments, the invention is not limited to the foregoing detailed description, but is defined by the appended claims.

Ο 187

Claims (1)

200948790 VII Patent application scope: A compound of formula (Ι-A) Ar2 R2 n^ya R3 OH (IA) wherein: R1 is -H, alkyl, -OCm, leuco, -CN, _CF3 '-N(Ra)Rb or monocyclic cycloalkyl, of which Ra and Rb is each independently _H, optionally substituted by _〇H, C(alkyl), N(Rm)Rn 'where RiRn is _H, Q*alkyl; or Κ and Κ are formed together with the nitrogen to be attached a 4- to 7-membered heterocycloalkyl ring; Ar1 is a phenyl, naphthyl group, a 5- or 6-membered monocyclic heteroaryl group at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group at the point of attachment. Each of which is unsubstituted or substituted by the following groups; (1) one or three Re moieties wherein each RC moiety is independently 4 alkyl, -Cl.4 alkyl _OH, _Ci4 alkyl-CN, -CF3, _0H, _〇Ci 4 yard base, _〇CF3, _〇chf2, -〇ch2cf3, -s(〇v2c)_4 burnt base, _SCF3, _s〇2CF3, _CH〇, -COQ-4 alkyl, _c〇2Ci 4 hospital base, _c〇2li, _N(Rd)Re, j〇2NRdRe, _NRds〇2Re, _c(〇)NRdRe, ·2, cn, phenyl, 比pyridyl or dentate, each independently • a 4-base alkyl group, or a nitrogen-connected nitrogen-bonded 4- to 4-membered heterocycloalkyl ring; or an unsubstituted Substituted by one or two fluoro groups - hydrazine (CH2), · 30 - ' and the third ship part (when present) is _Cl_4 200948790 alkyl, -Cm alkyl-OH, -Cm alkyl - CN, -CF3, -OH, -OCm alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(0)〇2Ci_4 alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -CC^ Cw alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -NO2, -CN or halo, wherein Rd&amp;Re are each independently -H or -Cm alkane X is N or C(Rf), wherein Rf is -Η or fluorenyl; Ar2 is: (1) phenyl substituted by the following groups: (a) -, two or three are each in the meta position or The Rg moiety of the para position, and optionally one or two additional Rg moieties in the ortho position; wherein each R% fraction is independently alkyl, alkyl-OH, -Cm alkyl-CN, perhalo Alkyl, all-alkoxy, _0Cl 4 alkyl, -oCmalkyl-(monocyclic cycloalkyl), _s(0)〇2Ci 4 alkyl, _SCf3, -S02CF3, -CHO, -COCm a group, -COzCm alkyl, -C02H, -NCR^R1, -S02NRjRk, -NRhSC^Ri, -C(0)NRjRk, -N02, -CN or _ group; or unsubstituted or via the following groups Alternately oxy, benzyl, phenethyl or benzhydryl: _cU4 alkyl, -Oci 4 alkyl, all-dentylalkyl, perhaloalkoxy, -N02, -CN or halo; Rh is -H or -CV4 alkyl; R1 is -C!.4 alkyl or monocyclic cycloalkyl; or Rh and R1 together with the atom to which they are attached form a monocyclic heterocycloalkyl ring; Is -H or alkyl; and Rk is -Η, -Cm alkyl or monocyclic cycloalkyl; or R and R together with the atom to which they are attached form a monocyclic heterocyclic alkyl group 200948790 ring; or (b The two adjacent Rg moieties together form a monocyclic heteroaryl which is unsubstituted or substituted with one or two fluoro groups - CHJuO-; (11) substituted by one, two or three Rg moieties a group wherein each Rg moiety is independently or two adjacent Rg moieties together form an unsubstituted or one or two fluoro group substituted _〇(CH1)i 2〇—; or (川) a naphthyl or bicyclic heteroaryl group substituted or substituted with one, two or three Ri moieties; wherein each R1 moiety is independently -C _4 alkyl, -OCm alkyl, perhaloalkyl, all Haloalkoxy, -N〇2, -CN or halo; R1 Is -H or fluorenyl; and R2 3 is -H or fluorenyl; however, 'there is a condition that Ar1 is unsubstituted phenyl, Ar1 is not -CHO or para-substituted-〇cf3; or A pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable pre- or a therapeutically active metabolite. 190 1 The compound of claim 1, wherein Ri is _H, methyl, isopropyl, trifluoromethyl, decylsulfanyl, decylsulfinyl, sulfonyl sulfonate, Amino, mercaptoamine, dimethylamino or cyclopropyl. 2 3. The compound of claim 1, wherein R1 is an amine group. 3 For example, the compound of claim 1 of the patent scope, wherein Ri is _H. 5. A compound as claimed in claim 1 wherein Ar1 is a phenyl group which is replaced by one or two, two or three Rc moieties. 6. The compound of claim 1 wherein each ruler is used. Partially independent f is a fluoro group, a chloro group, a nitro group, a trifluoromethyl group, a decyloxy group, a hydroxyl group, or a trifluoromethoxy group, or two adjacent groups are formed together - 〇(CH2)^〇 — or _o(cf2)〇· 〇7· A is a compound of claim 1, wherein Ar1 is stupid, ❹4-fluorophenyl, 4-nitrophenyl, 4·trifluoromethyl Stupid, 4·chlorophenyl, 4-, phenyl, 4-methoxyphenyl, 4-pyridyl-3-decyloxyphenyl, 3,4-diphenyl, 3,4_2 Fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 3-methoxyphenyl: decyloxy, 3,5-dichlorophenyl, 3-trifluorodecyloxy, fluoro Benzo 4-milo-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethyl phenyl-, pyridylpyridyl, 3-pyridyl, 4-pyridyl, 1,3- Benzodioxolyl, or 2,2-difluoro-indole, 3-benzodioxolyl. ❹ 8. The compound of claim 1, wherein the Ar1 is a phenyl group which is unsubstituted or substituted with up to 2 Rc moieties. 9. The compound of claim 1, wherein the X system is C(Rf). 1. A compound according to claim 9 wherein Rf is -η. 11. The compound of claim 3, wherein A# is a phenyl group substituted by one, two or three portions each of a meta or para position. 191 200948790 12. The compound of claim 1, wherein the Ar2 is an oxenyl group, a fluorenyl group, a mouth bite group, or a η thiol group, each of which is substituted by one, two or three Rg moieties. . 13. The compound of claim 3, wherein each Rg moiety is independently methyl, ethyl, isopropyl, tert-butyl, hydroxymethyl, hydrazine-ethylidene, cyanomethyl , cyano-dinonyl-fluorenyl, trifluoromethyl, decyloxydiethoxy, propoxy, isopropoxy, butoxy, isobutoxy, trifluoromethoxy, difluoro Methoxy, trifluoroethoxy, cyclopropylmethoxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, decylsulfonyl, decyl, oxime -Methylamino, morphin-4-yl, aminyl fluorenyl, bis- ylsulfonyl, cyclopropylaminosulfonyl, piperidinyl-sulfonyl, pyridin-1 - sulfonyl, nitro, cyano, chloro, fluoro, iodo, oxy, benzyl, benzhydryl or phenethyl, or two adjacent Rg moieties - forming - oxime (CH2) I_2〇- or _〇(cf2)〇-. 14. 14· The compound of claim i, wherein Αγ2 is 3 4 -didecylphenyl, 4-tert-butylphenyl, 4-cyanophenyl, 4-ethylidene , ❹ 4·decylphenyl, 4-acetoyl, 4-fluorophenyl, d-methylphenyl, 4-methoxyphenyl, 4-decylphenyl, 3-hydrazino, 3_ Trifluoromethoxyphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3,4-dichlorophenyl, 3-phenylphenyl, 314-trifluoromethylphenyl, 4-ethoxy Phenylphenyl, 4·isopropoxyphenyl, 4-phenoxyphenyl, 3·gas·4_ethoxymethyl, 3-chloro-4-isopropoxyphenyl, 3-fluoro-4 -methylphenyl, 4-cysomethylphenyl, 4-bromophenyl, 3-:nonylphenyl, 4-trifluoroethoxyphenyl, 3•trifluoroethoxyphenyl , 4-dis-3-ylphenyl, 4-nitroxylphenyl, 4-chloro-3-phenyl trifluoromethylphenyl, 192 200948790 3-fluoro-4-trifluoromethoxyphenyl, 4-ethyl Oxy-3-fluorophenyl, 4-ethoxy-3-indolylphenyl, 4-cyclopropylmethoxyphenyl, 4-butoxy-3-fluorophenyl, 4-butoxy Phenyl, 3-fluoro-4-propoxyphenyl, 3-fluoro-4.isopropoxyphenyl, 4-isobutoxyphenyl, 4- Oxy-3-indolylphenyl, 3-chloro-4-indolylphenyl, 3,5-dimercaptophenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5- Trifluorodecylphenyl, 3-a-5-fluorophenyl, 4-propoxyphenyl, 4-isopropoxy-3-indolylphenyl, 4-difluoromethoxy-3,5 -difluorophenyl, 4-(cyano-diindenyl-indenyl)phenyl, 4-ethenyl-3-fluorophenyl, 3,5-diindenyl-4-isopropoxyphenyl , 3,4,5-trifluorophenyl, 4-benzylnonylphenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 4-didecylaminophenyl, 4- Mercaptosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl, 3-fluoro-4-decyloxyphenyl, 1,4-benzodioxin-6-yl, 4-dimercaptoyl phthalocyanine phenyl, 4-α chen-1-lanyl phenyl, 4-pyrrolidin-1-sulfonyl phenyl, 3- fluoro-4-fluorophenyl 4-methylsulfanylphenyl, 4-cyano-3-fluorophenyl, 3-cyano-4-fluorophenyl, 4-isopropylsulfanylphenyl, 4-cyanothiol Phenyl, 4-ethylsulfanylphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 3-butoxyphenyl, 4-trifluoromethoxyphenyl, 3-tri Fluorylphenyl, 4-(2-o-indolephenyl-ethyl)phenyl, 3-gas-4 -(1-trans-ethyl-ethyl)phenyl, 4-anthracenephenyl, 4-ethoxy-3-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3-decyloxybenzene , 2,4-bis(trifluoromethyl)phenyl, 2-methoxy-4-(trifluoromethoxy)phenyl, 4-ethoxy-2-methylphenyl, 2,2 -difluoro-1,3-benzodioxan-5-yl, 1,3-benzoquinone-yttrium-pentosyl-5-yl, 5-ethinosyl-2-yl, 6-anthraquinone Base ntb〇-3-yl, 6-ethylidyl π than -3-yl, 6-morphin-4-yl σ ratio ^-3-yl, 6-gas-5-fluorenyl _ mouth bite 3-yl, 6-carbylindole-11--3-yl, 6-(didecylamino)σ ratio -3-yl, 2-morpholin-4-ylpyrimidin-5-yl, or 1 -benzyl-1Η-pyrazol-4-yl. 193 200948790 15. The compound of claim 1, wherein the Ar2 is naphthyl, benzooxadiazolyl, fluorenyl, benzothienyl, quinolyl or oxazolyl, each unsubstituted Or replaced by one, two or three R1 parts. 16. The compound of claim 1, wherein each of the Ri moieties is independently fluorenyl. 17. The compound of claim 1, wherein the Ar2 is naphthyl, 2,1,3-stupid and oxadiazole-5-yl, 1H-indol-5-yl, ΐίΐ-吲哚- 6-yl, 1-methyl-1Η-«pyridin-2-yl, 1-mercapto-1Η-吲哚_5-yl, 5-methyl-1-benzofluorenylthiophen-2-yl, benzene And thiophene stomach 3_yl, benzothiophene-5-yl, quinoline-3-yl or 3-methyl-1Η-carbazole-6-yl. 18. The compound of claim 1, wherein R2 is _Η. 19. The compound of claim 1, wherein R3 is _Η. 20. A compound selected from the group consisting of 1(1R&gt;2_({6-[4-(ethyloxy)_3_(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) _1-stupylethanol; (1RH-stupyl-2-({6_[4_(trifluorofyl)phenyl)pyrimidinyl 1-ylethanol; ()2 ({6-[3-gas_4_(trifluoro曱))phenyl] 〇 _4_yl)amino)_1_ phenylethanol; (^)-2-({6-[3_chloro_4·(trifluoromethyl)phenyl]pyrimidine _ 4_yl}amino) small phenylethanol hydrochloride; 194 200948790 (lR)-2-({6-[4-(l-methylethyl)phenyl]-)-yl-amino} )_ι_phenylethanol; (lR)-2-[(6-{3-chloro-4-[(1·methylethyl)oxy]phenyl}pyrimidinyl)amino]-1-benzene (lR)-2-{[6-(3-fluoro-4-mercaptophenyl) phosphin-4-yl]amino hydrazine-phenylethanol; (lR)-2-({6_[ 4-(hydroxymethyl)phenyl]pyrimidin-4-yl}amino)_1-phenylethanol; ^ 4-(6_{[(2R)-2-Phenyl-2-phenylethyl]amine }唆唆_4_基)phenylfurfural; 3-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenylfurfural; (1R) 1-phenyl-2-[(6-{4-[(2,2,2-trifluoroethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; (1R)-1 -phenyl-2-[(6-{3 [(2,2,2-trifluoroethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; (lR)-2-{[6-(4-gas-3-fluorenyl) Phenyl)pyrimidin-4-yl]aminophenylhydrazine Ethyl alcohol; (lR)-2-{[6-(4-Ga-3-fluorophenyl)pyrimidin-4-yl]aminopurinyl-phenyl Ethanol; (lR)-2-({6_[4-chloro-3-(-trifluoromethyl)phenyl]pyrimidin-4-yl}amino)+phenylethanol; (lR)-2-({6- [3-fluoro_4_(trifluoromethoxy)phenyl]pyrimidinyl}amino)-1-phenylethanol; (lR)-2-{[6-(4-ethoxy-3-oxide Phenyl) mouth bit I group] amine H phenylethanol; 195 200948790 (lR)-2-{[6-(4-ethoxy-3-indolylphenyl)pyrimidin-4-yl]amino} -l-phenylethanol; (lR)-2-({6-[4-(cyclopropyldecyloxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (11^ -2-{[6-(4-Butoxy-3-phenylphenyl)'7-denyl-1-1-phenyl]amino}-1-phenylethanol; (lR)-2-{[ 6-(4-Butoxyphenyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(3-fluoro-4-propoxyphenyl) Pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[3-fluoro-4-(1-mercaptoethoxy)phenyl]pyrimidin-4-yl }amino)-1-phenylethanol; (lR)-2-({6-[4-(2-methylpropoxy)phenyl]pyrimidine-4- }Amino)-1-phenylethanol; (lR)-2-{[6-(4-decyloxy-3-methylphenyl)pyrimidin-4-yl]amino}-1-phenylethanol (11^)-2-{[6-(3-Ga-4-indolylphenyl) '1 dimethyl 11 -4-yl]amino}-1-phenylethanol; (lR)-2- {[6-(3,5-Dimercaptophenyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[3-fluoro-4-(three) Fluorinyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3-fluoro-5-(trifluoromethyl)phenyl]pyrimidine 4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(3-a-5-fluorophenyl)pyrimidin-4-yl]amino}-1-phenyl Ethanol; 196 200948790 (1R)-1-phenyl-2_{[6-(4-propoxyphenyl)pyrimidinyl]amino}ethanol; (lR)-2-{[6-(2,l , 3-benzooxadiazole _5-yl)pyrimidin-4-yl]amino}Phenylphenylethanol; (lR)-2-({6-[3-indolyl-4-(1-fluorenyl) Ethoxy)phenyl]0-1,4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3- gas-4-(trifluoromethyl)phenyl] -mercaptopyrimidin-4-yl}amino)-1-phenylethanol; (1R)-2-({6-[3-|l-4-(trifluoromethyl)phenyl]-5-A (pyridyl-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[4-(difluoromethoxy)-3,5-difluorophenyl]-anthracene- 4 -yl}amino)-1-phenylethanol; 2-[4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl] -2-methylpropanonitrile; 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidine-4-yl)phenyl] Ethyl ketone; (lR)-2-({6-[3,5-dimethyl-4-(1-methylethoxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol (lR)-2-{[6-(lH-indenyl)pyrimidin-4-yl]amino}p-phenylethanol; (1R)-1-phenyl-2-{[6-(3 , 4,5-trifluorophenyl)-densyl]amino}ethanol; (lR)-2-{[6-(l-methyl-1H-indol-2-yl)u-milidine ice-based] Aminobutyl 1-phenylethanol; (lR)-2-{[6-(5-methyl-1-benzothiophen-2-yl)pyrimidin-4-yl]amino}-1-benylethanol ; 197 200948790 [4-(6-{[(2R)-2-Phenyl-2-phenylethyl]amino} 啶 _ 4-yl) phenyl] (phenyl) ketone; (lR) -2-{[6-(3,5-difluorophenyl)pyrimidin-4-yl]aminodiphenyl 1-phenylethanol; (lR)-2-{[6-(3,4-difluorobenzene ()pyrimidin-4-yl]amino}}_ι_phenylethanol; (lR)-2-({6-[3- gas-4-(trifluoromethyl)phenyl]-2-(mercaptosulfuryl) Alkyl)pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-({2_fecyl-6-[3- gas-4-(trifluoromethyl)benzene) Mouth bit-4-yl]·Amino)-1-phenylethanol; (lR)-2-({H3·Chloro_4_(trifluoromethyl)phenyl]- phenant-4-yl}amino )-1-(4-fluorophenyl)ethanol; (lR)-2-{[6-(6-decyloxypyridin-3-yl)pyrimidin-4-yl]amino}-1_phenyl alcohol (lR)-2-{[6-(6-ethoxyβ is more than _3_yl) biting _4_yl]aminopyrylethanol; (lR)-2-({6-[ 4-(didecylamino)phenyl ρ _4_yl}amino) small phenylethanol; (lR)-2-({6-[4-(indolyl)phenyl] 〇4_yl}amino) small phenylethanol; N-cyclopropyl-4-(6-{[(2R)-2-yl-2-phenylethyl]amino} Bite _4 base) Benzoamine, (lR)-2-{[6-(3-chloro-4-ethoxyphenyl)carcinoma _4_yl]amino}-1-phenylethanol (lR)-2-[(2'-morpholin-4-yl-4,5'-bipyrimidin-6-yl)amino]-1-phenylethanol; 198 200948790 (lR)-2-{ [6-(6-morpholin-4-ylacridin-3-yl)pyrimidin-4-yl]amino}-l-phenylethanol; (lR)-2-{[6-(3fluoro-4 - decyloxyphenyl)-pyridin-4-yl]amino}p-phenylethanol; (lR)-2-{[6-(2,3-dihydro-1,4-benzodioxin- 6-yl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)) (2-R-yl)pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(l-benzyl-1H-indazol-4-yl)pyrimidine- 4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(6-fluoro-5-fluorenylacridin-3-yl)pyrimidin-4-yl]amino} 1-phenylethanol; - 4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)-indole, anthracene-indenyl stupid amine; 5-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)acridin-2-indene nitrile; (lR)-2-({6-[ 6-(dimethylaminobenzimidin-3-yl]pyrimidin-4-yl}amino)-1-phenylethanol; (1R)-1-phenyl-2-({6-[4- (piperidin-1-ylsulfonyl)phenyl]pyrimidine_4_yl}•amino)ethanol; phenyl_2-({6_[4-decapyridin-1-ylsulfonyl)phenyl] Pyrimidine·4_yl}amino)ethanol; 4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyridinyl-4-yl)benzamine; lR)-2-{[6-(4-fluorophenyl pyridine-4-yl)aminopurin-phenylethanol; 199 200948790 (lR)-2-{[6-(3-gas-4- Fluorophenyl)glycine_4_yl]amino}p-phenylethanol; (1R)_2-({6-[3_(mercaptosulfanyl)phenyl]eridine-4-yl}amino) -1-phenylethanol; (lR)-2-{[6-(lH-吲哚_5_yl)pyrazine_4 (1R)-1-phenyl-2-[(6-quinolin-3-ylpyrimidin-4-yl)amino]ethanol; (lR)-2-{ [6-(l-benzothiophene-3-yl)pyrimidin-4-yl]aminobenz-phenylethanol; 2-fluoro-4-(6-{[(2R)-2-hydroxy-2-benzene Ethylethyl]amino}pyrimidin-4-yl) © benzoquinone; 2-fluoro-5-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidine-4 -yl)benzonitrile; _(lR)-2-{[6-(l-methyl-1H-indol-5-yl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-[(6-{4-[(l-decylethyl)sulfanyl]phenyl}pyrimidin-4-yl)amino]-1-phenylethanol; [4-(6 -{[(2R)-2-hydroxy_2.phenylethyl]aminopyrimidin-4-yl)phenyl]indole acetonitrile; (lR)-2-({6-[3-chloro-4- (trifluoromethyl)phenyl]_2(trifluoromethyl)pyridin-4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(3,4-dichloro Phenyl) 2 - fluorenylpyrimidin-4-yl]amino}_丨-phenylethanol; (lR)-: 2-{[6-(3'4-dichlorophenyl)-indolyl_4_yl Aminodiphenylethanol; 200 200948790 (lR)-2-({6-[4-(ethylsulfanyl)phenyl]pyrimidinyl)amino)-1-phenyl.ylethanol; lR)-2-{[6-(3-ethoxyphenyl)pyrimidin-4-yl]amino}-1-phenylethyl Alcohol; (1R)-1-phenyl-2·{[6-(3-propoxyphenyl) pulverized _4_yl]amino}ethanol; (lR)-2-{[6-(3 -butoxyphenyl) 唆_4_yl]aminopipa phenyl phenylethanol; hydrazine (lR)-2-{[6-(l-benzothiophen-5-yl)pyrimidine _4_yl Amino}_1_phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2-(dimethylamino)pyrimidin-4-yl }amino)-1-phenylethanol; • (lR)-2-({6-[3-fluorogas 4-(trifluoromethyl)phenyl]_2_(methylsulfanyl)pyrimidine-4 -yl}amino)-1-phenylethanol; (1R)-1-phenyl_2_({4-[4-(trifluoromethyl)phenyl)^^王耕·2 base} Amino) Ethanol; chloro-4-(trifluoromethyl)phenyl]-1,3,5-triton-2-yl}amino)-1-phenylethanol; (1R)-1-phenyl-2 -({6-[3-(Trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; (1R,2S)_1_phenyl_2_[(6]4_[(trifluorodecyl) Oxy]phenyl}pyridin-4-yl)amino]propan-1-ol; (lR,2R)-2-[indenyl (6-{4-[(trifluoromethyl)oxy]] Phenyl}, _4_yl)amino]-1-phenylpropan-1-ol; (lR,2S)-2-[indenyl (6-{4-[(trifluoromethyl)oxy]] Phenyl}pyrimidine_4_yl)amino]-1-phenylpropan-1-ol; 200948790 (lR)-2-({6-[3_ · 4_(1-Phenylethyl)phenyl]indole _4_yl}amino)-1-phenylethanol; (lR)-2-{[2·cyclopropyl-6·(3, 4-diphenylphenyl) sulfazin-4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(3,4-dichlorophenyl)-2-(1- Methyl ethyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-({6_[3·chloro-4-yl-(trifluoromethyl)phenyl]_2-(methylsulfonate) (醯R)-2-pyrene-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3-aluminum (trifluoromethyl)phenyl]_2-(decylsulfinyl)醯基) ^密11定-4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(3-indolyl-lH-η弓巴坐基)Bite bite_4 _yl]amino}capacity ethanol; (lR)_2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2_(decylamino) oxime-4-yl} Amino)-1-phenylethanol; (lR)-2-{[6-(4-Mothyl) oxapyridin-4-yl]amino}-1·phenylethanol; (lR)-2- [6-(3-Chloro-4-disindolyl-phenyl)_feed bite_4_ylamino]-l-(3,4-di-phenyl-phenyl)-ethyl yeast; (lR)- L-(4_Chloro_3_gas-phenyl)-2_[6_(3_chloro.4_trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-ethanol; (lR)-2_ ({6-[2,4-bis(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenylphenyl oxime; (lR)-2-({6-[2-oxime Base_4- (trifluorodecyloxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(4-ethoxy-2-methylphenyl) Biting _4_yl]aminophenylethanol; (lR>2-{[6-(3,4-dichlorophenyl)-2-methylheptan-4-yl]amino} small 202 200948790 Phenylethanol; (lR)-2-{[6-(3,4-dichlorophenyl)-pyrimidin-4-yl]amino}p-phenylethanol; (lR)-2_({2-[( 2-Aminoethyl)amino]-6-[3-chloro-4-yl(trifluoromethyl)carbonyl]13-dimethylidene-4-yl]-amino)-1-phenylethyl; lR)-2-[(6-[3-chloro-4-(trifluoromethyl)phenyl]didecylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-benzene (lR)-2_({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(ethylamino)piperidin-4-yl]-amino)-1 -phenylethanol; (lR)-2-({6_[3-chloro-4-(trifluoromethyl)phenyl]-2.[(2-hydroxyethyl)amino]pyrimidin-4-yl} Amino)-1-phenylethanol; (lR)-2-({2-aza-J-butylbutan-1-yl-6-[3-chloro-4-(trimethylsulfonyl)phenyl]pyrimidine _4-yl}amino)_ι_phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(cyclopropylamino) Pyrimidin-4-yl}amino)-1-phenylethanol; (1R)_2_[(6_[3-chloro_4_(trifluoromethyl) Phenyl]_2_{[2_(decylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol; (lR)-2_({6_[3-气冬( Trifluoromethyl)phenyl]_2_oximeoxypyrimidine_4_yl}amino)-1-phenylethanol; (lR)-2-{[6-(3-methyl-1,2-benzene And (6R)-1-phenyl-; 2-[(6-啥淋_6_ylpyrimidine ice Ethyl)ethanol; hydrazine-t-butyl-4-(6-{[(2R)-2-yl-2-phenylethyl]amino}pyrimidin-4-yl)benzenesulfonamide (1R)-1-phenyl-2-({6·[4_(thiomorpholinanylsulfonyl)phenyl]pyrimidin-4-yl}amino)ethanol; 203 200948790 (lR)- L-(4-fluorophenyl)·2-({6·[3-fluoro-4-(trifluoromethyl)phenyl]oxaridin-4-yl}amino)ethanol; (lR)-l- (4-fluorophenyl)-2-({6-[3-fluoro-4-(trifluoromethoxy)phenyl]carbanid-4-yl}amino)ethanol; (lR)-2_({ 6-[3_Gas_4_(Trifluoromethoxy)phenyl]p-density_4_yl}amino)-1-(4-fluorophenyl)ethanol; (lR)-l-(4- Fluorophenyl)-2-({6-[3-(pentafluoroethyl)-1,2-benzisoxazole-6-yl]pyrimidin-4-yl}amino)ethanol; (lR)- L-(4-fluorophenyl)-2-({6-[3-(trifluoromethyl)-1,2-benzisoxazole-6-yl]pyrimidine -4-yl}amino)ethanol; (lR)-2_({6-[3·fluoro-4-(2,2,2-trifluoroethoxy)phenyl]«melidine_4_yl}amine (lR,2S)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidine-4-yl}amino)-1 -Phenylpropan-1-ol; (1R)-1-phenyl-2-[(6·{4·[(trifluoromethyl)thioalkyl]phenyl}peryl-4-yl)amino ]ethanol; (lR&gt;2-({6-[3·chloro_4_(tri-f-methoxy)phenyl]β) _4_yl}amino)-1·stupylethanol; (1R)- 1-phenyl-2-({6-[3-(trifluoromethyl)), 2-benzoisomeric. (6R)-2-{[6-(2,2-difluoro-1,3-benzodioxin_5_yl) spray咬-4-yl]amino}_1-phenylethanol; (1R)_1-phenyl-2-({6-[5-(trifluoromethyl)_ι_benzoxenyl]pyrazine_4 (1R)-1-phenyl-2-({6-[5-(trifluorodecyloxy)_ι_benzocytyl]pyrimidin-4-yl}amino Ethanol; 204 200948790 (1R)-1-benyl 2-({6-[6-(trifluoromethyl)benzophenan-2-yl]- phenidin-4-yl}amino)ethanol (lR)-2-{[6-(5-fluoro-1-benzothiophen-2-yl)pyrimidin-4-yl]amino phenyl phenylethanol; (lR)-2-({6-[ 3-(pentafluoroethyl)_1,2 benzisoxazole-6-yl]pyrimidin-4-yl}amino)-1-phenylethanol; (1R)-phenyl-2-{6·[ 4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]pyrimidin-4-ylamino}-ethanol; and hydrazine (1R)-phenyltetrafluoro -1-trifluoromethyl-ethyl)-phenyl]-pyrimidin-4-ylamino}_ethanol; (1R)-phenyl-2-[6-(3-trifluoromethyl-benzo[ b] thiophene-6(yl)pyrimidine-4-ethanol; and 4-(3-chloro-4-trifluoromethyl-phenyl)-6-(2-hydroxy-2-phenyl-(1R)-ethyl Amino)-pyrimidine-2-indoleonitrile, or a pharmaceutical compound of the compound Acceptable salt thereof, before pharmaceutically acceptable drug or pharmaceutically active metabolite thereof. 〇 21. - Compound of formula (I-B): R1 is -Cm alkyl, -0 (^4 alkyl, _S(0)() 2Cl 4 alkyl, -CN, _CF3, -N(Ra)Rb or monocyclic cycloalkyl, wherein Ra &amp; Rb are each _Ci 4 alkyl, N(Rm)Rn, wherein R*^Rn is _H, Ci 4 alkyl; or Ra and 205 200948790, respectively, which are _H, optionally substituted by _〇11 The nitrogen together form a 4 to 7 membered heterocycloalkyl ring; the Ar1 is a phenyl group, a naphthyl group, a postal monocyclic heteroaryl group at the point of attachment of the carbon or a 9 or 10 member bicyclic heteroaryl at the point of attachment a group which is unsubstituted or substituted by the following groups; (1) one, two or three Rc moieties, wherein each Re moiety is independently _Cl_4 alkyl, _Ci 4 alkyl 〇H, _Ci 4 alkyl -CN, -CF3, -OH, -OCm alkyl, -〇CF3, -〇CHF2, -〇CH2CF3, -S(0)〇.2CM alkyl, _SCF3, -S02CF3, -CHQ, COCw, burnt a group, _c 〇 2H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, _N02, -CN, phenyl, anthracenyl or halo, wherein R and R are each independently - Η or -Cm alkyl, or Rd and R6 together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl ring; or (ii) two or three Re moieties, Rc two portions in lines adjacent to each other and form an unsubstituted or substituted with one or two fluoro groups substituted with the -OCCH2) 3 ·〗 together. -, and the third Rc moiety (when present) is _c]4 alkyl, -C)-4 alkyl-OH, -C!_4 alkyl-CN, -CF3, -OH, -OCm alkane Base, -ocf3, -〇chf2, -〇ch2cf3, -SCO^Cw alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -COWw alkyl, -C02H, -N(Rd)Re, _S 〇2NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN or a halo group, wherein Rd&amp;Re are each independently _H or -Cm alkyl; X is N or C(Rf), wherein Rf The system is -Η or fluorenyl; the Ar2 is: (1) a phenyl group substituted by one or two: one, two or three Rg portions each located between 2009 and 200948790 or para, and optionally one or two An additional Rg moiety in the ortho position; wherein each &quot; moiety is independently -Cm alkyl, -Cm alkyl-OH, -Cm alkyl-CN, perhaloalkyl, perhaloalkoxy, - OCm alkyl, -〇Cm alkyl-(monocyclic cycloalkyl), _s(o)0 2Cl 4 alkyl, _SCf3, -S02CF3, -CHO, -COCm alkyl, -CO/m alkyl, - C02H, -N^R1, -S02NRjRk, -NRhS02Ri, -C(0)NRjRk, _N02, -CN or a halogen group; or a phenoxymethyl group, a benzyl group which is unsubstituted or substituted by the following groups, Phenylethyl or benzhydryl: -Cm alkyl, -OCm alkyl, perhaloalkyl, perhaloalkoxy, _N〇2, -CN or halo; wherein Rh is -H or -C !_4 alkyl; R1 is _CM alkyl or monocyclic cycloalkyl; or Rh and R1 together with the atom to which they are attached form a monocyclic heterocycloalkyl ring; • Rj is -H or -Cw burned And Rk is -H, -Cw alkyl or monocyclic cycloalkyl; or ^ and 0 together with the atom to which they are attached form a monocyclic heterocycloalkyl fluorene ring or (b) two adjacent The Rg moieties together form -0((:^)^0-; (ii) a monocyclic heteroaryl group having one, two or three Rg moieties which are unsubstituted or substituted with one or two fluoro groups, Wherein each of the oxime moieties independently or two adjacent Rg moieties together form _〇(CH2)i 2〇—unsubstituted or substituted with one or two fluoro groups; or (iii) unsubstituted or a naphthyl or bicyclic heteroaryl substituted by one, two or three Ri moieties; wherein each R1 moiety is independently _c _4 alkyl, _〇Ci4 alkyl, perhaloalkyl, perhalogen Alkenyloxy, _N02, -CN or halo; 207 200948790 R2 is -Η or fluorenyl; R3 is - hydrazine or hydrazino; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite of the compound. 22. A compound according to claim 21, wherein R1 is fluorenyl, isopropyl, trifluoromethyl, decylsulfanyl, methylsulfinyl, methanesulfonyl, amine, hydrazine Alkylamino, dimethylamino, or cyclopropyl. 23. The compound of claim 21, wherein R1 is an amine group. 24. The compound of claim 21, wherein the Ari is a phenyl group, each of which is unsubstituted or substituted with one, two or three Re moieties. 25. The compound of claim 21, wherein each Rc moiety is independently a fluoro, chloro, nitro, trifluoromethyl, decyloxy, hydroxy or trifluoromethoxy group, or two phases The adjacent Rc portions together form _〇(CH2)i 2〇_ or -〇(CF2)〇-. 26. The compound of claim 21, wherein the Ari is phenyl, 4-fluorophenyl, 4-nitrophenyl, 4-trifluorodecylphenyl, 4-chlorophenyl, 4-cysyl Phenyl, 4-decyloxyphenyl, 4-hydroxy-3-indolylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2-p-phenyl, 3-chloro Phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dichlorophenyl, 3-trifluoromethoxyphenyl, 3-fluorophenyl, 4-chloro-3- Fluorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 2-° ratio, 3-. Bipyridyl, 4-acridinyl, 1,3-benzodioxol 208 200948790 Alkenyl or 2,2-difluoro-I,3-benzodioxolyl. 27. The compound of claim 21, wherein the Afl is a phenyl group which is unsubstituted or substituted with up to two 1^ moieties. 28. The compound of claim 21, which is also c(Rf). 29. The compound of claim 28, wherein Rf is _H. 〇 30. A compound according to claim 21, wherein Αγ2 is a phenyl group substituted by one, two or three Rg moieties each of a meta or para position. 31. The compound of claim 21, wherein the Αγ2 is a thiophene group, a pyridyl group, a pyrimidinyl group, or a pyrazolyl group, each of which is substituted with one, two or three Rg moieties. 32. The compound of claim 21, wherein each part is methyl, ethyl, isopropyl, tert-butyl, hydroxymethyl, hydroxyethyl, cyanomethyl, Cyanodimethyl-indenyl, trimethylmethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, trifluoromethoxy, difluoromethoxy , trifluoroethoxy, cyclopropylmethoxy, methylsulfanyl, ethylsulfanyl 'isopropylsulfanyl, methylsulfonyl, methyl, ethyl, hydrazine Amino group, morphine-based, amine-based, dimethylaminosulfonyl, cyclopropylaminosulfonyl, piperidinylsulfonyl, t-small, nitro, Cyano, chloro, carbyl, deuterated, phenoxy, benzyl, benzhydryl or phenethyl, or two adjacent moieties together form -0(CH2)]-2〇-4_〇( Cf2) 〇·. 209 200948790 33. The compound of claim 21, wherein the Ar2 is 3,4-didecylphenyl, 4-tert-butylphenyl, 4-cyanophenyl, 4-ethenylbenzene , 4-nonylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluorodecylphenyl, 4-decyloxyphenyl, 4-nitrophenyl, 3-mercaptobenzene , 3-trifluorodecyloxyphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-ox-4-dione Nonylphenyl, 4-ethoxyphenyl, 4-isopropyllacylphenyl, 4-phenoxy-phenyl, 3-chloro-4-ethoxyphenyl, 3-ox-4-iso Propoxyphenyl, 3-fluoro-4-methylphenyl, 4-hydroxydecylphenyl, 4-nonylphenyl, 3-decylphenyl, 4-trifluoroethoxyphenyl , 3-trifluoroethoxyphenyl, 4-cyclo-3-indenylphenyl, 4-ox-3-phenylphenyl, 4-ox-3-disuccinylphenyl, 3-air-4 - Di-halomethoxy. Phenyl, 4-ethoxy-3-disorganophenyl, 4-ethoxy-3-methylphenyl, 4- lysylpropyloxyphenyl, 4-butyl Oxy-3-phenylphenyl, 4-butoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-fluoro-4-isopropoxyphenyl, 4-isobutoxyphenyl, 4-decyloxy-3-nonylphenyl, 3-chloro-4-mercaptophenyl, 3,5-dimercaptophenyl, 3-air-4-dimethylnonylphenyl, 3- gas -5-dimethylphenyl, 3-chloro-5-phenylphenyl, 4-propoxyphenyl, 4-isopropoxy-3-indolylphenyl, 4-difluorodecyloxy- 3,5-difluorophenyl, 4-(cyano-diindenyl-indenyl)phenyl, 4-acetoxy-3-phenylphenyl, 3,5-diindenyl-4-isopropoxy Phenyl, 3,4,5-trifluorophenyl, 4-benzylnonylphenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 4-didecylaminophenyl, 4-decylsulfonylphenyl, 4-cyclopropylaminophenyl acid, 3-ox-4-methoxyphenyl, 1,4-benzoquinonediox-6-yl, 4-Dinylamino-based phenyl, 4-Big sigma-1-continued 'suppleylphenyl, 4-ntb^n-dec-1-yl-phenylphenyl, 3-nitro-4- Phenyl phenyl, 4-mercaptothiopyrylphenyl, 4-ranyl-3-ylphenyl, 3-murly-4-oxophenyl, 4-isopropylsulfanylphenyl, 4-cyano Base mercaptophenyl, 4-ethylsulfanylphenyl, 3-ethoxy 210 200948790 base, 3-propoxyphenyl, 3-butoxyphenyl, 4-trifluoromethoxyphenyl , 3-trifluoromethylphenyl, 4-(2-o-indolephenyl-ethyl) Phenyl, 3-p--4-(1-trans-ethyl)phenyl, 4-iodophenyl, 4-ethoxy-3-trifluoromethylphenyl, 3,4-dimethoxy Phenyl, 3-decyloxyphenyl, 2,4-bis(trifluoromethyl)phenyl, 2-methoxy-4-(trifluoromethoxy)phenyl, 4-ethoxy-2 -nonylphenyl, 2,2-difluoro-1,3-benzodioxan-5-yl, 1,3 benzodioxan-5-yl, 5-ethenyl-thiophene-2 ·6,6-methoxypyridine-3-yl, 6-ethoxypyridin-3-yl, 6-morphin-4-ylacridine-3-yl, 6-fluoro-5-mercapto-pyridine 3-yl, 6-cyanoindolylpyridin-3-yl, 6-(didecylamino)acridin-3-yl, 2-morpholin-4-ylpyrimidin-5-yl' or 1 -Benzyl_ιΗ_pyrazole_4_yl. _ 34. The compound of claim 21, wherein the Ar2 is naphthyl or fluorene. A stagnation base, called 朵 朵 、, Benzene ° thiophene, 啥 基, or σ 引 β sit, 'each of which is unsubstituted or replaced by one, two or three R1 parts. 35 'A compound as claimed in claim 21, wherein each R1 moiety is independently methyl. 36. A compound according to claim 21, wherein the Ar2 is naphthyl, 2,1,3-benzooxadiazole-5-yl, 1Η_σ哚哚_5_yl, old-吲哚-6- , 1-methyl-1H-吲哚_2_yl, 1_mercapto-1H_吲哚·5-yl, 5-methyl-1-benzophenant-2-yl, benzothiophene- 3-Based, benzothiophen-5-yl, quinolin-3-yl or 3-methyl-1 Η-σ 卜 坐-6-yl. 37. The compound of claim 21, wherein R2 is -Η. 211 200948790 38. The compound of claim 21, wherein R3 is _H. 39. The compound of claim 21, wherein the secondary hydroxyl group adjacent to Ari is in the following configuration: /γΑΓ1 OH 〇 40. - a compound selected from the group consisting of: (lR)-2-({6-[3-Gas-4-(trifluoromethyl)phenyl]_2.(methylsulfanyl)methethin-4-yl}amino)-1-phenyl Ethanol; (lR)-2_({2·Amino_6-[3_aero((trifluoromethyl)phenyl))) _4_yl}amino)-1-phenylethanol; (lR) -2_({6-[3-Gas_4-(Trifluoromethyl)phenyl]_2-methyloxadolyl}amino)-1-phenylethanol; (lR)-2-({H3- Gas (trifluoromethyl)phenyl]_2(trifluoromethyl)pyridin-4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(3,4·Dichlorophenyl)_2_fluorenyl is compared to _4_yl]aminopyabyl phenylethanol; (lR)-2-({6-[3 -Chloro-4-(trifluoromethyl)phenyl]_2-(didecylamino)carbendyl-4-ylethanol-1-phenylethanol; (trimethylmethyl)phenyl]_2_( Mercaptothiol), biting-4-yl}amino)-1-phenylethanol; (lR)-2-{[2·cyclopropyl·6_(3,4_diphenyl) 4_yl]amino}p-phenylethanol; (11〇-2-{[6-(3'4-dichlorophenyl)_2_(1-methylethyl) thiol]amino}- 1-phenylethanol; 212 200948790 (lR)-2-({6-[3-chloro-4-(dislactyl)phenyl]_2_(methyl stellite) }Amino)-1·benylethanol, (lR)-2-({6-[3-chloro-4-(-trifluoromethyl)phenyl]_2-(methylsulfinyl)pyrimidine-4- (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2-(methylamino)pyrimidine•4- (amino)-1-phenylethanol·, (111)-2-{[6-(3,4-dichlorophenyl)-2-indolyl spurring _4-yl]amino}- 1-phenylethanol; (lR)-2-({2-[(2-aminoethyl)amino]-6-[3-chloro-4-(trifluoromethyl)phenyl] _4-yl}amino)-1-phenylethanol; (lR)-2-[(6-[3- gas-4-(trifluoromethyl)) Phenyl]-2-{[2_(dimethylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol; (lR)-2-({6-[3 - gas-4-(three-decyl)phenyl]-2-(ethylamino)-glycol-4*•yl]amino)-1-phenylethanol; (1 ft)-2-( {6-[3- gas_4-(trifluoromethyl)phenyl]-2-[(2-carbylethyl)amino]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-({2-azetidin-1-yl-6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1- Phenylethanol; (lR)_2-({6-[3_chloro-4-(trifluoromethyl)phenyl]_2-(cyclopropylamino)-cyclo-4-amino}amino)-1- Phenylethanol; (lR)-2_[(6-[3-gas_4_(trifluoromethyl)phenyl]_2-{[2_(decylamino)ethyl]amino}pyrimidin-4-yl Amino]-1-phenylethanol; (lR)_2-({6_[3-chloro-4-(trifluoromethyl)phenyl]-2-oxooxyindole_4_yl}amino) -1-phenylethanol; and 4-(3-chloro-4-trifluoromethyl-phenyl)-6-(2-hydroxy-2-phenylethylamino)-pyrimidine-2-carbonitrile; 213 200948790 A pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutically active metabolite of a compound. 41. A compound of the formula (Ι-C): Wherein: 0Ci-4 alkyl, -SiO^Cw alkyl, -CN, R is -H, -Cm alkyl, -N(Ra)Rb or monocyclic cycloalkyl, wherein Ra&amp;Rb are independently _H, optionally substituted by _〇H, _Ci*alkyl b, N(Rm)Rn 'wherein Rm and Rn are _H, Ci 4 alkyl; or Ra & R forms with the attached nitrogen 4 to 7 membered heterocycloalkyl ring; Ar is phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl at the point of attachment or 9 or 10 membered bicyclic heteroaryl at the point of attachment, Each of which is unsubstituted or substituted by the following groups; (i) one, two or three Re moieties, each of which is independently -Cm alkyl, -Cm alkyl-OH, -CM alkyl - CN, -CF3, -OH, -OCm alkyl, -〇CF3, -OCHF2, -OCH2CF3, alkyl, -SCF3, -so2cf3, -CHO, -COCm alkyl, -CC^Cm alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN, a base, a 0-sigma group or a halo group, wherein R^Re are each independently -Η or -Cm An alkyl group, or Rd and Re together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl group; or 200948790 (ii) two or three Re moieties, wherein two Re moieties Adjacent to each other and together form -CXCHJuO-' which is unsubstituted or substituted with one or two fluoro groups and the third moiety (when present) is 4 alkyl, -Cm alkyl-OH, -Cm alkyl-CN, -CF3, -OH, -oq 4 alkyl, -OCF3, -OCHF2, -〇CH2CF3, -8(0)0.2(^.4 alkyl, -SCF3, -SO2CF3, -CH0 , -COCi_4 alkyl, -CC^Cu alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN or _ base, ❹ where Rd and Re Each is independently -H or -Cm alkyl; X is N or C(Rf), wherein Rf is -Η or fluorenyl; Rx, Ry, and Rz are each independently a) to c): a) R and Rz are each -H, XRy is -N〇2, -C2-3 alkyl, -〇C2-4, or phenoxy; b) R and R are each -Η 'Ry is - OCF3, and Ar1 is substituted phenyl or unsubstituted or substituted η thiol; or ❹ C) RX, R) ^ RZ is one of -CBu-F or -CF3, and the other two It is: (i) independently the ~H4Rg moiety, the restriction condition is that when Ry is #, then Rx and Rz are not -CF3; wherein each oxime moiety is -Cm alkyl, -Ci_4 alkyl_0H, _Ci 4 alkyl_CN, perhaloalkyl, full _ Alkoxy, _〇Ci 4 alkyl, 〇 〇Ci 4 alkyl-(monocyclic cycloalkyl), 4(0)0-2 (^-4 alkyl, -SCF3, -S02CF3, _CHO, - COCm^ group, -C〇2c14 alkyl group, -C〇2h, _S〇2NRjRk, -NRhS02Ri, -C(0)NRjRk, -N02, -CN or _ group; or unsubstituted or via the following groups Substituted phenoxy, benzyl, phenethyl or benzhydryl: _Cl_4 alkyl, 〇Ci 4 alkyl, 215 200948790 di-alkyloxy, 2, or halo; wherein R is -H or - Cw alkyl; R1 is -C _4 alkyl or monocyclic cycloalkyl; the attached atoms together form a monocyclic heterocyclic ring; RJ is -H or -Cm alkyl; and Rk Is a monocyclic heteroweiyl ring; or R: and Rk and the material to which it is attached form a monocyclic heteroweiyl ring; or (8) two adjacent Rg moieties which form unsubstituted or substituted by one or two fluoro groups - 〇(CH2)] 2〇-; or (111) unsubstituted or via one or two or a naphthyl or bicyclic heteroaryl group substituted with three Ri moieties; wherein each R1 moiety is independently -Cm alkyl, _〇Ci4 alkyl, perhaloalkyl, perhaloalkoxy, -N02 , -CN or halo; R2 is -H or methyl; and R3 is -H or methyl; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite of the compound. 42. The compound of claim 41, wherein Ri is _H, methyl, isopropyl, trifluoromethyl, decylsulfanyl, decylsulfinyl, hydrazine, Amino, mercaptoamine, dinonylamino' or cyclopropyl. 43. The compound of claim 41, wherein R1 is an amine group. 44. The compound of claim 41, wherein R1 is Η. 216 200948790 Partially substituted ====, one of which is phenyl, &amp; as in the compound of claim 41, the site is gas-based, chloro, nitro, tri-methyl: two, 4: 蜀 or -〇(cf2)0_. ^ —起形成-〇m Shen Fan (4) 41 compounds, (4) is stupid, Schottyl phenyl, 4-trifluorodecyl phenyl, 4- chlorophenyl, 4 ϋΐ %, / methoxy phenyl, 4 _ base - 3·methoxyphenyl, 3,4_diif di, fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 3-methoxybenzene 3 soil second secret base, 3,5_ Dichlorophenyl, 3-trifluoromethoxyphenyl, : benzyl difluorinated phenyl, 3|4-hydrophenyl, 3-trifluoromethylphenyl b-yl, 3·«, 4 _Base, 1,3, benzodioxanyl or 2,2·difluoro I benzodioxol ^ ' ❹ 48. Compound of the 41st section of the patent scope Wherein Ar1 is a phenyl group which is unsubstituted or substituted with up to 2 V moieties. 49. A compound according to claim 41, wherein X is C(Rf). 5. The compound of claim 49, wherein Rf is _H. 51. The compound of claim 41, wherein rX is _ci or -F, RZ is, and Ry is _H or Rg. 217 200948790 52. The compound of claim 41, 苴 or -F, Rz is $, and Ry is % 4 alkyl, _CF3, _ 〇 (^ * alkyl, -OCF3 or halo. 53 The compound of claim 41, wherein R2 is π. 54. The compound of claim 41, wherein r3 is _h. 55. For example, the compound of the patent scope, and Afl The adjacent secondary via system is of the following configuration: /yAr1 OH 〇* 56. A compound selected from the group consisting of: (lR)_2_({6-[4-(ethyloxy)) _3_(三ιmethyl)phenyl]money_4 amino)-1-phenylethanol; 2-{[6-(4-chlorophenyl) pulverized _4_yl]amino}1_phenyl Ethanol; 〇2-{[6-(4-fluorophenyl)pyrimidin-4-yl]amino}-p-phenylethanol; phenyl-2-({6-[4-(trifluoromethyl)) Phenyl]pyrimidin-4-yl}amino)ethanol; 2-{[6-(4-nitrophenyl)pyrimidin-4-yl]aminodipyridyl-phenylethanol; 2-{[6-( 4-ethylphenyl)pyrimidine stomach 4-yl]aminodipyridyl-phenylethanol; 2-({6-[4-(1-mercaptoethyl)phenyl]pyrimidin-4-yl}amino group Small base ethanol; &amp; 2-{[6-(3,4-diphenyl)pyrimidine_4_ Aminopyrazine·stupylethanol·, 218 200948790 2-{[6-(3-chlorophenyl)pyrimidin-4-yl]amino}-l-phenylethanol; 2-({6-[3 -chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; 2-({6-[4-(ethyloxy)phenyl]pyrimidine- 4-yl}amino)p-phenylethanol; 2-[(6-{4-[(1-mercaptoethyl)oxy]phenyl}-nose _4_yl)amino]-1-benzene Ethanol; 1-phenyl-2-({6-[4_(phenyloxy)phenyl)P 唆4_yl}amino)ethanol; 2- ({6-[3_氯_4_ (ethyloxy)phenyl]carcinoma _4-yl}amino) small phenyl 0 ethanol; (1R)-1-phenyl-2-({6-[4-(trifluoromethyl)benzene) Alkylpyrimidin-4-yl}amino)ethanol; (lR)-2-({6_[3-chloro-4-yl-(trifluoromethyl)phenyl]-mouthed ylyl}amino)phenylethanol; lR)-2_({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenylethanol hydrochloride; (lR)-2-({6- [4-(l-methylethyl)phenyl]pyrimidinyl)amino)-! phenyl 0-ethanol; (lR)_2-[(6-{; 3-chloro·4_[(1·曱) Ethyl)oxy]phenyl}glycolyl)amino]-1·phenylethanol; (lR)-2-{[6-(3-fluorodecylphenyl)oxypropyl]amino }小phenylethanol; (lR)-2-{[6-(4_ (lR)-2-{[6-(4-Ga-3-fluorophenyl)-l-yl]-]]]]]]]]]]]]]]]] Amino}Phenylphenylethanol; 219 200948790 (lR)-2-({6-[4-chloro-3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenyl Ethyl alcohol; (lR)-2-({6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2 -{[6-(4-ethoxy-3-cyclophenyl) σ-Min-4-yl]amino}-1-phenylethanol; (11^)-2-{[6-(4- Butoxy-3-phenylphenyl) '1 dimethyl 11 -4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(4-butoxyphenyl)咬-4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(3-disorder-4-propoxyphenyl)amino}-1-phenylethanol; (lR)-2-({6-[3-Ga-4-(1-mercaptoethoxy)phenyl] σ-Bitter-4-yl}•Amino)-1-phenylethanol; (lR )-2-({6-[4-(2-mercaptopropyl)phenyl]p-butyl-4-yl}•amino)-1_phenylethanol; (1 ft)-2-{[ 6-(3-chloro-4-mercaptophenyl)13-denyl-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[3-fluoro-4- (trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3-fluoro-5-(trifluoromethyl)phenyl) Pyrimidine 4-yl}amino)-1-phenylethanol; (1 ft)-2-{[6-(3-gas-5-phenylphenyl)11-denyl-4-yl]amino}- 1-phenylethanol; phenyl-2-{[6-(4-propoxyphenyl)pyrimidin-4-yl]amino}ethanol; 220 200948790 (lR)-2_({6-[3-chloro +(trifluoromethyl)phenyl]methylpyrimidine_4_yl}amino)·1-phenylethanol; (lR)-2-({6-[3-fluoro_4, (tri-methyl) )phenyl]_5_fluorenyl. Michidine _4_yl}amino)-1-phenylethanol; (lR)-2-({6-[4-(difluoromethoxy)_3,5-difluorophenyl]pyrimidine_4_ Alkyl)-1-phenylethanol; H2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}[ _4_yl)phenyl] Ethyl ketone; ❹ (1R)-1-phenyl_2-{[6~(3,4,5-trifluorophenyl)-hydan-4-yl]amino}ethanol; (lR)-2-{ [6-(3,5-Difluorophenyl)-n-yl]-4-yl]amino}-indole-phenylethanol; (lR)-2-{[6-(3,4-difluorophenyl) Pyrimidine-4-yl]amino}-1-phenylethyl-ol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(methyl) Thioalkyl)pyrimidin-4-yl}amino)-1-phenylethanol; Q 010-2-((2-amino-6-[3- gas-4-(trifluoromethyl)phenyl] Pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl], butyl-4-yl}amine (lR)-2-{[6-(3-chloro-4-ethoxyphenyl)pyrimidin-4-yl]amino}- phenyl Ethanol; (lR)-2-{[6-(3-fluoro-4-decyloxyphenyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)_2-({6- [3_Gatro-4-(trifluoromethyl)phenyl]-2-mercaptopyrimidin-4-yl}amino)-1-phenylethanol; 221 200948790 (lR)-2-{[6-( 4-fluorophenyl)pyrimidin-4-yl]amino}-l-phenylethanol; (lR)-2-{[6-(3-chloro-4-fluorophenyl)pyridin-4-yl] Amino}Phenylphenylethanol; 2-#L_4-(6-{[(2R)-2-yl-2-ylethyl]amino}. Benzene-4-yl)benzonitrile; -Fluoro-5-(6-{[(2R)-2-carboxy-2-phenylethyl]amino}. 密4_基) benzoquinone; (lR)-2-({6- [3- gas-4-(disindolyl)phenyl]_2-(trifluoromethyl), indol-4-yl}amino)-1-phenylethanol; (lR)_2-{[6_( 3,4-dichlorophenyl)-2_fluorenyl acetonate]amino] 小 € ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) (1R)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2-(didecylamino) (i)Phenyl-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]_2-(mercaptosulfane (i)pyrimidin-4-yl}amino)-1-phenylethanol; (1R)-1-phenyl-2-({4-[4-(trifluoromethyl)phenyl] tri-farming_ 2_yl} Ο Amino)ethanol; (lR)-2-({4-[3-chloro-4-(trifluoromethyl)phenyl]_1,3,5_三11 well_2_yl} Amino)-1-phenylethanol; (1R)-1-phenyl-2-({6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; 1-(4-Nitrophenyl)-2-[(6-{4_[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; 222 200948790 2-[(6- {4-[(Trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]][4-(trifluoromethyl)phenyl]ethanol; 1-(4-chlorophenyl)-2 -[(6-{4-[(trifluoromethyl)oxy)phenyl)pyrimidin-4-yl)amino]ethanol; 4-{1~hydroxy-2-[(6-{4-[(3) Fluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethyl}phenol; 1-[4-(indolyl)yl]_2_[(6-{4-[(trifluoro) Methyl)oxy]phenylpyrimidin-4-yl)amino]ethanol; ❹ 4-{1-trans-base_2-[(6-{4-[(trifluoromethyl)oxy]phenyl} Acridinium-4-yl)amino]ethyl}-2-(fluorenyloxy)phenol; 1-(4-fluorophenyl)-2-[(6·{4-[(trifluoromethyl)) Alkyl]pyrimidyl}pyrimidine_4_yl)amino]ethanol; '1-(3,4-dichlorophenyl)_2_[(6_{4_[(trifluoromethyl)oxy]phenyl}-pyrimidine -4-yl)amino]ethanol; Η2·chlorophenyl)-2-[(6]4-[(trifluoromethyl)oxy]phenyl} ate)amino]ethanol; ❹ Η3- Chlorophenyl)-2·[(6-{4·[(trifluoromethyl)oxy]phenyl} guan-4-yl)amino]ethanol; WH methyloxy)phenyl]-2 -[(6-{4-[(trifluoromethyl)oxy]benzene }}-pyrimidin-4-yl)amino]ethanol; W2-(decyloxy)phenyl]-2-[(6·{4-[(trimethylhydrazino)oxy]phenyl}-pyrimidine 4-yl)amino]ethanol; 1-(2,2-difluoro-1,3-benzobis-chromo-5-yl)-2-[(6-{4-[(trifluoromethyl) Oxy]phenyl}pyrimidin-4-yl)amino]ethanol; buptidin-2-yl-2-[(6-{4.[(trifluoromethyl)oxy]phenyl}. Michidine _4_yl)amino]ethanol; 223 200948790 1-Acridine-3-yl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl Amino]ethanol; pyridine-4-yl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; 1-(3 ,5-dichlorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidin-4-yl)amino]ethanol; 1- (1,3- Benzodioxa-5-yl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidin-4-yl)amino]ethanol; (lS)-2 -({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-( {6-[3- Scrambled 4-(1-ethylideneethyl)phenyl]13-dimethylpyrimidin-4-yl}amino)-1-phenylethanol; 2-({6-[3-gas-4-(trifluoro) Mercapto)phenyl]pyrimidin-4-yl}amino)-1-[3-(trifluorodecyloxy)phenyl]ethanol; 2-({6-[3-chloro-4-(tris) Phenyl] phenyl sulfonate-4-yl]amino)-1-(3-phenylphenyl)ethanol; 2-[6-(3-chloro-4-trimethyl decyl-phenyl)-mouth 〇定-4-ylamino]-1-(3,4-difluoroi-phenyl)-ethanol, 1-(4-gas-3-fluoro-phenyl)-2-({6-[3 - gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; 1-(3- gas-4-fluorophenyl)-2-({6-[3-chloro- 4- (Trifluoromethyl)phenyl]pyrimidin-4-yl}amino) Ethanol, 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amine (1)-[3-(trifluoromethyl)phenyl]ethanol; (lR)-2-{[2-cyclopropyl-6-(3,4-dichlorophenyl)pyrimidin-4-yl Amino}-1-phenylethanol; 224 200948790 (lR)-2-{[6-(3,4-dichlorophenyl)-2-(1-methylethyl)pyrimidin-4-yl] Amino}-1-phenylethanol·; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(methylsulfonyl)pyrimidine-4 -yl}amino)-1-phenylethanol; (1 ft)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(indenyl) Pain 11 -4-yl}amino)-1-phenylethanol, (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(A) Amino)pyrimidin-4-yl}amino)-1-phenylethanol; 0 (lS)-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidine-4- Amino]-1-(3,4-dioxa-phenyl)-ethyl yeast, (lR)-2-[6-(3-chloro-4-disindolyl-phenyl)-D 4-ylamino]-l-(3,4-di-phenyl)-ethanol, (lS)-l-(4-chloro-3-a-phenyl)-2-[6-(3 -chloro-4-tris-methyl-phenyl)-pyrimidin-4-ylamino]-ethanol; (lR)-l-(4-chloro-3-fluoro-phenyl)-2-[6- (3-Gas-4-trifluoromethyl-phenyl) _ mouth bite-cardylamino]-ethanol; (lR)-2-{[6-(3,4-dichlorophenyl)-2-indolyl oxime-4-yl]amino}_ 1 _ Phenylethanol; (lR)-2-{[6-(3,4-dichlorophenyl)-octane-4-yl]amino}-1-phenylethanol; (lR)-2-({ 2-[(2-Aminoethyl)amino]-6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; lR)-2-[(6-[3-Ga-4-(trifluoromethyl)phenyl]-2-{[2-(didecylamino)ethyl]amino}pyrimidin-4-yl Amino]-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(ethylamino)pyrimidine-4- (amino)-1-phenylethanol; 225 200948790 (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2_[(2-hydroxyethyl)amine (i) 咬 咬 -4-yl}amino)-1 phenylethanol; (lR)-2-({2-azetidin-1-ylchloro-4-(trifluoromethyl)benzene (i)pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2_({6-[3·gas_4_(trifluoromethyl)phenyl]_2-(cyclopropylamino) Pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2_[(6-[3-chloro-4-(trifluoromethyl)phenyl]_2·{[2_(decylamine) Ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol; (lR)-2_({6-[3-gas_4·(trifluoro Phenyl; phenyl; j_2_ methoxypyrimidine _4_ yl}amino)-1-phenylethanol; 1-({6-[3_gas_4-(trifluoromethyl)phenyl]pyrimidine _ 4-yl}amino)-2-phenylpropan-2-ol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl] oxindole _4-yl}amino -1_[4-(decylsulfanyl)phenyl]ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-n--4-yl}amino) -1_. Benzen-3-ylethyl Sf·; 2-({6-[3- gas-4-(trifluoromethyl)phenyl]-n--4-yl}amino)-1-(1,3-thiazole -2-yl)ethanol; (lR)-l-(4-fluorophenyl)·2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amine Ethyl alcohol; (lR)-l-(4-fluorophenyl)-2-({(5-[3-fluoro_4_(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino) Ethanol; (lR)-2-({6-[3_chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino)-1-(4-fluorophenyl)-ethyl yeast (lR)-2-({6-[3-Fluoro-4·(2,2,2-trifluoroethoxy)phenyl]pyrimidinyl)amino)-1_phenylethanol; 200948790 ( lR,2S)_2-({6_[3-chloro-4-(trifluoromethyl)phenyl]p-dimethyl _4_yl}amino)·1-phenylpropan-1-ol; (lR )-2-({6-[3-chloro-4-(trifluorodecyloxy)phenyl] mouth bite _4-yl}amino)-1-phenylethanol; 2-({6-[3 -Chloro_4_(trifluoromethyl)phenyl] mouth bite _4_yl}amino)-1-[2-(difluorodecyloxy)phenyl]ethanol; 2-({6-[3_ Chloro_4_(trifluoromethyl)phenyl]η 咬4-yl}amino)-1-(4-fluorophenyl)ethanol; 0 4-[2-({6-[3-chloro- 4-(trifluoromethyl)phenyl] mouth bite _4-yl}amino)-1·hydroxyethyl]benzonitrile; 2-({6_[3_chloro_4_(trifluoromethyl)benzene) base] Bite _4_yl}amino)_1_naphthalen-2-ylethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl] mouth bite _4_yl}amino group )_ι_(4_ . &quot;bipyridin-2-ylphenyl)ethanol; 2-({6_[3_chloro-4_(trifluoromethyl)phenyl]indole _4_yl}amino) small (4_Thien-2-ylphenyl)ethanol; ❹Biphenyl-4_yl-2-({6-[3·gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl} Amino Ethanol; 1-(1-benzothiophen-2-yl)-2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol ; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)fluoro-4-(trifluoromethyl)phenyl]ethanol; 2-( {6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl)amino)-1-{3-[(trifluoromethyl)sulfanyl]phenyl}ethanol; 2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-ylhydrazinyl)dihydro-1,4-benzobis. Ethyl octyl)ethanol; 227 200948790 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl)amino)-1-[4_(1Η-imidazole-1 -yl)phenyl]ethanol; 1-(1-benzothiophen-3-yl)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl} Amino)ethanol; 2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino hydrazine#,; dimethoxyphenyl)ethanol; (3-A-4-methoxyphenyl)_2_({6_[3_gas_4_(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; 2·({6-[ 3-oxo-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}aminodihydro-2Η-1,5-benzodioxan-7-yl)ethanol; 2- ( {6-[3_Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl)amino)indole-5-(trifluoromethyl)phenyl]ethanol; 3- [2 -({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)hydroxyethyl]benzonitrile; 2-({6-[3-chloro- 4-(Trifluoromethyl)phenyl]pyrimidin-4-yl}amino)·ι·(3_phenylisoxazol-5-yl)ethanol; 2-({6_|&gt;chloro-4-( Trifluoromethyl)phenyl]pyrimidinyl)amino)di(4-pyrrolidin-1-ylphenyl)ethanol; 2_({6·[3·chloro-4-yl-(trifluoromethyl)phenyl] Set ice base} Base)_ι_(5_ ° ratio °-2-yl 0-cephen-2-yl)ethanol; 5-[2-({6-[3_chloro-4_(trifluoromethyl)phenyl] sneeze_ 4-({}}amino)_1_hydroxyethyl]-2-fluorobenzonitrile; 2-({6-[3·gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino )_ι_(2,6·one gas phenyl) ethyl yeast, 2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidine, 4-amino}amine) small (2_ Fluorophenyl)ethanol; 228 200948790 2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidine _4_ylamino] small [3-(3,4-dichloro- Phenyl)-isoxazole-5-yl]-ethanol; 1-[3-(4-chloro-phenyl)-isoxazole-5-yl]_2-[6-(3_气-4-3 I-methylphenyl)-pyrimidin-4-ylamino]-ethanol; A 2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidine 4-ylamino] small [3 -(2,4·Dichloro-phenyl)_ is different. Ethylpyrrol-5-yl]-ethanol; 1-benzothiazol-2-yl-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]ethanol; 1-[3,5-bis(difluoroindolyl)phenyl]_2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; -(5-bromo-1-benzothienyl)_2_({6·[3-chloro-4.(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; and 4-(3 -Chloro-4-trifluoromethyl-phenyl)_6_(2-hydroxy-2-phenyl-(1R)ethamidyl)-pyrimidine-2-carbonitrile; a pharmaceutically acceptable prodrug or A pharmaceutically acceptable salt of a compound, a pharmaceutically active metabolite. 57. A pharmaceutical composition comprising: (4) an effective amount of at least one FAAH-regulator selected from the group consisting of compounds of formula (1): Wherein: R1 is -H, -C"_4 alkyl, -0C]_4 alkyl, -S(0)() 2Ci_4 alkyl, -CN, -CF3, -N(Ra)Rb or monocyclic naphthenic Base, 229 200948790 wherein Ra&amp;Rb are each independently -Η, optionally substituted by 〇H - CM alkyl, N(Rm)Rn, wherein !HRn is _H ' Ci 4 alkyl; or Ra and Rb forms a 4 to 7 membered heterocycloalkyl ring together with the attached nitrogen; Ar1 is phenyl, naphthyl, 5 or 6 membered monocyclic heteroaryl at the point of attachment or carbon is at the point of attachment 9 or a 10-membered bicyclic heteroaryl group, each unsubstituted or substituted by the following groups; (1) one, two or three Re moieties, wherein each Rc moiety is independently -CM alkyl, -Cm alkyl-OH -Cw alkyl-CN, -CF3, -OH, -OCw alkyl, -〇CF3, -OCHF2, -〇CH2CF3, -SCOkCw alkyl, -SCF3, -S02CF3, -CHO, ❹-COCm alkyl, -CC^Cw alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N02, -CN, phenyl, alpha ratio octyl or pendant, wherein Rd&amp; Re is each independently -Η or -Cm alkyl, or Rd and Re form a 4 to 7 membered heterocycloalkyl ring together with the attached nitrogen; or (ii) two or three Re part, two of which are adjacent to each other and together form -CXCHAjO- which is unsubstituted or substituted by one or two fluorine groups, and the third Rc moiety (when present) is _Cl 4 〇 Alkyl, -Ci_4 alkyl-OH, -C]_4 alkyl-CN, -CF3, _OH, -〇Ci_4 alkyl, -OCF3, -OCHF2, -〇CH2CF3, -SCO^zCw alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -CC^Cw alkyl, -C02H, -N(Rd)Re, -S02NRdRe, -NRdS02Re, -C(0)NRdRe, -N〇2, -CN or halogen a group, wherein each of Rd&amp;Re is independently _H or -Cm alkyl; X is N or C(Rf), wherein Rf is -Η or methyl; 230 200948790 Ar2 is: (i) a group substituted phenyl: (a) —, two or three Rg moieties each located in the meta or para position, and optionally one or two additional Rg moieties in the ortho position; wherein each part is independently Is -Ci-4 Hyun, -Ci_4 alkyl-OH, -Ci-4 alkyl-CN, perhaloalkyl, perhaloalkoxy, _〇cM alkyl, -OC^alkyl- (monocyclic cycloalkyl), 4(0)0-2 (^-4 alkyl, -SCF3, -S02CF3, -CHO, -COCm alkyl, -CC^Cm alkyl, -C02H, -NCR^R1, -S02NRJRk, -NRhsC^Ri, _C(0)NRjRk, _N〇2, -CN or a halogen group; Or a phenoxy, benzyl, phenethyl or benzhydryl group which is unsubstituted or substituted by the following groups: _Ci 4 alkyl, _〇c^alkyl, perhaloalkyl, perhaloalkoxy a group, _N〇2, _CN or a halogen group; wherein Rh is -H or -CM alkyl; R1 is -Cm alkyl or monocyclic cycloalkyl; or RhW forms a monocyclic relationship with its secondary U a transalkyl ring; is -H or -Cm alkyl; and Rk is -H, -Cm alkyl or a monocyclic net ring; or (b) = an adjacent W moiety - forming an unsubstituted group Substituted -0 (0^秦; (H) a single shirt replaced by the following groups: eight Yiwanghefangji · one, two or three Rg tits are independently or two adjacent &quot; Substituting together to form unsubstituted or -0(ch2) _20-; or ^ (iii) naphthyl or double 231 unsubstituted or substituted by one, - ten _ / , ~ or two R moieties 2009 487 Cycloheteroaryl; perhalo group, the T moiety thereof is independently alkyl, - 〇cM alkyl 2 alkyl, fully secluent, oxy, 2, _CN Or a dentate group; R is -H or methyl; and R is -H or methyl; pharmaceutically acceptable salts and pharmaceutically active metabolites of the compound of formula (1) before pharmaceutically acceptable; and (b Pharmacologically acceptable excipients 58=Applicable for the remaining amount of medical expenses of Section 57, which is administered orally. 59. If the composition of claim 58 is applied, the composition The pharmaceutical composition is administered to a subject in a dosage range of from about 0.0001 to about 200 mg of compound per kilogram of body weight per day. 60. The pharmaceutical composition of claim 59, wherein the at least one agent is selected from the group consisting of Group··(lR)-2-({6-[4-(ethyloxy)_3_(trifluoromethyl)phenyl]pyrimidin-4-yl)-1-phenylethanol; &amp; 2 -{[6-(4-chlorophenyl)pyrimidin-4-yl]amino}_ι_phenylethanol; 2-{[6-(4-fluorophenyl)pyrimidin-4-yl]amino group 1 _phenylethanol; 1-styl-2-({6-[4-(trifluoromethyl)phenyl]. succinyl) amine) ethanol; 2- {[6-(4-nitro Phenyl)pyrimidin-4-yl]amino}pyridylethanol; 2-{[6-(4-ethylphenyl)pyrimidinyl]amino}-1-phenylethanol 2-({6-[4-(1_decylethyl)phenyl]. sigma _4_yl}amino) small phenylethanol; 232 200948790 2-{[6-(3,4- Dichlorophenyl) η-melidine _4_yl]aminopyridinium phenylethanol; 2-{[6-(3-chlorophenyl)pyrimidin-4-yl]amino}p-phenylethanol; 2- ({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-ylamino)p-phenylethanol; 2-({6-[4-(ethyloxy) Phenyl]pyrimidin-4-yl}amino)+phenylethanol; 2-[(6-{4-[(1-mercaptoethyl)oxy]phenyl}glycin-4-yl)amine Phenylethanol; 1-phenyl-2-({6-[4-(phenyloxy)phenyl]pyrimidin-4-yl}amino)ethanol; Ο 2_((6_[3-chloro- 4-(ethyloxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (1R)-1-phenyl_2-({6_[4_(tri-indenyl)benzene) (i)&gt;2-({6-[3·chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenyl phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-nosyl-4-yl}amino)p-phenylethanol hydrochloride; 〇l-[4- (6-{[(2R)-2-hydroxy-2-phenylethyl]aminobupyridyl-4-yl)phenyl]ethanone; (lR)-2-({6-[4_(l - mercaptoethyl)phenyl]pyridinyl-4-yl}amino) benzene (lR)-2-[(6-{3-chloro-4-[(l-fluorenylethyl)oxy]phenyl}pyrimidin-4-yl)amino]-1-phenylethanol (lR)-2-{[6-(3-fluoro-4-indolyl)pyrimidinyl]amino}-l-phenylethanol; (lR)-2-({6_[4-( Phenyl)phenyl]pyrimidin-4-yl}amino)p-phenylethanol; 233 200948790 4-(6-{[(2R)-2-hydroxy_2-phenylethyl]amino}pyrimidine _ 4-(phenyl)benzaldehyde; 3-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzaldehyde; (1R)-1-phenyl- 2-[(6-{4-[(2,2,2-trifluoroethyl)oxy]phenyl}pyrimidinyl)amino]ethanol; (lR)-l-phenyl-2-[(6 -{3-[(2,2,2-trifluoroethyl)oxy]phenyl} „Minidine_4_yl)amino]ethanol; (lR)-2-{[6-(4-chloro- 3-methylphenyl) stagnation _4_yl]amino} small phenylethanol; (lR)_2-{[6-(4·chloro_3_fluorophenyl) mouth biting _4_yl]amine (iR)-2-({6-[4-chloro-3-(trifluoromethyl)phenyl] sulfonate aryl}amino)-1_phenylethanol; lR)-2_({6-[3_fluoro_4_(trifluoromethoxy)phenyl]pyrimidinyl)amino)phenyloxyethanol; (lR)-2-{[6-(4_B Oxy-3-fluorophenyl)pyrimidine-ζμ-yl]amino-based ι_phenylethanol; (lR)_2-{[6-(4_ Oxydodecylphenyl) mouth bit, 4-yl]aminodiphenyl 1-phenylethanol; (lR)-2-({6-[4-(cyclopropyldecyloxy)phenyl]pyrimidine_ 4-(yl)amino)phenyl phenylethanol; (lR)-2-{[6-(4-butoxy-3-fluorophenyl) tick-4-yl]amino}-1_phenyl Ethanol; (lR&gt;2-{[6-(4-butoxyphenyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)_2_{[6-(3-fluoro·4 _Propoxyphenyl). Michidine _4_yl]amino}-1_phenylethanol; (lR)-2-({6-[3-fluoro-4-(1-mercaptoethoxy)phenyl]-bearing ice base }Amino)-Phenylethanol; 200948790 (lR)-2-({6-[4-(2-Mercaptopropoxy)phenyl]«Myridine-4-yl}amino)-1- Phenylethanol; (lR)-2-{[6-(4-decyloxy-3-mercaptophenyl)glyin-4-yl]amino}p-phenylethanol; (lR)-2-{ [6-(3_Chloro-4-indolyl)pyrimidin-4-yl]amino}p-phenylethanol; (lR)-2-{[6-(3,5-diamidinophenyl)pyrimidine _4_yl]amino}}_ι_phenylethanol; (lR)-2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-丨_stupylethanol, (lR)-2-({6-[3-fluoro-5-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-indole-phenylethanol; (lR -2-{[6-(3-chloro-5-fluorophenyl)pyrimidin-4-yl]aminophenylethanol; • (1R)_1-phenyl-2-{[6_(4-propoxy (phenyl)pyrimidin-4-yl]aminopurine ethanol; (lR)-2-{[6-(2,l,3-benzooxadiazole-5-yl)pyrimidin-4-yl]amino丨 丨 笨 乙醇 乙醇; (lR)-2-({6-[3-methyl-4-(1-mercaptoethoxy)phenyl]pyrimidin-4-yl}amine oxime)-1- Phenylethanol; (lR)-2-({6-[3- gas-4-(trifluoromethyl)phenyl]-5-methylpyrimidine _4_yl"amino)-1-phenylethanol; (lR)-2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]_5_mercaptopyrimidine_4_yl} Amino)-1-phenylethanol; (lR)-2-({6-[4-(difluoromethoxy)_3,5-difluorophenyl]pyrimidin-4-yl}amino)-1- Phenylethanol; 2-[4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl]-2-decylpropanone; 235 200948790 1-[2_Fluoro-4-(6-{[(2r)_2_hydroxy-2-phenylethyl bromidyl) phenyl]ethanone; (lR)-2-({ 6-[3,5-Dimethyl-4-(1-mercaptoethoxy)phenyl]pyrimidin-4-yl}amino)-1·phenylethanol; (1R)_2_{[6-( 1H-吲哚-6-yl) succinyl]amino}p-phenylethanol; (1R)-1-phenyl_2_{[6_(3,4,5-trifluorophenyl)pyrimidinyl Amino}ethanol; (1R)-2_{[6_(1·methyl-ΙΗ-η引嗓_2_yl)) pyridine-4-yl]amino}-1_phenylethanol; (lR) -2-{[6-(5-mercapto-1-benzophenan-2-yl) oxime _4_yl]amino-phenylethanol; ❹ [4-(6-{[(2R)- 2-(hydroxy-2-phenylethyl)amino}pyrimidin-4-yl)phenyl](phenyl)fluorenone; (lR)-2_{[6-(3,5-difluorophenyl)n (iR)_2-{[6-(3,4-difluorophenyl)octidine·4 _yl]amino}p-phenylethanol; (lR)-2_({6_[3- gas·4_(trifluoromethyl)phenyl]_2-(mercaptosulfanyl)- phenanthr-4-yl}amine (lR)-2-({2_amino-6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidine)}amino)-1- Phenylethanol; ◎ (1R)_2_({H3-chloro_4_(trifluoromethyl)phenyl]pyrimidinyl)amino)]-(4-fluorophenyl)ethanol; (1R&gt;2][6 -(6. methoxyl ratio to pyridine-3-yl &gt;pyridine-4-yl]amino}-1-phenylethanol; (lR)_2-{[6-(6-ethoxy η ratio Acridine_3_yl)-glycolyl-4-yl]aminopurine phenylethanol; (1 ft)_2-({6-[4-(didecylamino)phenyl]pyrimidinyl)amino group Small phenylethanol; 236 200948790 (1R)_2_({6 [4-(f sylylene) phenyl] sputum _4 yl}amino) phenylethanol; N_cyclopropyl·4·( 6_ί[(2]1)_2嚷基_2phenylethyl]amino}}_yl) benzenesulfonamide; (lR)-2-{[6-(3·chloro*4·ethoxyl) Phenyl) ♦ _4_yl]amino (a) phenylethanol; (lR) -2-[(2'· 参 4- 4-yl-4,5,- lian _6_yl)aminobenzene Ethyl alcohol; (lR)-2-{[6-(6-?-line_4-ylindole)3•yl)|_4_yl]amino}}_ι_phenylhydrazine Ethyl alcohol; (1R)-2- {[6-(3-|l-4-methoxy) Phenyl)carbanidyl-4-yl]aminopyabylethanol; (lR)-2-{[6-(2,3-dihydro-i,4-benzodioxin_6-yl) 4-(yl)amino}-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2-mercaptopyrimidine_4_ (lR)-2-{[6-indoleyl-1H-indazol-4-yl), pyridine-4-yl]amino}·1-stupid Basement ethanol; (lR)-2-{[6-(6-fluoro-5-methylacridinyl)-hydan-4-yl]aminopyr 1-phenylethanol; 4- (6-{[ (2R)-2-Phenyl-2-phenylethyl]amino} sulfonyl-4-yl)_N,N-dimethylbenzene continual amine; 5-(6-{[(2R)-2 -hydroxy-2-phenylethyl]amino}cyclohexan-4-yl)acridin-2-indene nitrile; (1R)_2_({6-[6-(dimethylamino))pyridinium- 3-yl]pyrimidin-4-yl}amino)]-phenylethanol; 237 200948790 (1R)-1-phenyl-2-({6-[4-(^^-l-yl) Phenyl]P _4_ yl} Amino) Ethanol; (1R)&quot;* 1 · Benji·2_({6**[4-( 口比洛 bit-1 _基石黄-) Benzene Base] secret. _4_yl}amino)ethanol; 4-(6-{[(2R)-2-yl-2-ylethyl]aminopyridinyl)benzenesulfonamide; (lR)-2- {[6-(4-Fluorophenyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(3-chloro-4-fluorophenyl)oxylidine 4-yl]amino}-1_phenylethanol; (lR)-2_({6-[3_(decylsulfanyl)phenyl]pyrimidinyl)amino)]-phenylethanol; (lR)-2-{[6-(lH-吲哚_5_yl)pyrimidin-4-yl]aminophenylethanol; (lR)-l-phenyl·2-[(6-quinoline- 3-ylpyrimidin-4-yl)amino]ethanol; (lR)-2-{[6-(l-benzothiophen-3-yl)eridine-4-yl]aminobenzylethanol; -fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzonitrile; 2-fluoro-5-(6-{[( 2R)-2-Phenyl-2-phenylethyl]amino}glycine-4-yl)benzonitrile; Ο(lR)-2-{[6-(l-曱基_ih" -5-yl) shoutin-4-yl]amino}_1_phenylethanol; (lR)-2-[(6-{4-[(l-methylethyl)sulfanyl]phenyl} [4-(6-{[(2R)-2-yl-2-(phenylethyl)]amino} sulfonyl] 4-ylethanol Acetonitrile; (lR)-2-({6-[3- gas-4.(trifluoromethyl)phenyl]-2-(trifluoromethyl)pyrimidine_4_yl} -1-phenylethanol; 238 200948790 (lR)-2-{[6-(3,4-dichlorophenyl)-2-methylpyrimidin-4-yl]amino}-l-phenyl Ethanol; (lR)-2-{[6-(3,4-dichlorophenyl)-pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[ 4-(ethylsulfanyl)phenyl]pyrimidin-4-yl}amino)p-phenylethanol; (lR)-:2-{[6-(3-ethoxyphenyl)" 4-yl]amino}-1-phenylethanol; (1R)-1-phenyl^-2-{[6-(3-propoxyphenyl) octyl-4-yl]amino}ethanol (lR)-2-{[6-(3-butoxyphenyl)-nough _4_yl]amino}-1-phenylethanol; ❹ (lR)-2-{[6-(l -benzothiophen-5-yl)histidine-4-yl]amino}p-phenylethanol; (lR)-2-({6_[3·chlorine (trifluoromethyl)phenyl]_2_(two Hydrazinyl))-pyridin-4-yl}amino)-1-phenylethanol; (1R)-2_((6-[3-fluoro-4_(trifluoromethyl)phenyl]-2- (methylsulfanyl)pyrimidine- _4-yl}amino)-1-phenylethanol; (1R)-1-phenyl-2-({4-[4-(trifluoromethyl)phenyl] {3,5-Triton-2-yl}amino)ethanol; Q (1R)-2_((4-[3-chloro-4·(trimethyl)phenyl)-1,3,5- Triton-2-yl}amino)-1-phenylethanol; (1R)-1·phenyl·2_({6-[3_(trifluoromethyl)phenyl] (1R)Phenylphenyl-2-[(6-{4_[(trifluoromethyl)oxy]phenyl}-pyridyl-4-yl)amino]ethanol ; 1-(4-nitrophenyl)-2·[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; 2- [(6 -{4_[(difluoroindolyl)oxy]phenyl)-feeding _4_yl)amino]heart-(tetra)trifluoromethyl)phenyl]ethanol; 239 200948790 1_(4-chlorophenyl)- 2-[(6-{4-[(Trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; & 4-{l-carboxy-2_[(6-{4-[ (trifluoromethyl)oxy]phenylmidine-4-yl)amino]ethyl}phenol; 1-[4-(fluorenyloxy)benzyl]-2-[(6-{4- [(Trifluoromethyl)oxy]phenyl b. Metidin-4-yl)amino]ethanol; 4-{1-carbamic-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino Ethyl}-2-(fluorenyloxy)phenol; 1-(4-fluorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}piperidine _ 4-yl)amino]ethanol; 1-(3,4-dioxaphenyl)-2_[(6·{4-[(trifluoromethyl)oxy]phenyl) _4_yl)amino Ethanol; 1-(2-chlorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl)-amino]ethanol] 1-(3-benzene -2_[(6-{4-[(Tri-indenyl)oxy)phenyl}pyrimidin-4-yl)amino]ethanol; 1-[3-(methyloxy)benton]- 2-[(6-{4-[(trifluoromethyl)oxy)]piperidin-4-yl)amino]ethanol; 1-[2-(fluorenyloxy)benzyl]-2-[ (6-{4-[(Trifluoromethyl)oxy]phenyl}-carcin-4-yl)amino]ethanol; (1R,2S)-1-phenyl_2·[(6-{ 4·[(三败曱基)oxy]phenyl}0-melidine_4_yl)amino]propan-1-ol; (1R,2R)-2-[mercapto (6-{4-[ (trifluoromethyl)oxy]phenyl}ergda-4_yl)amino]-1 -phenylpropan-1 - leaven; (1R,2S)_2_[methyl(6-{4-[ (trifluoromethyl)oxy]phenyl}pyridinyl-4-yl)amino]-1-phenylprop-1-propylate; 240 200948790 mono-1,3-benzene And 2,[(6-{4-[(trifluoromethyl)oxy]benyl}pyrimidin-4-yl)amino]ethanol; ^ ratio °_2_yl-21{4_[ (trifluoromethyl)oxy]phenyl} face-4-yl)amino]ethanol; Ι-t 士士基刊(四)王fluoromethyl)oxy]phenyl ΜI group) Amino] Ethanol; ^比唆_4_yl-2-[(6_{4'[(trifluoromethyl)oxy]phenyl}-indolyl)-amino]ethanol; Ο ❹ 1-(3'5 -dichlorophenyl)_2|{4_[(trimethylmethyl)oxy]phenyl)ylamino)ethanol; ^(1'3 benzo-p-methyl-5)_2|{4_ [(Trifluoromethyl)oxy]phenylpyrimidin-4-yl)amino]ethanol; (js)-2_({6_[3_Chloro_4_(trifluoromethyl)phenyl) bite 4 amine Ethanol; (lR)-2-({6-[3-fluoro-ice (1)-ylethyl)phenyl] benzoate _4 yl}amine phenylethanol; 2 ({6 [3-gas_4- (二), phenyl] mouth biting ice base} amino)trifluoromethoxy)phenyl]ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl] Pyrimidine-4-ylamino)l-(3fluorophenyl)ethanol; 2-[6-(3-chlorotrifluoromethyl-phenylpyridylamino)diureate phenyl)-ethanol; 1-(4·Chloro_3_fluoro-phenyl)-2_({6-[3_gaso(trifluoromethyl)phenyl] acetylene _4_yl}amino) ; 1-(3_Chloro·4_fluorophenyl)_2_({6-[3_gas_4_(trifluoromethyl)phenyl]pyridin-4-yl}amino)ethanol; 241 200948790 2-( {6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)443-(trifluoromethyl)phenyl]ethanol; (lR)-2-{[2 -cyclopropyl-6-(3,4-dichlorophenyl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-{[6-(3,4-dichloro Phenyl)_2_(ι·decylethyl) „Mididine_4_yl]amino}-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoro) Methyl)phenyl]_2-(methylthenyl)pyrimidin-4-yl]amino)-1-phenylethanol; (lR)-2_({6-[3-gas_4_(trifluoroanthracene) Phenyl]-2-(phenylsulfonyl)pyrimidin-4-yl}amino)-1-phenylethanol; @(lR)-2-{[6-(3-indolyl-1H-吲嗤-6-yl)pyrimidin-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[3- gas·4-(trifluoromethyl)phenyl] _2-(fluorenylamino) stagnation ice base}amino)-1-phenylethanol; (lR)_2-{[6-(4-mothylphenyl) hydrazinyl-4-yl]amino}} _Phenylethanol; (lS)-2-[6-(3-chloro-4-trifluorodecyl-phenyl)-bist-4-ylamino]-l-(3,4-difluoro- Phenyl)-ethanol; (1 ft)-2-[6-(3-gas_4-trimethylsulfonyl-phenyl)-mouth -4-amino-yl]-1-(3,4- 〇Difluoro-phenyl)-ethanol; (lS)-l-(4-Ga-3-fluoro-phenyl)-2-[6-(3-chloro-4·trifluoromethyl-phenyl)pyrimidine -4-ylamino]-ethylidene; (lR)-l-(4-a-3-fluoro-phenyl)-2-[6-(3-a-4-trifluoromethyl-phenyl) 2-[{-[4-(indolyloxy)phenyl]pyrimidin-4-yl}amino H-phenylethanol; 2-{[6 -(3-mercaptophenyl)pyrimidin-4-yl]amino}p-phenylethanol; 242 200948790 1-phenyl-2-[(6-{3-[(trifluoromethyl)oxy]benzene (1S,2R)-1-phenyl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidine_4_ Amino]propan-1-ol; (1S)-1-phenyl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino ] ethanol; (lR)-2_({6-[2,4-bis(trifluoromethyl)phenyl]pyridinyl-4-yl}amino)phenylethanol; (lR)_2_({6- [2. methoxy_4_(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2_{[6-(4_ethoxy) 2_mercaptophenyl) mouth biting ice base] aminyl 1 phenylethanol; 2-{[6-(3,4-dimercaptophenyl)pyrimidin-4-yl]amino}}ι_ Phenylethanol; 2-({6-[4-(1,1-didecylethyl)phenyl ρ _4_ base }amino)_ι_phenylethanol; 2-[6-(4-mercaptothioalkyl-phenyl)-carcinoma-4-ylamino]_1_phenyl-ethanol; 4-{6-[ (2-carbo-2-phenylethyl)amino] 咬-4-yl} benzoic nitrile; 2-(6-benzo[b]thiophen-2-yl-anthran-4-ylamine Small phenyl-ethanol; 1-(4-{6-[(2-carbo-2-phenylethyl)amino]carcinoma-4-yl}phenyl)ethanone; 2- [6 -(3,4-dimethoxy-phenyl)-pyrimidin-4-ylamino]-phenylene-ethanol; 2-{[6-(4-mercaptophenyl)pyrimidine-4-yl] Amino}-1-phenylethanol; 1-phenyl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyridinyl-4-yl)amino]ethanol; 2- (6-Benzo[1,3]dioxazole-5-yl-pyrimidin-4-ylamino)-1-phenyl-ethanol; 2-[6-(3-decyloxy-phenyl)_ Pyrimidine-4-ylaminophenyl-ethanol; 2-[6-(3-nitro-phenyl)melidyl-4-ylamino]phenyl-ethanol; 243 200948790 2-[(6-naphthalene- 2-ylpyrimidin-4-yl)amino]-1-phenylethanol; 1-{5-[6-(2-hydroxy-2-phenylethylamino)-. (iR)-2-{[6-(3,4-dichlorophenyl)-2-indolylpyrimidin-4-yl]amine Base}_1_phenylethanol; (lR)-2-{[6-(3,4-chlorophenyl)amino}-1-phenylethanol; (lR)-2-({2-[( 2-Aminoethyl)amino]-6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2_ [(6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-{[2-(didecylamino)ethyl]amino)amino]-1-phenylethanol (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-(ethylamino)pyrimidin-4-yl}amino)-1-phenyl Ethanol; (lR)-2-({6-[3-gas(trifluoromethyl)phenyl)2-[(2-hydroxyethyl)amino]pyrimidin-4-yl}amino)-1 -Phenylethanol; (lR)-2-({2-azetidin-1-yl-6-[3-chloro-4-yl](trifluoromethyl)phenyl] π-[rho]- -4-yl] Amino)-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2-(cyclopropylamino)pyrimidin-4-yl}amine (1-)-phenylethanol; (lR)-2_[(6-[3-chloro_4_(trifluoromethyl)phenyl]_2_{[2·(methylamino)ethyl]amino} Mouth bit-4-yl)amino]_1_phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2_ Oxypyrimidine _4_yl}amino)-1-phenylethanol; (lR)-2-{[6-(3-methyl-1,2-benzisoxazole-6-yl)pyrimidine_4 _yl]amino}-1-phenylethanol; 1-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)_2• stupid 244 200948790 Prop-2-propanol; 2-({6-[3-chloro-4-(tri-methyl)phenyl]pyrimidine-4-amino}amino)-1-[4-(methylsulfanyl) Phenyl]ethanol; 2-({6-[3_chloro_4·(difluoroindolyl)phenyl]pyrimidin-4-ylamino)dithiophen-3-ylethanol; 2-({6 -[3-chloro-4-(difluoroindolyl)phenyl]pyrimidin-4-yl)amino)p-(n-thiazol-2-yl)ethanol; (1R)-1-phenyl-2-[( 6-quinoline-6-ylpyrimidin-4-yl)amino]ethanol; ❹ Ν-t-butyl-4-(6-{[(2R)-2-hydroxyphenylethyl]amino}pyrimidine 4-yl)benzenesulfonamide; (1R)-1-phenyl-2-({6-[4_(thiomorpholinanylsulfonyl)phenyl]pyrimidin-4-yl}amino) Ethanol; (1R)_1_(4_fluorophenyl)-2_({6_[;3_fluoro_4_(trimethylmethyl)phenyl]eridine--4-yl}amino)ethanol; (1R) Small (4-phenylphenyl), 2_({6_[3_fluoro_4·(trifluoromethoxy)phenyl(tetra)pyridin-4-yl}amino)ethanol; 〇(1R)-2-({ 6-[3_Chloro_4-(trifluoromethoxy)phenyl] mouth Titrate}amino)-1-(4-fluorophenyl)ethanol; (1R)-1-(4_|L phenyl&gt;2-({6_[3_(pentafluoroethyl H,2-benzene) And (iso)-6-yl]pyrimidin-4-yl}amino)ethanol; (lR)-l-(4.fluorophenyl)4({6_[3_(trif)), 2_benzo Isoxazol-6-yl]pyrimidin-4-yl}amino)ethanol; (1R)_2_({6-[3·fluoro-4'(2,2,2-trifluoroethoxy)phenyl] ♦定冰基}Amino)-1-phenylethanol; (lR,2S)-2-({6-[3-t^4^ fluoromethyl)phenyl]β唆唆_4_yl}amine ))-1-phenylpropan-1-ol; 245 200948790 (1R)-1-phenyl-2-[(6·{4-[(trifluoromethyl)sulfanyl; Iphenyl] „ dense (lR)-2-({6-[3·chloro-4-(trifluoromethoxy)phenyl] sputum _4-yl}amino)-1 -Phenylethylidene; (1R)-1-phenyl-2-({6-[3-(trifluoromethyl)), 2-benzoisoxazole-6-yl]pyrimidin-4-yl}amine Ethyl alcohol; (lR)-2-{[6-(2,2-difluoro-1,3·benzodioxan-5-yl)pyrimidin-4-yl]amino}-1-phenyl Ethanol; (1R)-1-phenyl-2-({6-[5-(trifluoromethyl)-1-benzothiophen-2-yl]pyrimidin-4-yl}amino)ethanol; (1R )-1-phenyl-2-({6-[5-(trifluoromethoxy)_1• benzothiophene-2-yl]pyrimidine-4 -(amino)amino)ethanol; (1R)-1-phenyl-2-({6-[6-(trifluoromethyl)_1•benzothiophene-2-yl]pyrimidin-4-yl}amino Ethyl alcohol; (lR)-2-{[6-(5-fluoro-1-benzothiophen-2-yl)pyrimidinyl]-amino]phenyl phenylethanol; (1R) 2-({6-[ 3-(five rat ethyl)_ι,2-benziso.恶0坐_6_基] 咬-4-yl}amino)-1-phenylethanol; 2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidine _4 _yl}amino)-1-[2-(difluoromethoxy)phenyl]ethanol; 2_({6-[3_gas-4-(tri-Imethyl)phenyl]pyrazine_4_ 4-amino-)-(4-fluorophenyl)ethanol; 4-[2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) Hydroxyethyl]benzonitrile; 2_({6-[3·chloro-4·(trifluoromethyl)phenyl]0-pyridine 4-amino}amino)-2-naphthalen-2-ylethanol; 246 200948790 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(4-oxaridin-2-ylphenyl)ethanol; 2_( {6-[3-Chloro-4-(triponyl)phenyl]-bromo-4-yl}amino)-1-(4-thien-2-ylphenyl)ethanol; 1-biphenyl 4-yl-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; 1-(1-benzothiophen-2-yl) )-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethylidene, 2- ({6-[3-gas-4- (trifluoromethyl)phenyl]carto-4-yl]amino)-1-[3_fluoro-4-((trifluoromethyl)phenyl]ethanol; 2-({6-[3-gas- 4-(Trifluoromethyl)phenyl]-piperidin-4-yl}amino)-1-{3-[(trifluoromethyl)sulfanyl]phenyl} Alcohol; 2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(2,3-dihydro-1,4-benzo) Dioxin-6-yl)ethanol; 2-({6-[3-chloro_4_(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)_1_[4-(1H-imidazole-1 -yl)phenyl]ethanol; 1-(1-benzothiophen-3-yl)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl} Amino)ethanol; 2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(3,4-dimethoxyphenyl) Ethanol; 1-(3-chloro-4-methoxyphenyl)-2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) Ethanol; 2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-l-(3,4-dihydro-2H-l,5- Benzodioxan-7-yl)ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[ 2-fluoro-5-(trifluoromethyl)phenyl]ethanol; 247 200948790 3-[2-({6-[3-chloro-4-(dimethylmethyl)phenyl]. Bite-heart group]-amino)-1-hydroxyethyl]benzonitrile; 2-({6-[3-chloro-4-(disindolyl)phenyl]. Amino)-1-(3-phenylisoxazol-5-yl)ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl} Amino)-1-(4-pyrrolidin-1-ylphenyl)ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl} Amino)-1-(5-pyridin-2-ylthiophen-2-yl)ethanol; 5-[2-({6-[3- gas-4-(dioxamethyl)phenyl] guanidine 4-yl}amino)-1-hydroxyethyl]-2-fluorobenzonitrile; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl }Amino)-1-(2,6-difluorophenyl)ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) 1-(2-fluorophenyl)ethanol; 2-[6-(3-chloro-4-trifluoromethyl••phenyl)-pyrimidin-4-ylamino]-l-[3-(3 ,4-dichloro-phenyl)-isoxazole-5-yl]-ethanol; 1-[3-(4-chloro-phenyl)-isoxazole-5-yl]-2-[6-( 3-Chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]•ethanol; 2-[6-(3-Gas-4-dimethyl-phenylamino)- 1-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-ethanol; 1-benzox0-oxo-2-yl-2-[6-(3-chloro -4-dimethylmethyl-乙)- 鸣.定-4_基基基]-ethanol; 1-[3,5-bis(trifluoromethyl)phenyl]-2-({6-[3-chloro-4-(trifluoromethyl) Phenyl]pyrimidin-4-yl}amino)ethanol; 1-(5-bromo-1-benzothiophen-2-yl)-2-({6-[3- gas-4-(trifluoro) Methyl)phenyl]pyrimidin-4-yl}amino)ethanol; 248 200948790 (1R)_phenyl-2]6-[4_(1,2,2,2-tetrafluoro-1-trifluoromethyl -ethyl)-phenyl]-pyrimidin-4-ylaminodiethanol; (1 ft) _phenyl-2-{6-[3-(1,2,2,2-tetrafluorotrifluorodecyl) -ethyl)-phenyl]-pyrimidine-4-ylamino hydrazine-ethanol; (1R)-phenyl-2-[6-(3-trifluoromethyl-benzo[b]thiophene)- Bite • 4-ethanol; 4-(3-chloro-4-trifluoromethyl-phenyl)_6_(2-hydroxy-2-phenyl-(1R)-ethylamino)pyrimidine-2-methyl Nitrile; ❹ 2-[6-(2,6-difluoro-phenyl)-pyridin-4-ylamino]-1-phenyl-ethanol; 4_[6-(2-hydroxyphenyl-ethyl Amino)-pyrimidin-4-yl]-phenol; 2-[6.(3,5-bis-trifluoromethyl-phenyl)-pyrimidin-4-ylaminophenyl-ethanol; 2-[6 -(3-Amino-phenyl)-mouth butyl-4-ylamino]-1-phenyl-ethanol; • 2-[6-(4-Hydroxymethyl-phenyl)-pyrimidin-4-yl Amino]-1-phenyl-ethanol; N-{3-[6-(2-amino-2·benzene) -ethylamino) _ phenyl hydrazide] _ phenyl} _ aryl amine; Ο 1 _ phenyl 2 - (6-phenyl-pyrimidin-4-ylamino)-ethanol; 1-phenyl- 2-(6-嗟-phen-2-yl, anthranylamino)-ethanol; and 1-phenyl·2-(6-thiophene-3-yl-pyridinylamino)-ethanol; or A pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite of the compound. μ The pharmaceutical composition of claim 57, which further comprises: an analgesic selected from the group consisting of opioids and a non-steroidal inflammatory drug. 249 200948790 62. The pharmaceutical composition of claim 57, further comprising: selected from the group consisting of aspirin, acetaminophen, quinone, ibuprofen, naf〇 (napr〇) Additional active ingredients of the group consisting of xen), c〇x_2 inhibitor, gabapent&gt;T (gabape), pregabalin, and tomabao (iv) brain. 63. The pharmaceutical composition of claim 57, wherein the compound or pharmaceutically acceptable salt has an IC50 value of less than 0.1 iM measured in a human FAAH activity assay. 64. The pharmaceutical composition of claim 57, wherein the compound or the phytopharmaceutical salt has an IC50 value of less than 0.01 iM measured in the human FAAH activity assay. 65. The pharmaceutical composition of claim 57, wherein the compound or pharmaceutically acceptable salt has an IC50 value of less than 0.005 ilV measured in the detection of human F A A H activity. 66. Use of a compound as defined in claim 57 of the patent application for the manufacture of a medicament for the treatment of an individual having or diagnosed with a disease, condition or medical condition mediated by it. 67. Use of a medicament for the manufacture of a medicament for treating an individual having or diagnosed with a disease 'disease or medical condition mediated by FAAH activity, wherein the medicament is selected from the group consisting of: 250 200948790 (lR)-2-({6-[4_(Ethyloxy)_3_(trifluoromethyl)phenyl]indolyl)-1-phenylethanol; 2-{[6-(4 -Chlorophenyl)pyrimidinyl]amino}_丨-phenylethanol; 2-{[6-(4-fluorophenyl)pyrimidin-4-yl]aminophenyl-phenylethanol; 1-phenyl-2 -({6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol, · 2-{[6-(4-nitrophenyl)pyrimidin-4-yl]amino Bubuphenylethanol; 2-{[6-(4.ethylphenyl)pyrimidin-4-yl]amino}-1 phenylethanol; 2-({6-[4-(1-methyl) Phenyl]pyrimidin-4-yl}amino) 丨 丨 基 乙醇 乙醇 { { 2-{[6-(3,4-dichlorophenyl)pyrimidin-4-yl]aminophenyl 1 phenyl Ethyl alcohol; 2-{[6-(3-chlorophenyl)pyrimidin-4-yl]aminophenyl phenylethanol; 2-({6-[3_ gas-4-(trifluoromethyl)phenyl] Pyrimidine _4_yl}amino)phenylethanol; • (ethyloxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; - 2-[(6-{4-[ (1-methylethyl)oxygen Phenyl anthraquinone-yl)amino]-1-phenylethanol; 1-phenyl-2-({6-[4-(phenyloxy)phenyl]pyrimidin-4-yl}amino Ethyl alcohol; ❹ 2-({6-[3_chloro-(ethyloxy)phenyl]pyrimidin-4-yl}amino)phenyloxyethanol; (1R)-1-phenyl·2-( {6_[4-(Trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; (lR)-2-({6-[3-chloro- 4-(trifluoromethyl)phenyl) (lH)_2-({6-[3-chloro- 4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)- 1-phenylideneethanol hydrochloride; l_t4_(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl]ethanone; 251 200948790 (lR) -2-({6-[4-(l-methylethyl)phenyl] π-Bite-4-yl}amino)_1_phenylethanol; (lR)-2-[(6-{3 - gas-4-[(l-methylethyl)oxy]phenyl}pyrimidin-4-yl)amino]-1-phenylethanol; (lR)_2_{[6-(3-fluoro_4 · mercaptophenyl) guan-4-yl]amino}-1-phenylethanol; (lR)-2-({6-[4-(transmethyl)phenyl]pyrimidine-4-yl }Amino H-phenylethanol; 4-(6-{[(2R)-2-yl-2-phenylethyl]amino} oxime-4-yl)benzazole; 3-(6 -{[(2R)-2-yl-2-phenylethyl]amino}pyrimidine-4- Benzoaldehyde; hydrazine (1R)-1-phenyl-2-[(6-{4-[(2,2,2-trifluoroethyl)oxy]phenyl} 〇 〇 _4_ base) Amino]ethanol; (1R)-1-phenyl-2-[(6-{3-[(2,2,2-tris)ethyl)oxy]phenyl}-biting _4·yl)amine (lR)-2-{[6-(4-chloro-3-methylphenyl)pyrimidin-4-yl]amino} phenylphenyl-alcohol; (lR)-2-{[ 6-(4-chloro-3-fluorophenyl)-mouth -4-yl]amino}-1-phenylethanol; (lR)-2-({6-[4-chloro-3-(trifluoro) Methyl)phenyl]pyrimidin-4-yl}amino)methanol hydrazine; (lR)-2-({6-[3-fluoro-4-(trifluoromethoxy)phenyl) mouth bite 4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(4-ethoxy-3-fluorophenyl)pyrimidin-4-yl]amino}-1- Phenylethanol; (lR)-2-{[6-(4-ethoxy-3-indolylphenyl) "mididin-4-yl]amino H-phenylethanol; 252 200948790 (lR)-2 -({6-[4-(cyclopropylmethoxy)phenyl]pyrimidin-4-yl}amino)phenylideneethanol; (lR)-2-{[6-(4-butoxy- 3-Fluorophenyl&gt;Mididine-4-yl]amino}Phenylphenylethanol; (lR)-2-{[6-(4-Butoxyphenyl)pyrimidin-4-yl]amino} -1-phenylethanol; (lR)-2-{[6-(3-fluoro-4-propoxyphenyl)D-dimethyl-4-yl]amino}-1-phenyl Ethyl alcohol; (lR)-2-({6-[3-fluoro-4-(1-mercaptoethoxy)phenyl]pyrimidin-4-yl}amine 0-yl)-1-phenylethanol; (lR )-2-({6-[4-(2-methylpropoxy)phenyl]pterin-4-yl}amino)-1-phenylethanol; (lR)-2-{[6- (4-methoxy-3-methylphenyl)" dimethyl-4-yl]amino}p-phenyl-ethanol; (lR)-2-{[6-(3-chloro-4-indolyl) Phenyl) benzyl 4-amino]amino}·1_phenylethanol; (lR)-2-{[6-(3,5-didecylphenyl) η -4-yl]amine } -1-phenylethanol; ❹ (lR)-2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]α 咬4_yl}amino)phenyl Ethyl alcohol; (lR)-2-({6-[3_gas_5-(trifluoromethyl)phenyl]nonoxime_4_yl}amino)_ι-phenylethanol; (lR)-2_{ [6-(3·Chloro-5-fluorophenyl) feeding _4_yl]amino phenyl phenylethanol; (1R)-1-phenyl-2-{[6-(4-propoxy phenyl) Base) mouth bite ice base] amine base} ethanol; (1 foot)-; 2-{[6-(2,1,3-benzo- oxadioxin-5-yl) feeding 0--4 base] Amino}Phenylphenylethanol; (lR)-2-({6-[3-Mercapto-4-(1-indolylethoxy)phenyl]pyrimidin-4-yl}amino)-1- Phenylethanol; 253 200948790 (lR)-2-({6-[3-chloro, 4, (trimethyl)methyl) thiol thiol base)-1 -Phenylethanol; (11〇2]({6-[&gt;Fluorine, 4_(三说曱基)phenylsulfonyl group _4_yl"amino)-1-phenylethanol; 2:( -(Difluoromethoxy (4) difluorophenyl] as ice-based}amino)-1-benylethanol; 2_[4_(6_{[(2R)-2,yl 1phenylethyl]amine }毅_4基) Stupid base]-2-mercaptopropenyl nitrile; H2-Fluoro-4-(6-{[(2ί^_2_Phenyl-2-phenylethyl)amino} _4·yl)phenyl]ethanone; (lR〇_2-({6- [3,5-Dimethyl_4_(1-decylethoxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-{[6-(lH -吲哚_6_yl)pyrimidine_4_yl]aminopurine small phenylethanol; (1R)-1-phenyl-2-{[6-(3,4,5-trifluorophenyl) ring (iR)-2-{[6-(l_methyl_1Η_Π弓卜多_2_yl)) 胺 _ 4 4 4 ] ] 苯基 苯基 苯基 苯基 苯基 苯基 苯基 苯基 (lR)-2-{[6-(5-fluorenyl)-benzothiophene-2-yl) methylene chloride]amino}p-phenylethanol; [4-(6-{[(2R)-) 2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl](phenyl)fluorenone; (lR)-2-{[6-(3,5-difluorophenyl) Pyrimidine-4-ylaminopyrazine-phenylethanol; (lR)-2-{[6-(3,4-difluorophenyl)pyrimidin-4-yl]aminopyribyl 1-phenylethanol; (lR)-2-({6-〇chloro-4_(trifluoromethyl)phenyl]_2_(indolylthioalkyl)pyrimidin-4-yl}amino)-1-phenylethanol; (lR )-2-({2-amino-6-[3-chloro-4-(trifluoromethyl)phenyl]-mouth _4-yl}amino)-1-phenylethanol; 254 200948790 (1Κ&gt ; 2_({6·[3_Chloro_4_(trifluoromethyl)phenyl]-n-fluorophenyl)ethanol; (lR)-2-{[6-(6-methoxyindole-3- (i)pyrimidin-4-yl]amino}p-phenylethanol; (lR)-2_{[6-(6-ethoxypyridine-3-yl)pyrimidinyl]aminophenyl L-phenylethanol; (1 «&gt;2-({6-[4-(Didecylamino)phenyl]pyrimidinyl)amino)+phenylethanol; ❹(1R)-2-({6_[4_(methylsulfonate) Phenyl)phenyl]«mididin-4-yl}amino)-1-phenylethanol; N-cyclopropyl-4-(6-{[(2R)-2-hydroxy-2-phenyl) Amino]pyrimidin-4-yl) benzenesulfonamide; lR)-2-{[6-(3-Chloro-4-ethoxyphenyl)pyrimidin-4-yl]amino}_1_phenylethyl t-ol; (lR)-2_[(2'_?琳-4-yl-4,5'- conjugated)amino]-1-phenylethanol; (lR)-2-{[6-(6-morpholin-4-ylacridine_3_ (lR)-2-{[6-(3-fluoro-4-methoxyphenyl)pyrimidin-4-yl]amine }}_丨_phenylethanol; (lR)-2-{[6-(2,3-dihydro-1,4-benzodioxin_6_yl)pyrimidin-4-yl]amino}- 1-phenylethanol; (lR)-2-({6-[3- gas-4-(trifluoromethyl)phenyl]_2-methylpyrimidin-4-yl}amino)-1-phenyl Ethyl alcohol; (lR)-2-{[6-(l·]-l-l-H-carbazole-4-yl). Michidine _4_yl]amino quinone phenylethanol; 255 200948790 (lR)-2 -{[6-(6-fluoro-5-fluorenyl η than -3-yl) cancer bit -4-yl]aminopyr 1-phenylethanol; 4-(6-{[(2R)-2 -transyl-2-phenylethyl]amino}pyrimidin-4-yl)-indole, hydrazine-dimethylbenzenesulfonamide; 5-(6-{[(2R)-2-hydroxy-2-benzene) (ethyl)-amino}pyrimidin-4-yl)acridin-2-indene nitrile; (lR)-2-({6-[6-(dimethylamino)acridin-3-yl]pyrimidine_ 4-yl}amino)p-phenylethanol; (IR)-l-benyl-2-({6-[4-(pino-1-yl))phenyl] (11^)-1_benyl-2-({6-[4-(11 piroxime-1-decyl)phenyl]carcinoma 1»定_4_ base Amino)ethanol; 4-(6-{[(2R)-2-yl-2-phenylethyl]amino}pyrimidin-4-yl)benzenesulfonamide; (lR)-2-{ [6-(4-Fluorophenyl)pyrimidin-4-yl]amino}-1·stupylethanol; (lR)-2-{[6-(3-Ga-4-fluorophenyl)methicin- 4-yl]amino}-1-phenylethanol; (lR)-2-({6-[3-(mercaptosulfanyl)phenyl]pyrimidin-4-yl}amino)heptaphenylethanol (lR)-2-{[6-(lH-吲哚-5-yl)&gt;dimethyl-4-yl]amino}-1-phenylethanol; (1R)-1-phenyl-2- [(6-嗤琳-3-ylphony-4-yl)amino]ethanol; (lR)-2-{[6-(l-benzothiophen-3-yl)pyrimidin-4-yl]amine Small phenylethanol; 2-fluoro-4-(6-{[(2R)-2-yl-2-phenylethyl]amino}pyrimidin-4-yl)benzonitrile; 2-fluoro -5-(6-{[(2R)-2-hydroxy-2.phenylethyl]amino}}pyridyl) benzonitrile; 200948790 (lR)-2-{[6-(l-A Base-m-ten _5_yl) _4 yl]amino} small phenylethanol; (lR)-2-[(6_{4-[(l-methylethyl)sulfanyl]] Alkyl]-1-phenylethanol; [4-(6-{[(2R)-2-yl-2-ylethyl]amino} 〇) Phenyl]acetonitrile; (lR)-2-({6-[3-aluminum (trifluoromethyl)phenyl]_2-(trioxymethyl))- 4_yl}amino)-1-phenyl Ethanol; ❹ (1R)-2_{[6_(3,4-dichlorophenyl)-2-fylpyridin-4-yl]amino}-1_phenylethanol; (lR)-2-{ [6-(3,4-diphenylphenyl-p-pyridinyl-4-yl)amino-i-phenylethanol; (lR)-2_({6-[4-(ethylsulfanyl)) Pyrimidine-4-yl)amino)phenylethanol; (lR)-2-{[6-(3-ethoxyphenyl)pyrimidin-4-yl]aminopurinyl-phenylethanol; 1R)-1-phenyl-2-{[6-(3-propoxyphenyl)eridine-4-yl]amino}ethanol; (lR)-2-{[6-(3-butoxy Phenylphenyl)pyrimidin-4-yl]amino}_;[_phenylethanol; hydrazine (lR)-2-{[6-(l-benzothiophen-5-yl)-infantyl]amino }small phenylethanol; (lR)-2_({6-[3-chloro_4_(trifluoromethyl)phenyl]_2-(ditiaryylamino); pyrimidin-4-yl}amino)-1 -phenylethanol; (lR)-2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]-2-(methylsulfanyl)pyrimidin-4-yl}amino) -1-phenylethanol; (1R)-1-phenyl-2-({4_[4_(trimethylmethyl)phenyl tritonyl-2-yl}amino)ethanol; (lR)-2_({ 4-[3-Chloro(trifluoromethyl)phenyl]·ι,3,5·three tillage_2-yl}amine -1-phenylethanol; 257 200948790 (1R) succinyl-2-({6-[3-(trifluoromethyl)phenyl] hydroxy]amino)ethanol; (1R)-1- Phenyl-2-[(6-{4_[(trifluoromethyl)oxy]phenyl) 4 amino)amino]ethanol; 1-(4-nitrophenyl)-2-[(6- {4-[(Trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; 2-[(6-{4_[(dioxamethyl)oxy]phenyl] mouth bite _4_yl)amino]_ι·[4·(trifluoromethyl)phenyl]ethanol; 1-(4-phenylphenyl)-2·[(6-{4-[(trifluoromethyl)) Oxy]phenyl}pyrimidin-4-yl)amino]ethanol; ❹ 4-{1-hydroxy-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidine_4 _yl)amino]ethyl}phenol; 1-[4-(fluorenyloxy)phenyl]-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidine Bite _4_yl)amino]ethanol; 4_{1-light keto-2-[(6·{4·[(trifluoromethyl)oxy]phenyl bromidyl]-4-yl)amine Ethyl 2-(methyloxy)pred; b (heart fluorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}) Amino]ethanol; Ο 1-(3,4-dichlorophenyl)-2-[(6_{4-[(tris)methyl)oxy]phenyl] _4_yl)amino] Ethanol; 1-(2_chlorophenyl)-2-[(6_{4_[(trifluoromethyl) Oxy]phenyl}-penetrating _4_yl)amino]ethanol; 1-(3-chlorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl Amino acid]ethanol; 1-[3-(methyloxy)phenyl]_2-[(6-{4-[(trifluoromethyl)oxy]phenyl]-pyridine- 4-yl)amino]ethanol; 258 200948790 1-[2-(indolyloxy)phenyl]Vinyl (tetra)-fluoroindolyloxy]phenyl]pyridin-4-yl)amino]ethanol; (1R,2S)-1-phenyl_2_[(6_{4_[(trifluoromethyl)oxy]phenyl} ♦ borneylamino] propan-1-ol; [methyl (6) 4 -[(Tri-Imethyl)oxy]phenyl} mouth niche base) amino]-1-phenylpropan-1-ol; (JR, 2S^2-[曱基(6_{4_[(三) Fluoromethyl)oxy]phenylidene _4·yl)amino]-1-phenylpropan-1-ol; ❹ ❹ difluoro-u-stupid 2D oxo_5_yl)_2 micro卜[(三敦methyl)oxy]benzine} mouth bite_4_yl)amino]ethanol; 匕bite=·基·2_[(6·{4·[(trifluoromethyl)oxy) Phenyl} ♦ icyl) amino] ethanol, =1 = 3-yl_2_[(6_{4_[(trifluoromethyl)oxy]phenyl]ethanol; Base 2-[(6'{4-[(trifluoromethyl)oxy)phenyl}) -4-yl)amine^=^ base&gt;2 v {4 side methyl)oxy]benzene Kibim im {6_[3*4dmethyl) stupid quinone·4·fine base)+benzene benzoic acid 4.·(10) ylethyl) paste ice _base) small 2_(,[3_chloro_4_(trifluorof-base) Methoxy)phenyl]ethanol; soil / makeup 丞) ip (一贶259 200948790 2-({6-[3- gas ice (trifluoromethyl)phenyl]pyrimidin-4-amino}amino) small (3-fluorophenyl)ethanol; 2_[6-(3_chloro-4-trifluoromethyl-phenyl)-indenyl arylamino]·w3,4·difluoro-phenyl)-ethanol ; K4-gas-3-fluoro-phenyl)_2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidine_4_yl}amino)ethanol; 1- (3- Gas-4-fluorophenyl)_2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-dosing _4_yl}amino)ethanol; 2- ({6_[3·chlorine _4-(Trifluoromethyl)phenyl]pyrimidinyl}aminofluoroindolyl)phenyl]ethanol; ❹ (lR)-2-{[2-cyclopropyl-6-(3,4-di Chlorophenyl)pyrimidin-4-yl]amino}-p-phenylethanol; (lR)-2-{[6-(3,4-dichlorophenyl)_2_(ι_methylethyl) bite slightly _4_yl]amine. yl-1-phenylethanol; (lR)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]_2-(methylsulfonyl) Pyrimidine _4~yl}amino)-1-phenylethanol; (lR)-2_({6-[3_gaso(trifluoromethyl)phenyl]_2_(decylsulfinyl)pyrimidine- 4-yl}amino)-1 -Phenylethanol; hydrazine (lR)-2-{[6-(3-indolyl-lH-n azole -6-yl) acetyl _4 yl]amino} ΐ phenylethanol; lR)_2-({6-[3-chloro-4_(trifluoromethyl)phenyl]_2_(decylamino)pyrimidin-4-yl}amino)-1 -phenylethanol·, (lR) -2-{[6-(4-iodophenyl)pyrimidinyl]aminophenylpyrazine-phenylethanol; (lS)-2-[6-(3- gas-4-trifluoromethyl]phenylpyrimidine _4_ylamino-mono-subunit)·ethanol; 260 200948790 (lR)-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino] - one gas - the base) ** ethanol ·; (lS)-l-(4-chloro-3-fluoro-phenyl)-2-[6-(3- gas-4-trifluoromethyl-phenyl) Pyrimidin-4-ylamino]-ethanol; (lR)-l-(4-chloro-3-fluoro-phenyl)_2-[6-(3-chloro-4-trifluoromethyl-phenyl)_ Pyrimidin-4-ylamino]-ethanol; 2-({6-[4-(indolyloxy)phenyl]pyrimidin-4-yl}amino)phenylethanol; 2-{[6-(3 -Methylphenyl) 咬-4-yl]amino}-1-phenylethanol; 〇 phenyl-2-[(6_{3-[(trifluoromethyl)oxy]phenyl bumi (1S,2R)-1-phenyl-2-[(6-{4.[(trifluoromethyl)oxy]phenyl]pyrimidine-4-yl) Amino] propan-1-ol; • (1S)-1-phenyl_2-[(6-{4-[(three) Methyl)oxy]phenyl}bend _4_yl)amino]ethanol; (lR)-2-({6-[2,4-bis(trifluoromethyl)phenyl] 唆_4胺(amino)aminophenylethanol; ❹ (lR)-; 2-({6-[2-decyloxy_4_(trifluoromethoxy)phenyl] -1-phenylethanol; (lR)-2-{[6-(4-ethoxy-2-indolylphenyl) oxindole-4-yl]amino}-1_phenylethanol; 2 -{[6-(3,4-Dimercaptophenyl)pyrimidin-4-yl]amino}-l-phenylethanol; 2-({6-[4-(1,1-dimethyl) Phenyl] phenyl]-4-denid-4-yl}amino)-1-phenylethanol; 2-[6-(4-methylthioalkyl-phenyl)-pyridin-4-ylamino] -1-styl-ethanol; 4-{6-[(2-hydroxy-2-phenylethyl)amino]pyrimidin-4-yl}benzonitrile; 2-(6-benzo[b]fluorene Phen-2-yl-pyrimidin-4-ylamino)-1-phenyl-ethanol; 261 200948790 1- (4-{6-[(2- mercapto-2-phenylethyl)amino] spray 2-[6-(3,4-dimethoxy-phenyl)-β-diyl-4-ylamino]-1-phenyl-ethanol; -{[6-(4-Methylphenyl)penta-11--4-yl]amino]-1-phenylethanol; 1-phenyl-2-[(6_{4-[(difluoroantimony) Oxy]phenyl}pain 1»定_4_yl)amino]ethanol; 2-(6-benzo[1,3] °恶11 坐-5-yl-bite-4-ylamino)-1_phenyl-ethanol; 2-[6-(3-methoxy-phenyl)- 唆-4-ylamino ]-1-phenyl-ethanol, · 2-[6-(3-Shosyl-phenyl)-anthracepin-4-ylamino]-1-phenyl-ethanol; 2-[(6-naphthalene-2) -yl-4-yl)amino]-1-phenylethanol; 1-{5-[6-(2-pyridyl-2-phenyl-ethylamino)-β-Bite_4_yl ]_嗟 _2 _ _ _ _2 ; ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Ethanol; (lR)-2_{[6-(3,4-dichlorophenyl)-. (iR)-2-({2-[(2-aminoethyl)amino]-6-[3- gas-4-(three) Fluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-[(6-[3-gas(trifluoromethyl)phenyl]_2) [2-(Didecylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol; (lR)-2-({6-[3-gas-4-( Trifluoromethyl)phenyl]-2-(ethylamino)pyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-({6-[3-chloro-4- (trifluoromethyl)phenyl]hydroxyethyl)amino]pyrimidin-4-yl}amino)-i-phenylethanol; (lR)-2-({2-azetidinyl_6_ [3_Chlorine (trifluoro-yl)phenyl; h-pyridin-4-yl}amino)_!-phenylethanol; (lR)-2-((6-[3_chlorodong (trifluoro) F-)phenyl]_2_(cyclopropylamino)pyrimidine 262 200948790 pyridine-4-yl}amino)-1-phenylethanol; (lR)-2-[(6-[3-chloro-4- (trifluoromethyl) phenyl]-2-{[2-(fluorenylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol; (lR)-2- ({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-oxyloxypyrimidin-4-yl}amino)-1-phenylethanol; (lR)-2-{[ 6-(3-methyl-1,2-benzisoxazole-6-yl)pyrimidin-4-yl]amino}-1-phenylethanol 1_({6_[3·Chloro(trifluoromethyl)phenyl]pyridin-4-yl}amino styrylpropan-2-ol; 2-({6-[3-chloro-4-(three) Fluoromethyl)phenyl]pyrimidin-4-yl}amino)-H4.(methylsulfanyl)phenyl]ethanol; 2-({6-[3- gas-4-(trifluoromethyl)) Phenyl]pyrimidin-4-yl}amino)-1_thiophen-3-ylethanol; 2-({6-[3-chloro-(trifluoromethyl)phenyl]pyrimidinyl)-amino)- 1-(1,3-thiazol-2-yl)ethanol; (1R)-1-phenyl-2-[(6-indole-6-yl)-amino)ethanol; N-tert-butyl-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzene continual amine; (1R)-1- Phenyl-2-({6-[4-(thiomorpholin-4-ylsulfonyl)phenyl]pyrimidin-4-yl}amino)ethanol; (lR)-l-(4-fluoro Phenyl)_2_({6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; GiO-H4-fluorophenyl) winter ({6-[3 -Fluoride (trifluorodecyloxy)phenyl]pyrimidin-4-yl}amino)ethanol; (1R)-2_({6-[3- gas_4·(trifluoromethoxy)phenyl] Pyrimidin-4-yl}amino)+(4-fluorophenyl)ethanol; 263 200948790 (lR)-l-(4-fluorophenyl)-2-({6_[3_(pentafluoroethyl W, 2) · Benzoisoxazole-6-yl]pyrimidin-4-yl}amino)ethanol; (l R)-l-(4-lphenyl)-2-({6-|&gt;(trifluoromethyl-benzazoisoxazole-6-yl)pyrimidin-4-yl}amino)ethanol; (lR)-2_({6_[3-Fluoro-4-(2,2,2-tri-ethoxy)phenyl]-penetrating _4_yl}amino)-1-phenylethanol; (lR, 2S)-2-({6_[3·Gas_4_(Trifluoromethyl)phenyl (tetra)) -4-yl}amino)-1-phenylpropan-1-ol; (1R)-1-benzene Benzyl-2-[(6-{4_[(tri-indolyl)sulfanyl]phenyl}- oxaridin-4-yl)amino]ethanol; (1R)_2_({H3-gas ice (trifluoromethane) Oxy)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol; (1R)-1-phenyl-2_({6·[3-(trifluoromethyl)-4,2-benzene And (1R)-2-{[6-(2,2-difluoro_1,3_benzobis) β密密_4_基] Amino}-1-phenylethanol; (1R)-1-phenyl-2-({6-[5-(trimethyl)benzobenzophenoxy]pyrimidine -4-yl}amino)ethanol; (1R) small phenyl-2-({6-[5-(trifluoromethoxy)benzophenan-2-yl]pyrimidin-4-yl}amino Ethyl alcohol; (1R)-1-phenyl_2-({6-[6-(tri-Imethyl)+ stupo-infrared thiopyridin-4-yl}amino)ethanol; (lR) -2-{[6-(5-fluoro.1_benzoporphin-2-yl)-bearing winter base]aminobenz phenyl Ethanol; (called 2-({6,[3-(pentafluoroethylbenzisoindolyl)-6-yl)-amino)-1-phenylethanol; 264 200948790 2-( {6-[3-chloro-4-(trifluoromethyl)phenyl] oxime 0 _4_yl}amino)-1-[2-(di-n-methoxy)phenyl]ethanol; ({6_[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(4-fluorophenyl)ethanol; 4-[2-({6_[3 -Chloro(trifluoromethyl)phenyl]benzole_4_yl}amino)]-hydroxyethyl]benzonitrile; 2-({6-[3-chloro-4-(trifluoromethyl) Phenyl]pyrimidin-4-yl}amino)_ι_naphthalen-2-ylethanol; ❹ 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidine _4_yl }amino)_ι_(4_0 is 唆-2-ylphenyl)ethanol; 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) _ΐ-(4-D-cephen-2-ylphenyl)ethanol; • 1-biphenyl-4-yl-2-({6-[3- gas-4.(trifluoromethyl)phenyl]pyrimidine _4-yl}•Amino)ethanol; 1-(1-benzothienyl)·2_({6·[3-gas(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) Ethyl alcohol; ❹ 2-({6-[3·chloro-4_(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[3- -4-(trifluoromethyl)phenyl ]ethanol; 2-({6-[3- gas-4-(trifluoromethyl)benzene) ]Bite _4-yl}amino)-1-{3-[(trifluoromethyl) fluorenyl]phenyl}ethanol; 2-«6-[3-chloro_4_(trifluoromethyl) Phenyl]pyrimidin-4-yl}amino) small (2,3-dihydro-1,4-benzodioxin-6-yl)ethanol; 2-({6-[3-chloro-4- (trifluoromethyl)phenyl]u succinyl}amino)-1-[4-(1Η-imidol-1-yl)phenyl]ethanol; 1-(1-benzothiophene-3- Benzyl-2-({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; 265 200948790 -yl]•amino)-1- (3,4- 2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidine_4 dimethoxyphenyl)ethanol; 1- (3-chloro-4-f oxygen) 2-({6-[3_chloro.4_(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; 2- ({6-[3- gas-4-( Difluoromethyl)phenyl]pigmented 4_yl}amino)b (3)dihydro-2H-1,5-benzodioxan-7-yl)ethanol; 2- ({6_[ 3-Chloro-4-(difluoromethyl)phenyl]pyrimidine _4_yl}aminofluoro·5_(trifluoromethyl)phenyl]ethanol; 3- [2-«6_[3_气-4-(Trifluoromethyl)phenyl]pyrimidinylamino)amino hydroxyethyl]benzonitrile; 2-({6-|&gt;chloro-4-(trifluoromethyl)phenyl] Pyrimidinyl)aminophenylisoxazole-5-yl Ethanol; 2·({6-[3- gas-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) small (4-pyrrolidin-1-ylphenyl)ethanol; 2-( {6_[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) small (5-pyridin-2-ylthiophen-2-yl)ethanol; 5-[2-( {6·[3-pipe (trifluoromethyl)phenyl]pyrimidine _4_yl}amino-w-hydroxyethyl]-2-fluorobenzonitrile; 2-({6-[3-gas- 4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino) small (2,6-difluorophenyl)ethanol; 2·({6-[3-gas-4_(trifluoromethyl) Phenyl]pyrimidin-4-yl}amino)-1-(2-fluorophenyl)ethanol; 2-[6-(3- gas-4-trifluoromethyl-phenyl)-pyrimidine_4_ Amino]-1-[3-(3,4-di-phenyl)-isoxazole-5-yl]-ethanol; 1-[3-(4-chloro-phenyl)-isoxazole _5_yl]-2-[6-(3- gas-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-ethanol; 266 200948790 2-[6-(3-chloro- 4-trifluoromethyl-phenyl)-pyrimidine _4_ylamino]-1-[3-(2,4·di-phenyl)-isoindole _5-yl]-ethanol; - benzoxazol-2-yl-2-[6-(3- gas-4-trifluoromethyl-phenyl)-mouth -4-amino-]-ethanol; 1-[3,5- Bis(trifluoromethyl)phenyl]_2-({6-[3-chloro-4-(trifluoromethyl)phenyl]indole-4-yl]•amine Ethyl alcohol; 1-(5-bromo-1-benzothiophen-2-yl)-2-({6-[3- gas-4.(trifluoromethyl)phenyl]pyrimidine_4_yl} Amino)ethanol; hydrazine (1R)-phenyl-2-(644-(12,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-bine-4-amine (1R)-phenyl-2-{6-[3-(l,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-pain- 4-ylamino]--ethanol; (1Κ·)-phenyl-2-[6-(3~trifluoromethyl-benzo[b]thiophen-6-yl)-pyrimidine. -4-ethanol; 4-(3-Gas-4-trifluoromethyl-phenyl)_6_(2-hydroxy-2-phenyl-(1R)-ethylamino)-pyrimidine-2-carbonitrile; 4-(3- Chloro-4-difluoroindolyl-styl)-6-(2-carbo-2-phenyl-(1R)-ethylamino)-pyrimidine-2-indene nitrile; 2- [6-(2 ,6-difluoro-phenyl)-n-propyl-4-ylamino]]-phenyl-ethanol; 4-[6-(2-hydroxy-2-phenyl-ethylaminopyridinyl) ; 2-[6-(3,5-bis-trifluorodecyl-phenyl)-pyrimidin-4-ylaminophenyl-ethanol; 2-[6-(3-amino-phenyl)-pyrimidine _4_ylamino]_丨_phenylethanol; 2-[6-(4-hydroxymethyl-phenyl)pyrimidin-4-ylamino]-indole-phenylethanol; N-{3- [6-(2-hydroxy-2-phenylethylamino)-pyrimidine_4_yl]-styl}} acetamidine 267 200948790 1-Phenyl-2-(6-phenyl-pyrimidin-4-ylamino); Ethanol; 1-Phenyl-2·(6-thiophen-2-yl-pyrimidin-4-ylamino) Ethanol; and 1-phenyl-2-(6-nonphen-3-yl-spray). Ornidyl)-ethanol; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite of the compound. ''. The use of claim 66, wherein the disease, condition or medical condition is selected from the group consisting of: anxiety, depression, pain, sleep disorders, eating disorders, inflammation, dyskinesia, fflv Consumption syndrome, mild head trauma, stroke, learning and memory disorders, (4) Alzheimer's disease, epilepsy, T〇urette, s 〇syndrome, Niemann-Pick's disease (Niemann_pick out of this shape, Parkinson's disease, Huntington's disease (^untmgton's Ch0rea), optic neuritis, autoimmune uveitis, drug or alcohol withdrawal, nausea, vomiting, sex Dysfunction, post-traumatic stress syndrome, cerebral vasospasm, glaucoma, colonic irritability, inflammatory bowel disease, inhibition, gastroesophageal reflux disease, pruritus, secluded diarrhea, stomach, ulcer, rheumatoid arthritis, Unintended pregnancy, high blood pressure, cancer, hepatitis, allergic airway disease, autoimmune diabetes, intractable itching, god, disaster, diabetes, metabolic syndrome Abnormal gold fat, fatty liver, steatohepatitis, obesity, insulin resistance, osteoarthritis, and osteoporosis. 69. As claimed in Article 66 of the patent application, wherein the disease, condition or medical condition is pain or inflammation. The use of the scope of claim 66, wherein the disease, condition or 268 200948790 medical condition is a domain, a sleep disorder, an eating disorder or a movement disorder. The use of the scope of claim 66, wherein the disease, condition bite medicine The condition is multiple sclerosis. ΓΧ 72. A compound selected from the group consisting of: fluorenyloxy) phenyl] ° lye base} amine) small phenylethanol. 2-{"6-( 3·methylphenyl)methanol-4-amino]amino}1_phenylethanol, · ' ❹ 1 phenyl phenylmethyl) oxy phenyl phenyl group _ 4 yl ) amino] ethanol; (1S'2R)-1_stupyl_27-6_{4_[(trimethylsulfonyl)oxy]phenyl bromide yl)amino]propan-1-ol; : (IS)-l- Phenyl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}) _4_yl), amino]ethanol; H4-(6-{[(2r)-2 -transalkyl 2_phenylethyl]amine} mouth bite 4 base) phenyl] B _ ; (1R)_1-phenyl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl) -4-yl)amino]ethanol; or pharmaceutically acceptable hydrazine compound Salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite. A process for the preparation of a compound of formula (I), which comprises the steps of: (II) 269 200948790 by a nucleophilic aromatic substitution in a single pot, in the presence of a suitable base, in a suitable polar solvent, at a temperature of from about 50 ° C to about 180 ° C, with an amino alcohol; And palladium mediated cross-coupling reaction with a suitable tanning acid in the presence of a base and at least one palladium-mediated cross-coupling reagent at a temperature of from about 50 ° C to about 180 ° C. 270 200948790 IV. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the component symbols of this representative figure: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3