WO2009105220A1 - Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase - Google Patents

Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase Download PDF

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WO2009105220A1
WO2009105220A1 PCT/US2009/001043 US2009001043W WO2009105220A1 WO 2009105220 A1 WO2009105220 A1 WO 2009105220A1 US 2009001043 W US2009001043 W US 2009001043W WO 2009105220 A1 WO2009105220 A1 WO 2009105220A1
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Prior art keywords
amino
phenyl
pyrimidin
phenylethanol
alkyl
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PCT/US2009/001043
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French (fr)
Inventor
Richard Apodaca
J. Guy Breitenbucher
Alison L. Chambers
Xiaohu Deng
Natalie A. Hawryluk
John M. Keith
Neelakandha S. Mani
Jeffrey E. Merit
Joan M. Pierce
Mark Seierstad
Wei Xiao
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Janssen Pharmaceutica N.V.
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Priority to EP09712375A priority Critical patent/EP2254415B1/en
Priority to CA2714743A priority patent/CA2714743C/en
Publication of WO2009105220A1 publication Critical patent/WO2009105220A1/en

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Definitions

  • Certain aryl-hydroxyethylamino-pyrimidine and triazine compounds, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity are provided. Certain methods of preparing the compounds are also disclosed.
  • THC ⁇ 9 -tetrahydro-cannabinol
  • FAAH integral membrane bound protein fatty acid amide hydrolase
  • FAAH is additionally responsible for the catabolism of a large number of important lipid signaling fatty acid amides including: another major endocannabinoid, 2- arachidonoylglycerol (2-AG) (Science 1992, 258, 1946-1949); the sleep-inducing substance, oleamide (OEA) (Science 1995, 268, 1506); the appetite-suppressing agent, N-oleoylethanolamine (Rodriguez de Fonesca, Nature 2001, 414, 209); and the anti-inflammatory agent, palmitoylethanolamide (PEA) (Lambert, Cum Med. Chem. 2002, 9(6), 663).
  • 2-AG 2- arachidonoylglycerol
  • the sulfonylfluorid ⁇ AM374 was also shown to significantly reduce spasticity in chronic relapsing experimental autoimmune encephalomyelitis (CRE ⁇ AE) mice, an animal model of multiple sclerosis (Baker, FASEB J. 2001 , 15(2), 300).
  • oxazolopyridine ketone OL-135 is reported to be a potent inhibitor of FAAH, and has been reported to have analgesic activity in both the hot plate and tail emersion tests of thermal nociception in rats (WO 04/033652).
  • a FAAH inhibitor may be useful for treating various conditions, diseases, disorders, or symptoms. These include pain, nausea/emesis, anorexia,, spasticity, movement disorders, epilepsy and glaucoma.
  • approved therapeutic uses for cannabinoids include the relief of chemotherapy-induced nausea and emesis among patients with cancer and appetite enhancement in patients with HIV/A I Ds who experience anorexia as a result of wasting syndrome.
  • Two products are commercially available in some countries for these indications, namely, dronabinol (Marinol ® ) and nabilone.
  • analgesia i.e., the treatment of pain.
  • Five- small randomized controlled trials showed that THC is superior to placebo, producing dose-related analgesia (Robson, Br. J. Psychiatry 2001 , 178, 107-115).
  • Atlantic Pharmaceuticals is reported to be developing a synthetic cannabinoid, CT-3, a 1,1 -dimethyl heptyl derivative of the carboxylic metabolite of tetrahydrocannabinol, as an orally active analgesic and anti-inflammatory agent.
  • CT-3 a synthetic cannabinoid
  • CT-3 a 1,1 -dimethyl heptyl derivative of the carboxylic metabolite of tetrahydrocannabinol
  • a number of individuals with locomotor activity-related diseases, such as multiple sclerosis have claimed a benefit from cannabis for both disease-related pain and spasticity, with support from small controlled trials (Croxford et el., J. Neuroimmunol, 2008, 193, 120-9; Svendsen, Br. Med. J. 2004, 329, 253).
  • various victims of spinal cord injuries, such as paraplegia have reported that their painful spasms are alleviated after smoking marijuana.
  • cannabinoids appear to control spasticity and tremor in the CREAE model of multiple sclerosis demonstrated that these effects are mediated by CBi and CB 2 receptors (Baker, Nature 2000, 404, 84-87).
  • Inhibition of FAAH using a small-molecule inhibitor may be advantageous compared to treatment with a direct-acting CBi agonist.
  • Administration of exogenous CBi agonists may produce a range of responses, including reduced nociception, catalepsy, hypothermia, and increased feeding behavior. These four in particular are termed the "cannabinoid tetrad.”
  • Cannabinoid tetrad Experiments with FAAH -/- mice show reduced responses in tests of nociception, but did not show catalepsy, hypothermia, or increased feeding behavior (Cravatt, Proc. Natl. Acad. Sci. USA 2001 , 98(16), 9371 ).
  • inhibitors of FAAhTs catabolism of other lipid mediators may be used in treating certain other therapeutic indications.
  • PEA has demonstrated biological effects in animal models of inflammation (Holt, et al. Br. J. Pharmacol. 2005, 146, 467-476), immunosuppression, analgesia, and neuroprotection (Ueda, J. BIoI. Chem. 2001 , 276(38), 35552).
  • Oleamide another substrate of FAAH, induces sleep (Boger, Proc. Natl. Acad. Sci.
  • This receptor is expressed predominantly in the pancreas in humans and activation improves glucose homeostasis via glucose- dependent insulin release in pancreatic beta-cells.
  • GPR119 agonists can suppress glucose excursions when administered during oral glucose tolerance tests, and OEA has also been shown independently to regulate food intake and body weight gain when administered to rodents, indicating a probable benefit energy metabolism disorders, such as insulin resistance and diabetes.
  • the FAAH substrate palmitoylethanolamide (PEA) is an agonist at the PPAR ⁇ receptor.
  • PPAR ⁇ agonism offers the potential for inducing a coordinated PPAR ⁇ response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes.
  • the FAAH substrate anandamkde (AEA) is an agonist at the PPAR ⁇ receptor.
  • Anandamide treatment induces 3T3-L1 differentiation into adipocytes, as well as triglyceride droplet accumulation and expression of adiponectin (Bouaboula et al., E. J. Pharmacol. 2005, 517, 174- 181 ).
  • Osteoporosis is one of the most common degenerative diseases. It is characterized by reduced bone mineral density (BMD) with an increased risk for bone fractures. CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion. A CBrselective agonism enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis and attenuates ovari ⁇ ctomy-induced bone loss (Ofek et al., Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 696-701). There is a substantial genetic contribution to BMD, although the genetic factors involved in the pathogenesis of human osteoporosis are largely unknown.
  • small-molecule FAAH inhibitors should be useful in treating pain of various etiologies, anxiety, multiple sclerosis, Parkinson's disease and other movement disorders, nausea/emesis, eating disorders, epilepsy, glaucoma, inflammation, itch, immunosuppression, neuroprotection, depression, cognition enhancement, and sleep disorders, and potentially with fewer side effects than treatment with an exogenous cannabinokj.
  • Certain amino-substituted pyrimidine compounds have been described in the literature.
  • Certain 2,6-substituted-4-monosubstituted pyrimidines were disclosed as prostaglandin D2 receptor antagonists (PCT Pat. Appl. Publ. No. WO 2006/044732).
  • the invention is directed to compounds of Formula (I-A):
  • R 1 is -H, -C ⁇ alkyl, -OC ⁇ alkyl, -S(O)o- 2 Ci.»alkyl, -CF 3 , -CN 1 -N(R a )R b , or a monocyclic cycloalkyl group, where R a and R b are each independently -H , -Ci ⁇ alkyl optionally substituted with -OH, N(R m )R n , where R m and R n are -H, C 1-4 alky1; or taken together with the nitrogen of attachment R a and R b form a 4-7 membered heterocycloalkyl ring;
  • Ar 1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered tricyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
  • R c moieties where each R c moiety is independently -d ⁇ alkyl, -d ⁇ alkyl-OH, -Ci ⁇ alkyl- CN, -CF 3 , -OH, -OC ⁇ alkyl, -OCF 3 , -OCHF 2 . -OCH 2 CF 3 , -S(O)o.
  • R c moieties where two R c moieties are adjacent to each other and together form -O(CH 2 )i- 3 O- unsubstituted or substituted with one or two fluoro groups, and the third R c moiety, when present, is -C-Malkyl, -C 1 . 4alkyl-OH, -C ⁇ alkyl-CN, -CF 3 , -OH, -OC ⁇ alkyl, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -S(O)o.
  • CN perhaloalkyl, perhaloalkoxy, -OC ⁇ alkyl, -OC 1 ⁇ alkyl-(monocyclic cycloalkyl). -S(O)o. 2 Ci ⁇ alkyl. -SCF 3 , -SO 2 CF 3 , -CHO.
  • R 1 is -C- M alkyl or monoyclic cycloalkyl group; or R h and R* taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R 1 is -H or -Ci ⁇ alkyl; and R k is -H, -C ⁇ alkyl or monoyclic cycloalkyl group; or R 1 and R k taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or (b) two adjacent R° moieties together form -O(CH 2 )i- 2 O- unsubstituted or substituted with one or two fluoro groups;
  • R 2 is -H or methyl; and R 3 is -H or methyl; provided, however, that Ar 2 is not -CHO or para substituted -OCFa when Ar 1 is unsubstituted phenyl; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
  • the invention is directed to compounds of Formula (I-B):
  • R 1 is -d ⁇ alkyl, -OC 1-4 alky1, -S ⁇ C ⁇ alkyl, -CN, -CF 3 , -N(R a )R b , or a monocyclic cycloalkyl group, where R a and R b are each independently -H, -C h alkyl optionally substituted with -OH, N(R m )R ⁇ , where R m and R n are -H, C ⁇ alkyl; or taken together with the nitrogen of attachment R a and R b form a 4-7 membered heterocycloalkyl ring;
  • Ar 1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
  • R c moieties where each R c moiety is independently -d ⁇ alkyl, -Ci ⁇ alkyl-OH, -C ⁇ alkyl-CN, -CF 3 , -OH, -OCi-»alkyl, -OCF 3 , -OCHF 2 . -OCH 2 CF 3 , -S(O)o.
  • R d and R ⁇ are each independently -H or -d ⁇ alkyl, or taken together R d and R ⁇ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring; or (ii) two or three R c moieties where two R c moieties are adjacent to each other and together form -O(CH 2 )i ⁇ O- un substituted or substituted with one or two fluoro groups, and the third R c moiety
  • R d and R ⁇ are each independently -H or -d ⁇ alkyi;
  • X is N or C(R f ), where R f is -H or methyl;
  • the invention is directed to compounds of Formula (I-C):
  • R 1 is -H, -C h alkyl, -OCi-»alkyl, -S(O)o- 2 Ci ⁇ alkyl, -CN, -CF 3 , -N(R')R b , or a monocyclic cycloalkyl group, where R" and R b are each independently -H 1 -C- M alkyl optionally substituted with -OH, N(R m )R n , where R m and R ⁇ are -H 1 C 1-4 alkyl; or taken together with the nitrogen of attachment R" and R b form a 4-7 membered heterocycloalkyl;
  • Ar 1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with; (i) one, two, or three R c moieties, where each R c moiety is independently -Ci -4 alkyl, -Ci -4 alkyl-OH, -d ⁇ alkyl-CN, -CF 3 , -OH, -OC 1-4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -S(O)o -2 C 1-4 alkyl,
  • R d and R e with the nitrogen of attachment form a 4-7 membered heterocycloalkyl
  • R c moieties where two R c moieties are adjacent to each other and together form -O(CH 2 )i -3 O- unsubstituted or substituted with one or two fluoro groups, and the third R c moiety, when present, is -Ci ⁇ alkyl, -Ci- 4 alkyl-OH, -C 1-4 alkyl-CN, -CF 3 , -OH, -OC 1-4 alkyl, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -S(O)o -2 C 1-4 alkyl, -SCF 3 , -SO 2 CF 3 , -CHO, -COC 1-4 alkyl, -CO 2 C 1 ..
  • R d and R e are each independently -H or -Ci -4 alkyl;
  • X is N or C(R f ), where R f is -H or methyl;
  • R Xl R y , and R z are each independently a) - c): a) R x and R 2 are each -H, and R y is -NO 2 , -C 2-3 alkyl, -OC 2-4 alkyl, or phenoxy; b) R x and R 2 are each -H, R y is -OCF 3 , and Ar 1 is a substituted phenyl group or an unsubstituted or substituted pyridyl group; or c) one of R x , R y , and R 7 is -Cl, -F, or -CF 3 , and the other two are: (i) independently -H or an R 9 moiety, provided that when R y is -H then R x and R z are not -CF 3 ; where each R 9 moiety is -C 1-4 alkyl, -C- ⁇ -4 alkyl-OH, -C 1-4 alkyl-CN, per
  • R h is -H or-Ci ⁇ alkyl
  • R* is -C 1 -4alkyl or monoyclic cycloalkyl group
  • R h and R* taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring
  • R 1 is -H or-Ci- 4 alky1
  • R k is -H, -Ci ⁇ alkyl
  • R 1 moiety is independently -C h alkyl, -OC 1 ⁇ alkyl, perhaloalkyl, perhaloalkoxy , -NO 2 , -CN 1 or halo;
  • R 2 is -H or methyl; and
  • R 3 is -H or methyl; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
  • the invention is directed to compounds described or exemplified in the detailed description below and their pharmaceutically acceptable salts.
  • compositions each comprising: (a) an effective amount of at least one agent selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of Formula (I):
  • R 3 OH wherein: R 1 is -H, -C ⁇ alkyl, -OC ⁇ alkyl, -S(O)o. 2 Ci. 4 alkyl, -CN 1 -CF 3 , -N(R a )R b , or a monocyclic cycloalkyl group, where R a and R b are each independently -H, -Ci ⁇ alkyl optionally substituted with -OH, N(R m )R n , where R m and R n are -H, Ci ⁇ alkyl; or taken together with the nitrogen of attachment R a and R b form a 4-7 membered heterocycloalkyl ring;
  • Ar 1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
  • R c moieties where each R c moiety is independently -C 1 ⁇ alkyl, -C ⁇ alkyl-OH, -d ⁇ alkyl-CN, -CF 3 , -OH, -OC ⁇ alkyl, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -S(O)o.
  • R d and R ⁇ are each independently -H or -C ⁇ alkyi;
  • X is N or C(R f ), where R f is -H or methyl;
  • R 1 a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R 1 moieties, where each R 1 moiety is independently -C h alkyl, -OCi ⁇ alkyl, perhaloalkyl, perhaloalkoxy , -NO 2 , -CN, or halo;
  • R 2 is -H or methyl; and R 3 is -H or methyl; and (b) a pharmaceutically acceptable excipient.
  • the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by FAAH activity, comprising administering to the subject in need of such treatment an effective amount of at least one agent selected from compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically active prodrugs, and pharmaceutically active metabolites.
  • the disease, disorder, or medical condition is selected from: anxiety, depression, pain, sleep disorders, eating disorders, inflammation, multiple sclerosis and other movement disorders, HIV wasting syndrome, closed head injury, stroke, learning and memory disorders, Alzheimer's disease, epilepsy, Tourette's syndrome, Niemann-Pick disease, Parkinson's disease, Huntington's chorea, optic neuritis, autoimmune uveitis, symptoms of drug or alcohol withdrawal, nausea, emesis, sexual dysfunction, post-traumatic stress disorder, cerebral vasospasm, glaucoma, irritable bowel syndrome, inflammatory bowel disease, immunosuppression, itch, gastroesophageal reflux disease, paralytic ileus, secretory diarrhea, gastric ulcer, rheumatoid arthritis, unwanted pregnancy, hypertension, cancer, hepatitis, allergic airway disease, auto-immune diabetes, intractable pruritis, neuroinflammation, diabetes, metabolic syndrome, and osteoporosis. Additional embodiments, features
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by / symbol), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and so on.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.
  • Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties: >. D. o. O. . . o. .0.
  • heterocycloalkyl refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members.
  • Illustrative examples of heterocycloalkyl groups include the following entities, in the form of properly bonded moieties:
  • heteroaryl groups refers to. a monOocycl.ic, fused or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • heteroaryl groups include the following entities, in the form of property bonded moieties:
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halo represents chloro, fluoro, bromo or iodo.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
  • the invention relates to compounds that are encompassed by Formulae (I-A), (I-B), and (I-C) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
  • the invention relates to pharmaceutical compositions each comprising a therapeutically effective amount of a FAAH-modulating agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
  • a FAAH-modulating agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
  • Compounds encompassed by Formulae (I), (I-A), (1-B) 1 and (I-C) having asymmetric or chiral centers may exist in different enantiomeric forms.
  • a structural formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C 1 14 C, 15 N, 18 O, 17 O, 32 P, 33 P, 35 S, 18 F, 38 CI, and 125 I, respectively.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C) 1 reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
  • SPECT single-photon emission computed tomography
  • an 18 F- or 11 C-labeled compound may be preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • R 1 is -H, methyl, isopropyl, trifluoromethyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl.
  • R 1 is amino.
  • R 1 is -H.
  • R 1 is methyl, isopropyl, trifluoromethyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl. In still other embodiments of Formula (I-B), R 1 is amino.
  • Ar 1 is a phenyl group, each unsubstituted or substituted with one, two, or three R c moieties.
  • each R c moiety is independently fluoro, chloro, nitro, trifluoromethyl, methoxy, hydroxy, or trifluoromethoxy, or two adjacent R c moieties together form -O(CH 2 )i- 2 O- or -O(CF 2 )O-.
  • Ar 1 is phenyl, 4-fluorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4- hydroxyphenyl, 4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3,4- dichlorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 2-methoxy phenyl, 3,5-dichlorophenyl, 3-trifluoromethoxyphenyl, 3-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3- trifluoromethylphenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1 ,3-benzodioxolyl, or 2,2- difluoro-1
  • Ar 1 is unsubstituted phenyl, 4-fluorophenyl, or 4-trifluoromethoxyphenyi.
  • X is C(R f ).
  • R f is -H.
  • Ar 2 is a phenyl substituted at either or both of the meta and para positions with one, two or three R 0 moieties.
  • Ar 2 is a thiophenyl, pyridinyl, pyrimidinyl, or pyrazolyl group, each substituted with one, two, or three R s moieties.
  • each R° moiety is independently methyl, ethyl, i so propyl, tert- butyl, hydroxymethyl, 1-hydroxyethyl, cyanomethyl, cyano-dimethy1-methyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, cyclopropylmethoxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, methylsulfonyl, formyl, acetyl, dimethylamino, morpholin-4-yl, sulfamoyl, dimethylsulfamoyl, cyclopropylsulfamoyl, piperidine-1-sulfonyl, pyrrolidine-1-sulfonyl, pyrrolidine-1-sulfony
  • Ar 2 is 3,4-dimethylphenyl, 4-tert- butylphenyl, 4-cyanophenyl, 4-acetylphenyl, 4-methylphenyl, 4-chlorophenyl, 4- fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 3- methylphenyl, 3-trifluoromethoxyphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3,4- dichlorophenyl, 3-chlorophenyl, 3-chloro-4-trifluoromethylphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-phenoxy-phenyl, 3-chloro-4-ethoxyphenyl, 3-chloro-4- isopropoxyphenyl, 3-fluoro-4-methylphenyl, 4-hydroxymethylphenyl, 4- formylphenyl,
  • Ar 2 is a naphthyl, benzoxadiazolyl, indolyl, benzothiophenyl, quinolinyl, or indazolyl, each unsubstituted or substituted with one, two, or three R 1 moieties.
  • each R 1 moiety is independently methyl.
  • Ar 2 is naphthyl, 2,1 ,3-benzoxadiazol-5-yl, 1 H-indol-5-yl, 1 H-indol-6-yl, 1-methyl-1H-indol-2-yl, 1- methyl-1H-indol-5-yl, 5-methyl-1-benzothk ⁇ phen-2-yl, benzothiophen-3-yl, benzothiophen-5-yl, quinolin-3-yl, or 3-methyl-1 H-indazol-6-yl.
  • R x is -Cl or -F
  • R z is -H
  • R y is -H or R 0 .
  • R x is -Cl or -F
  • R z is -H
  • R y is -d ⁇ alkyl, -CF 3 , -OCi ⁇ alkyl, -OCF 3 , or halo.
  • Ar 2 is 4-nitrophenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-ethoxyphenyl, 4-pro poxy phenyl, 4-isopropxy phenyl, 4- butoxyphenyl, 4-isobutoxyphenyl, or 4-phenoxyphenyl.
  • Ar 2 is 4-trifluoromethoxyphenyl.
  • Ar 2 is 4-chlorophenyl, 4-fluorophenyl, 4-trifluorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-chloro-4-trifluoromethylphenyl, 3-chloro-4-ethoxy phenyl, 3- chloro-4-isopropoxyphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3-methylphenyl, 4- chloro-3-trifluoiOmethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 4-butoxy-3- fluorophenyl, 3-fluoro-4-propoxyphenyl, 3-fluoro-4-isopropoxyphenyl, 3-chloro-4- methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 3- chloro-5-fluorophenyl, 4-acetyl-3-fluorophenyl,
  • R 2 is -H.
  • R 3 is -H.
  • R s and/or R 1 is perhaloalkyl or perhaloalkoxy.
  • perhaloalkyT refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain optionally substituting hydrogens with halogens.
  • perhaloalkyl groups include trifluoromethyl (CF 3 ), difluoromethyl (CF 2 H), monofluoromethyl (CH 2 F), pentafluoroethyl (CF 2 CF 3 ), tetrafluoroethyl (CHFCFa), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethylethyl (-CF(CFa) 2 ), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • perhaloalkoxy refers to a straight- or branched-chain alkoxy group having from 1 to 4 carbon atoms in the chain optionally substituting hydrogens with halogens.
  • perhaloalkoxy groups include trifluoromethoxy (OCF 3 ), difluoromethoxy (OCF 2 H), monofluoromethoxy (OCH 2 F), pentafluoroethoxy (OCF 2 CF 3 ), tetrafluoroethoxy (OCHFCF 3 ), trifluoroethoxy (OCH 2 CF 3 ), tetrafluorotrifluoromethylethoxy (- OCF(CFs) 2 ), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • the secondary hydroxyl group adjacent to Ar 1 is in the configuration as shown below:
  • the invention also relates to pharmaceutically acceptable salts of the free acids or bases represented by Formulae (I), (I-A), (I-B), or (I-C), preferably of the preferred embodiments described above and of the specific compounds exemplified herein.
  • a "pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by Formulae (I), (I-A), (1-B) 1 or (I-C) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts", J. Pharm. ScL 1 1977, 66:1-19, and Handbook of Pharmaceutical SaHs, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • a compound of Formulae (I), (I-A), (I-B), or (I-C) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hy ⁇ roxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, pheny
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic add, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like; or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid
  • an inorganic acid such as hydrochloric acid, hydrobromic add, sulfuric acid, sulfamic acid
  • a compound of Formulae (I), (I-A), (I-B), or (I-C) is an acid such as a carboxylic acid or sulfonic acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, or any compatible mixture of bases such as those given as examples herein.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
  • cyclic amines such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • the invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formulae (I), (I-A), (I-B), or (I-C).
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formulae (I), (I-A), (I-B), or (I-C)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formulae (I), (I-A), (I-B), or (I- C).
  • amino acid residues include the twenty naturally occurring amino adds, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone.
  • prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formulae (I), (I-A), (I-B), or (I-C) as amides or alkyl esters.
  • amides include those derived from ammonia, primary C 1 ⁇ alkyl amines and secondary di(Ci ⁇ alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties.
  • amides include those that are derived from ammonia, C 1 ⁇ alkyl primary amines, and di(C 1 -2alkyl)amines.
  • esters of the invention include Cwalkyl, Cs- 7 cycloalkyl, phenyl, and phenyl(Ci ⁇ alkyl) esters.
  • Preferred esters include methyl esters.
  • Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs.
  • acyloxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs.
  • Prodrugs of this type may be prepared as described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamkJes. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
  • the present invention also relates to pharmaceutically active metabolites of compounds of Formulae (I), (I-A), (I-B), or (I-C).
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formulae (I), (I-A), (I-B), or (I-C) or a salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.1997, 86 (J), 765-767; Bagshawe, Drug Dev. Res.
  • active agents The compounds of Formulae (I), (I-A), (I-B), and (I-C), and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites (collectively, "active agents") of the present invention are useful as FAAH inhibitors in the methods of the invention.
  • the active agents may be used in the inventive methods for the treatment of medical conditions, diseases, or disorders mediated through inhibition or modulation of FAAH, such as those described herein. Active agents according to the invention may therefore be used as an analgesic, anti-depressant, cognition enhancer, neuroprotectant, sedative, appetite stimulant, or contraceptive.
  • Exemplary medical conditions, diseases, and disorders mediated by FAAH activity include anxiety, depression, pain, sleep disorders, eating disorders, inflammation, multiple sclerosis and other movement disorders, HIV wasting syndrome, closed head injury, stroke, learning and memory disorders,
  • the active agents may be used to treat subjects diagnosed with or suffering from such a disease, disorder, or condition.
  • treat or “treating” as used herein is intended to refer to administration of an agent or composition of the invention to a subject for the purpose of effecting a therapeutic benefit through modulation of FAAH activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, reducing the incidence of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of FAAH activity.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • Modules include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate FAAH expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up- regulate FAAH expression or activity.
  • the invention relates to methods of using the active agents described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through FAAH activity, such as: anxiety, pain, sleep disorders, eating disorders, inflammation, movement disorders (e.g., multiple sclerosis), glucose and lipid metabolism (e.g. diabetes) and bone homeostasis (e.g. osteoporosis).
  • a disease, disorder, or condition mediated through FAAH activity such as: anxiety, pain, sleep disorders, eating disorders, inflammation, movement disorders (e.g., multiple sclerosis), glucose and lipid metabolism (e.g. diabetes) and bone homeostasis (e.g. osteoporosis).
  • Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases.”
  • pain may be associated with various diseases, disorders, or conditions, and may include various etiologies.
  • Illustrative types of pain treatable with a FAAH-modulating agent, in one example herein a FAAH-inhibiting agent, according to the invention include cancer pain, postoperative pain, Gl tract pain, spinal cord injury pain, visceral hyperalgesia, thalamic pain, headache (including stress headache and migraine), low back pain, neck pain, musculoskeletal pain, peripheral neuropathic pain, central neuropathic pain, neurogenerative disorder related pain, and menstrual pain.
  • HIV wasting syndrome includes associated symptoms such as appetite loss and nausea.
  • Parkinson's disease includes, for example, levodopa- induced dyskinesia.
  • Treatment of multiple sclerosis may include treatment of symptoms such as spasticity, neurogenic pain, central pain, or bladder dysfunction.
  • Symptoms of drug withdrawal may be caused by, for example, addiction to opiates or nicotine.
  • Nausea or emesis may be due to chemotherapy, postoperative, or opioid related causes.
  • Treatment of sexual dysfunction may include improving libido or delaying ejaculation.
  • Treatment of cancer may include treatment of glioma.
  • Sleep disorders include, for example, sleep apnea, insomnia, and disorders calling for treatment with an agent having a sedative or narcotic-type effect.
  • Eating disorders include, for example, anorexia or appetite loss associated with a disease such as cancer or HIV infection/AIDS.
  • an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • a "therapeutically effective amount” or “effective amount” means an amount or dose of a FAAH-modulating agent sufficient to generally bring about a desired therapeutic benefit in patients in need of treatment for a disease, disorder, or condition mediated by FAAH activity.
  • Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID).
  • a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
  • the additional active ingredients may be coadministered separately with an active agent of Formulae (I), (I-A), (I-B), and (I-C) or included with such an agent in a pharmaceutical composition according to the invention.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by FAAH activity, such as another FAAH modulator or a compound active against another target associated with the particular condition, disorder, or disease.
  • a composition according to the invention may contain one or more additional active ingredients selected from opioids, NSAIDs (e.g., ibuprofen, cyclooxygenase-2 (COX-2) inhibitors, and naproxen), gabapentin, pregabalin, tramadol, acetaminophen, and aspirin.
  • NSAIDs e.g., ibuprofen, cyclooxygenase-2 (COX-2) inhibitors, and naproxen
  • gabapentin pregabalin, tramadol, acetaminophen, and aspirin.
  • the active agents of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention.
  • a pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.
  • a "pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, earner, or diluent to facilitate administration of a agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art.
  • the compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the active agents may be formulated to yield a dosage of, e.g., from about 5 mg to 5 g daily, or from about 50 mg to 5 g daily, in single or divided doses.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
  • compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.
  • Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • compounds of Formulae (I), (I-A), (I-B), and (I-C) are prepared from pyrimidines or triazines (II), where Z is halo or another suitable substituent.
  • pyrimidines or triazines are commercially available or are prepared using known methods.
  • Pyrimidines of formula (III) are obtained via palladium-mediated cross-coupling of reagents (II) with suitable boronic acids.
  • pyrimidines of formula (II) are treated with the desired boronic acid in the presence of a base such as K 3 PO 4 or KF, in a suitable polar solvent such as CH 3 CN, 1 ,2-dimethoxyethane (DME) 1 tetrahydrofuran (THF), water, or a mixture thereof, at a temperature from about 50 °C to about 180 °C using conventional heating or a microwave reactor.
  • a base such as K 3 PO 4 or KF
  • a suitable polar solvent such as CH 3 CN, 1 ,2-dimethoxyethane (DME) 1 tetrahydrofuran (THF), water, or a mixture thereof
  • Pyrimidines (III) are converted to compounds of Formulae (I-A), (I-B), and (I-C) via nucleophilic aromatic substitution (SNA ⁇ ) with aryl-substituted amino alcohols in the presence of a suitable base such as NaHCO 3 , (JPr) 2 EtN 1 Et 3 N, or a mixture thereof, either neat or in a solvent such as 1 ,4-dioxane, THF, t-amyl alcohol, n-BuOH, or a mixture thereof, at a temperature from about 80 °C to about 150 °C.
  • a suitable base such as NaHCO 3 , (JPr) 2 EtN 1 Et 3 N, or a mixture thereof, either neat or in a solvent such as 1 ,4-dioxane, THF, t-amyl alcohol, n-BuOH, or a mixture thereof, at a temperature from about 80 °C to about 150 °C.
  • pyrimidines or triazines of Formulae (I-A), (I-B), and (I-C) are obtained by S N AT displacement of compounds (II) with amino alcohols, followed by palladium- mediated cross-coupling using known procedures.
  • Compounds of Formulae (I) 1 (1-A) 1 (1-B) 1 and (I-C) are additionally prepared in a one-pot fashion by nucleophilic aromatic substitution (Sr 4 Ar) displacement of compounds (II) with amino alcohols in the presence of a suitable base such as NaHCO 3 , in a suitable polar solvent such as CH 3 CN at a temperature from about 50 °C to about 180 °C; followed by a palladium-mediated cross-coupling reaction with a suitable boronic acid in the presence of a base such as K 3 PO 4 , and palladium-mediated cross-coupling reagents such as Pd(dppf)Cl2* CH 2 CI2 and Pd(OAc) 2 at a temperature from about 50 °C to about 180 °C.
  • a suitable base such as NaHCO 3
  • a suitable polar solvent such as CH 3 CN
  • palladium-mediated cross-coupling reaction with a suitable boronic acid in the presence of a base such
  • thioethers (V) obtained as described in Scheme A, are oxidized using generally known methods to provide sulfones (Vl).
  • Vl sulfones
  • the sulfone substituent is displaced by reaction with a suitable amine or alcohol in a solvent such as MeOH, EtOH 1 n-BuOH, t-amyl alcohol, THF, N,N-dimethylformamide (DMF) 1 dimethylsulfoxide (DMSO), toluene, or a mixture thereof, with or without the presence of a base such as NaOMe, NaOEt, KOtBu 1 Et 3 N, (1 ' Pr) 2 EtN, pyridine, or a mixture thereof, at a temperature from about room temperature to the reflux temperature of the solvent.
  • a suitable amine is performed by heating a sulfone (Vl) in t- amyl alcohol at 130 °C in a sealed tube.
  • ⁇ - Ketoesters are reacted with amidines or carboximidamides (XII) or with ureas or thioureas (XIII) where Y is O, S, or NR", for example, in the presence of a base : such as NaOEt or KOtBu 1 in a solvent such as EtOH 1 t-BuOH, or a mixture thereof, at a temperatures between about room temperature and the the reflux temperature of the solvent, to form hydroxy-pyrimidines (VIII). Hydroxy- pyrimidines (VIII) are then activated for use in the SNA ⁇ displacement by general procedures known in the art.
  • treatment with POCb, PBr 3 , or POBr 3 affords the corresponding halopyrimidines (IX) where Z 2 is a chloride or bromide.
  • hydroxy-pyrimidines are treated with POCI 3 in CH 3 CN at a temperature from about 80 °C to about 100 °C.
  • Chloropyrimidines (IX) are processed to compounds of Formulae (I-A), (I-B), and (I-C) via Sn-aryl • displacement as described in Scheme A.
  • Racemic or enantio-enriched amino-alcohols are commercially available or are prepared using generally known procedures.
  • amino-alcohols (X) where R 2 and R 3 are both -H, are prepared as shown in Scheme D.
  • aldehydes (Xl) are treated with trimethylsilylcyanide (TMSCN) in the presence of a catalyst such as Znl 2 , neat or in a solvent such as diethyl ether (Et 2 O), THF 1 1 ,4-dioxane, or a mixture thereof, to provide cyanohydrins (XII).
  • TMSCN trimethylsilylcyanide
  • enantio-enriched amino-alcohols reactions are are run in the presence of a chiral ligand, such as S-(-)-1 ,1'-bi-2-naphthol.
  • a chiral ligand such as S-(-)-1 ,1'-bi-2-naphthol.
  • the resulting cyanohydrin is formed as the trimethylsilyl ether.
  • Reduction of the nitrile using known general procedures, such as LiAIH 4 , or a borane complex (such as borane complexed with THF (BH 3 -THF), dimethylsulfide (BH 3 OMS) 1 or N-ethyl-N-isopropylaniline (BACH-EI)), in solvent such as THF or Et 2 O, provides amino-alcohols (X).
  • amino-alcohols (X) are accessed through the addition of azld ⁇ anion to a suitable ⁇ -haloketone and subsequent reduction of the azido group and the ketone.
  • reduction of a suitable ⁇ - haloketone to the corresponding halohydrin and displacement with ammonia, methylamine, or dimethylamine provides amino-alcohols (X).
  • Enantio-enriched amino-alcohols (X) are accessed through other stereoselective syntheses or chiral separation methods.
  • the reduction shown in Scheme D is optionally performed with a borane complex in the presence of a chiral catalyst such as (R)-2-methyl-CBS-oxazaborolidine (CBS) to generate chiral product.
  • a chiral catalyst such as (R)-2-methyl-CBS-oxazaborolidine (CBS)
  • racemic amino-alcohols (X) 1 where R 2 can be either -H or alkyl and R 3 is -H 1 are accessed via nitro-aldol addition as shown is Scheme E.
  • Aldehydes (Xl) are treated with nitromethane (CH3NO2) in the presence of base, such as NaOH, KOH, KOtBu 1 NaOtBu, TBAF, and NaH, in solvents such as THF and MeOH, at temperatures between 0 °C and the reflux temperature of the solvent, to form nitro-alcohols (XVII).
  • Amino alcohols (X) are obtained by reduction of the nitro group using generally known methods such as Pd-catalyzed hydrogenation using a hydrogen source such as H 2 , cyclohexadiene, or NH 4 HCO 2 in the presence of Zn, in solvents such as MeOH and EtOH at temperatures between room temperature and the reflux temperature of the solvent.
  • a hydrogen source such as H 2 , cyclohexadiene, or NH 4 HCO 2
  • solvents such as MeOH and EtOH
  • amino alcohols (X) 1 where R 2 and R 3 are both -H may be prepared from ⁇ -halo ketones (XIII) shown in Scheme F.
  • azido-alcohols Reduction of the azido-ketone using known methods, such as treatment with borane complex (BH 3 » THF and BH 3 OMS) or NaBH 4 , in solvent such as THF, MeOH and EtOH at temperatures between 0 °C and room temperature provide azido-alcohols (XVI).
  • azido-alcohols (XVI) are prepared by reduction of the ⁇ -halo ketone (XIII) to give ⁇ -halo-alcohols (XV) which are converted to azido-alcohols (XVI) by addition of NaN 3 .
  • azido-alcohols via known methods such as Pd-catalyzed hydrogentation using a hydrogen source such as H 2 , and cyclohexadiene or NH 4 HCO 2 in the presence of Zn, in solvents such as MeOH 1 EtOH or a mixture thereof, at temperatures between room temperature and the reflux temperature of the solvent, and at pressures ranging from 0-50 psi. provide amino-alcohols (X).
  • azido-alcohols (XVI) are reduced to amino-alcohols (X) using NaBH 4 in the presence of CuS ⁇ 4 # 5H 2 O in solvents such as EtOH 1 MeOH 1 or a mixture thereof at temperatures between 0 °C and reflux temperature of the solvent.
  • X ⁇ -halo ketones
  • Compounds of Formulae (I), (I-A), (I-B), and (I-C) may be converted to their corresponding salts by applying general techniques described in the art.
  • a compound of Formulae (I), (I-A), (I-B), and (I-C) may be treated with trifluoroacetic acid, HCI, or citric acid in a solvent such as Et 2 O 1 CH 2 Cl 2 , THF 1 or MeOH to provide the corresponding salt forms.
  • Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regio-specific synthesis, or by resolution.
  • Compounds prepared according to the schemes above may alternatively be obtained as racemic (1 :1 ) or non-racemic (not 1 :1) mixtures or as mixtures of diastereomers or regioisomers.
  • single enantiomers may be isolated using conventional separation methods, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation.
  • separation methods such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation.
  • regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.
  • reaction mixtures were stirred under a nitrogen atmosphere at room temperature (rt). Where solutions were "concentrated”, they were concentrated using a rotary evaporator under reduced pressure. Where solutions are dried, they are typically dried over a drying agent such as MgSO 4 or Na 2 SO 4 .
  • Microwave reactions were carried out in either a CEM Discover® or a Biotage InitiatorTM Microwave at specified temperatures.
  • Thin-layer chromatography was performed using Merck silica gel 60 F 2 ** 2.5 cm x 7.5 cm 250 ⁇ m or 5.0 cm x 10.0 cm 250 ⁇ m pre-coated silica gel plates.
  • Preparative thin-layer chromatography was performed using EM Science silica gel 60 F 25 4 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone.
  • Normal phase purification was typically done by normal phase flash column chromatography (FCC) with RediSep® silica gel columns using EtOAc/hexanes or CH 2 Cl 2 ZMeOH as eluent unless otherwise specified.
  • TFA trifluoroacetic acid
  • Preparative chiral HPLC was performed under the following conditions: Stationary Phase, Chiralpak AS-H SFC 250 x 21 mm (L x I.D.); Mobile Phase, 10% MeOH containing 0.2% triethylamine, 90% CO 2 ; Flow Rate, 31.5 mL/min; Back Pressure, 150 bar.
  • Hydrochloride salts were obtained by treating the corresponding free bases with HCI (4 N in dioxane, 2 M in Et 2 O, or 1.25 N in MeOH) at rt. The mixtures were either concentrated to obtain the HCI salt, or the resulting solid was isolated by filtration.
  • Trifluoroacetic acid salts were obtained by purification of the crude reaction product by preparative reverse phase HPLC.
  • Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers.
  • the format of 1 H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).
  • Mass spectra were obtainied on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass corresponds to the exact mass.
  • ESI electrospray ionization
  • the reaction mixture was diluted, filtered through a pad of celite and then filtered through a 0.45 ⁇ M nylon filter to remove residual palladium particulates, dried (Na 2 SO.*) and concentrated.
  • the crude material was purified (FCC) to yield the title compound as a green oil (1.41 g, 59%).
  • Step A 5-Trifluoromethyl-benzorbithioDhene.
  • a mixture of 5-trifluoromethyl- benzo[b]thiophene-2-carboxylic acid (2.00 g, 8.12 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (5.0 mL, 34 mmol) in DMA (13 mL) was heated via microwave irradiation at 200 °C for 1 h. The reaction was cooled to rt, diluted with HCI (1 N aq., 20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with water (10 mL), dried (Na 2 SO 4 ) and concentrated.
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • Step B To a 2-necked round bottom flask were added [lr(OMe ⁇ COD)] 2 (19 mg, 0.03 mmol) and 4,4'-di-tert-butyl-2,2 l -bipyridine (dtbpy) (15.0 mg, 0.06 mmol) and the flask was evacuated and refilled with N 2 .
  • Step A 4.4.5.5-Tetramethy1-2-(4-trifluorOmethyJsulfanyl-Dhenyl)--
  • Step B To a round-bottomed flask were added 4,4,5,5-tetramethyl-2-(4- trifluoromethylsulfanyl-phenyl)-[1 ,3,2]dioxaborolane (960 mg, 3.16 mmol) and sodium periodate (2.03 g, 9.48 mmol) in THF and water (4:1 , 26 mL). The resulting suspension was stirred at rt for 30 min. HCI (1 N aq., 2.21 mL) was added to the suspension and the reaction mixture was stirred at rt for 18 h. The resulting precipitate was removed by filtration and washed with hexanes.
  • Step A 1-(4-Bromo-2-hydroxy-Dhenyl>-2.2.2-trifluoro-ethanone.
  • 3-bromophenol 4.93 ml, 46.2 mmol
  • dichloroethane 185 mL
  • trifluoroacetic anhydride 9.3 mL, 67 mmol
  • Step B 1-(4-Bromo-2-hydroxy-phenyl)-2.2.2-trifluoro-ethanone oxime.
  • sodium acetate 9.46 g, 115 mmol
  • hydroxylamine hydrochloride 7.09 g, 102 mmol
  • MeOH 10 mL
  • To this mixture was added a solution consisting of 1-(4-bromo-2-hydroxy-phenyl)-2,2,2- trifluoro-ethanone (2.5 g, 9.3 mmol) and MeOH (62 mL).
  • the reaction vessel was heated at 64 °C for 7 h before cooling to rt and pouring the reaction mixture into ice water (100 mL).
  • Step C 6-Bromo-3-trifluoromethyl-benzord1isoxazole.
  • 1-(4- bromo-2-hydroxy-phenyl)-2 l 2 l 2-trifluoro-ethanone oxime (2.64 g, 9.29 mmol) was added acetic anhydride (14 mL) and the reaction mixture stirred for 18 h at rt.
  • the reaction mixture was concentrated and taken up in toluene and again concentrated to yield the acylated intermediate.
  • This intermediate was dissolved in pyridine (15 mL) and triethylamine (3.2 mL) and heated at 112 °C for 4.5 h.
  • Step D Title compound was prepared using methods similar to those described in Intermediate G.
  • Intermediate H 1 Route 2 3-Trifluoromethyl-benzo[d]isoxazole-6-boronic acid
  • Step A 1-(4-Bromo-2-fluoro-phenylV2.2.2-trifluoro-ethanol.
  • Step B 1-(4-Bromo-2-fluoro-Dheny1V2.2.2-trifluoro-ethanone.
  • Dess-Martin period inane (16.57 g, 39.06 mmol) was added to a solution consisting of 1-(4- bromo-2-fluoro-phenyl)-2,2 l 2-trifluoro-ethanol (10.66 g, 39.06 mmol) and DCM (100 mL) and the resultant mixture was stirred at rt for 1.5 h.
  • Na 2 S 2 O 3 (10% aq., 100 mL) was added and the resulting mixture extracted with CH 2 Cl 2 (100 mL).
  • the organic layer was washed with Na 2 S 2 O 3 (50 mL x 2), NaHCO 3 (satd. aq., 100 mL x 2), and brine (100 mL x 2).
  • the organic layer was dried (Na 2 SO 4 ) and concentrated.
  • the crude material was purified (FCC) to yield the title compound (3.20 g, 30%).
  • Step C 1-(4-Bromo-2-fluoro-DhenylV2.2.2-trifluoro-ethanone oxime.
  • a solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (3.12 g, 11.5 mmol) and MeOH (50 mL) were added hydroxylamine hydrochloride (4.00 g, 57.5 mmol) and sodium acetate (5.90 g, 71.9 mmol).
  • the resulting mixture was heated at 64 °C for 19 h, at which time additional hydroxylamine hydrochloride (2.40 g, 34.5 mmol) and sodium acetate (3.54 g, 43.1 mmol) were added.
  • Step D 6-Bromo-3-trffluoromethyl-benzordlisoxazole.
  • Step E Title compound was prepared using methods analogous to those described in Intermediate G.
  • Step A 4-Bromo-2-chloro-1-trifluoromethoxy-benzene.
  • a 0 ⁇ C solution consisting of 3-chloro-4-trifluoromethoxy-aniline (2.12 g, 10.0 mmol) and HBr (48% aq , 50 mL) was added NaNO 2 (2 M aq., 917.7 mg, 13.3 mmol) dropwise at a rate such that the reaction temperature remained below 5 °C.
  • urea 330 mg, 5.5 mmol
  • Step B Title compound was prepared using methods similar to those described in Intermediate G.
  • Intermediate J 3-Pentafluoroethy1-benzo[d]isoxazole-6-boronic acid.
  • Step A (1 RV2-Chloro-1-(4-fluoro-pheny1Vethanol.
  • a solution consisting of BH 3 -THF (1 M 1 150 mL) and (R)-( + )-2-methyl-CBS-oxazaborolidine (1 M in THF) (2.14 mL) was added a second solution consisting of 2-chloro-4'-fluoro- acetophenone (37.0 g, 214 mmol) and THF (100 ml) over 1 h at rt.
  • the resultant colorless reaction mixture was stirred for 45 min and then quenched with MeOH (75 mL).
  • Step B (1 RV2-Azido-1-(4-fluoro-Dhenyl)--ethanol.
  • Sodium azide (41.8 g, 642 mmol) was added to a solution consisting of (1R)-2-chloro-1-(4-fluoro-phenyl)- ethanol (37.4 g, 214 mmol) and DMF (214 mL) at rt.
  • the reaction mixture was heated to 100 °C for 3 h, diluted with water (500 mL), and extracted with EtOAc (700 mL).
  • the organic layer was washed with brine (500 mL), and the organic layer dried (MgSO 4 ), filtered, and concentrated, giving the title compound as a yellow liquid, which was used without further purification (39 g, 100%).
  • Step C To a solution consisting of (1 R)-2-azido-1-(4-fluoro-phenyl)-ethanol (38.8 g, 214. mmol) and EtOH (250 mL) was added 5% Pd/C (60% water, 38 g). The reaction mixture was subjected to 50 psi of hydrogen at rt for 1 h. The reaction mixture was filtered through a 0.45 ⁇ M nylon filter giving a black filtrate. HPLC analysis showed that the reaction was incomplete. Fresh Pd/C was added (38 g) and the reaction mixture re-subjected to hydrogenation at 50 psi and rt for 2 h.
  • Step A 4.4.5.5-Tetramethyl-2-[4-(1.2.2.2-tetrafluoro-1 -trifluoromethyl-ethyl)-- phenyn- ⁇ ,3.21dioxaborolane and 4.4.5.5-Tetramethyl-2-r3-(1.2.2.2-tetrafluoro-1- trifluoromethyl-ethyl)-phenyfl-ri.3.21dioxaborolane.
  • Title compounds was obtained as a mixtureusing methods analogous to those described in Intermediate F.
  • Step B Title compounds were obtained as a mixture using methods analogous to those described in Intermediate G.
  • Step A 4.4.5.5-Tetramethy1-2-(3-trifluoronriethyl-benzorb]thiophen-6-v1V- H .3.21dioxaborolane.
  • Title compound was prepared using methods analogous to those described in Intermediate E. (6-bromo-3-trifluoromethyl-benzo[b]thiophene was prepared as described in TeL Lett., 2003, 44, 7147).
  • Step B Title compound was prepared using methods analogous to those described in Intermediate G.
  • Example 1 M RV2-((6-[4-(Ethy1oxyV3-(trifluoromethyhphenyl]Dyrimidin-4- ynaminoV 1 -ohenylethanol.
  • Step A M RV2-K6-Chloropyrimidin-4-yltaminol-1-phenylethanol.
  • a solution consisting of (R)-(-)-2-amino-1-phenylethar ⁇ ol (4.80 g, 35.0 mmol) in and 1 ,4-dioxane (150 mL) at rt was added dropwise a solution consisting of 4,6- dichloropyrimidine (5.21 g, 35.0 mmol) and 1 ,4-dioxane (75 mL).
  • NaHCO 3 17.6 g, 0.210 mol
  • Step B 2-[(6-Chloropyrimidin-4-yl)amino]-1-phenylethanol (62.4 mg, 0.25 mmol), 3-chloro-4-ethoxyphenyl boronic acid (100 mg, 0.5 mmol), Pd(PPh 3 ) 4 (14.4 mg. 0.0125 mmol), and K 3 PO 4 (106 mg, 0.50 mmol) were placed in a two-necked round bottom flask and the flask evacuated. The flask was backfilled with N 2 and then charged with DME (2.0 mL) and degassed water (0.5 mL). The reaction mixture was heated at reflux (85 °C) for 17 h.
  • Example 2 The compounds in Examples 2-19 were prepared using methods analogous to those described in Example 1 , using either enantiomerically pure or racemic amino alcohols in Step A and substituting the appropriate boronic acids or esters in Step B. Final compounds were purified by FCC.
  • Example 2 2-f ⁇ 6-(4-ChlorophenyQpyrimidin-4-yl)amino)-1-phenylethanol.
  • Example 4 1 -Phenyl-2-(f6-[4-(trifluoromethy»phenynpyrimidin-4-yl)amino)ethanol trifluoroacetic acid salt.
  • Example 7 2-((6-[4-(1-Methy1ethyltohenyfloyrimktin ⁇ yl)aminoV1-phenylethanol.
  • Example 8 2-f ⁇ 6-(3.4-Dichlorophenyl)pyrimidin-4-v ⁇ amlno)-1 -phenylethanol.
  • Example 10 2-((6-r3-Chloro-4-t(rifluoromethyl)DhenyiiDyrimidin-4-yl)aminoV1- phenylethanol.
  • Example 11 2-K6-[4-(Ethyloxytohenynpyrimidin-4-yl)amino)-1-phenylethanol.
  • Example 12 2-[(6-(4-[(1-Methy1ethy1)oxy]phenyl)pyrimidin-4-yl)aminol-1- phenylethanol.
  • Example 13 1-Phenyl-2- ⁇ 6-[4-(Dhenyloxy ⁇ DhenyflDyrimidin-4-yl)amino Methanol.
  • Example 14 2-((6-r3-Chloro-4-(ethyloxytohenyl]pyrimldin-4-yl ⁇ aminoV1- phenyiethanol.
  • Example 15 MRV1-Phenyl-2- ⁇ 6-[4-ftrifluoromethyltohenynpyrimidin-4- yl)ami no Methanol.
  • Example 16 MRV2-f(6-r3-Chloro-4-(trifluoromethylbheny ⁇ Dyrimidin-4-yl)aminoV 1-phenylethanol.
  • Example 16A MRV2-((6-r3-Chloro-4-t(rifluoromethy»Dhenyl]Pyrimidin-4- vDaminoH-Dhenylethanol hydrochloride salt.
  • Example 17 1-[4-(6-ffl2RV2-Hvdroxy-2-Phenylethyflamino)pyrimidin-4- vQphenyflethanone.
  • Example 18 H RV2- ⁇ 6-[4-(1-Methylethy1tohenyl]pyrimidin-4-yl)aminoV1- phenylethanol.
  • Example 19 HRV2-r(6-l3-Chloro-4-rH-methylethyl ⁇ )xyiphenyl)pyrimidin-4- ylteminoi-1 -phenylethanol.
  • Example 20 HRV2-f ⁇ 6-(3-Fluoro-4-methylphenyltoyrimidin-4-yl]amino)-1- phenylethanol trifluoroacetic acid salt.
  • Step B (1 R)-2-[(6-Chloropy ⁇ imidin-4-y1)amino]-1-phenylethanol (62.4 mg, 0.3 mmol), 3-fluoro-4-methyl-phenyl boronic acid (42 mg, 0.30 mmol), Pd(PPh 3 ) 4 (2.9 mg, 0.0025 mmol), and K 3 PO 4 (106 mg, 0.50 mmol) were placed in a microwave vial and the vial evacuated. The vial was then backfilled with N 2 and charged with DME (2.0 mL) and degassed water (0.5 mL). The reaction mixture was heated in the microwave for 21 min at 180 °C.
  • Example 21-102 The compounds in Examples 21-102 were prepared using methods analogous to those described in Example 20, using either enantiomerically pure or racemic amino alcohols and appropriately substituted 4,6-dichloropyrimidines in Step A and substituting the appropriate boronic acids or esters in Step B.
  • Example 22 4-(6-f ⁇ f2RV2-Hvdroxy-2-phenylethynamino)pyrimldin-4- yl)benzaldehyde.
  • Example 24 M RV1-Phenyl-2-K6-(4-K2.2.2-trifluoroethyltoxyiphenyl)pyrimidin-4- ylteminoiethanol.
  • Example 25 M RV1 -Pheny1-2-r(6-/3-r(2.2.2-trifluoroethy1)oxy]Dheny1)Dyrimidin-4- yltaminolethanol.
  • Example 27 H RV2-f ⁇ 6-M-Chloro-3-fluorophenynpyrimidin-4-yl]amino)-1- phenylethanol trifluoroacetic acid salt.
  • Example 28 M RV2-f(6-[4-Chloro-3-ftrifluoromethyitohenyl]Dyrimidin-4-vi)aminoV 1-phenylethanol trifluoroacetic acid salt.
  • Example 30 (1RV2-ff6-(4-Ethoxy-3-fluorophenylbyrimidin-4-yl]amino)-1- phenylethanol trifluoroacetic acid salt.
  • Example 31 M RV2-f ⁇ 6-(4-Ethoxy-3-methylPhenyltoyrim8din-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
  • Example 33 M RV2-f ⁇ 6-(4-Butoxy-3-fluorophenynpyrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
  • Example 34 M RV2-f ⁇ 6-(4-Butoxyphenyl)pyrimidin-4-yl]amino)-1 -phenylethanol trifluoroacetic acid salt.
  • Example 35 M RV2-f ⁇ 6-(3-Fluoro-4-propoxyphenyltoyrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
  • Example 36 (1RV2-(f6-r3-Fluoro-4-M-methylethoxytohenynpyrimidin-4-yl)aminoV 1 -phenylethanol trifluoroacetic acid salt.
  • Example 37 HRV2-K6-[4-(2-Methylpropoxytohenyl]pyrimidin-4-yl)aminoV1- phenylethanol trifluoroacetic acid salt.
  • Example 38 MRV2-f ⁇ 6-(4-Methoxy-3-methylphenylk)yrimidin-4-yl]amino)-1- phenvlethanol trifluoroacetic acid salt.
  • Example 40 M RV2-f ⁇ 6-(3.5-Dimethylphenynpyrimidin-4-yl)amino)-1 - phenvlethanol trifluoroacetic acid salt.
  • Example 41 M RV2-((6-r3-Fluoro-4-t(rifluoromethyltohenynDyrimidin-4-vt)aminoV 1-Dhenylethanol trifluoroacetic acid salt.
  • Example 42 M RV2-((6-r3-Fluoro-5-(trifluoromethyltohenynpyrimidin-4-yl)aminoV 1-DhenylethanoJ trifluoroacetic acid salt.
  • Example 43 M RV24f6-(3-Chloro-5-fluoroDheny1 ⁇ Dyrimidin-4-yl]aminol-1 - phenyiethanol trifluoroacetic acid salt.
  • Example 44 H RV1-Phenyl-2- ⁇ r6-(4-propoxyphenyl)pyrimidin-4-yl]aminotethanol trifluoroacetic acid salt.
  • Example 45 f 1 RV2-f ⁇ 6-(2.1.3-Benzoxadiazol-5-v1byrimidin-4-v1laminoV1 - phenylethanol trifluoroacetic acid salt.
  • Example 46 M RV2-((6-r3-Methyl-4-(1 -methylethoxytohenyl]pyrimidin-4- vDamino V 1 -phenylethanol.
  • Example 47 M RV2-( ⁇ 6-r3-Chloro-4-(trifluoromethyl)phenyl]-5-methylPyrimidin-4- yl)aminoVI-Dhenylethanol trifluoroacetic acid salt.
  • Example 48 MRV2-((6-r3-Fluoro-4-(trifluoiOmethy»phenyl]-5-methylPyrimidin-4- yl)aminoV1-phenylethanol trifluoroacetic acid salt.
  • Example 49 MRV2-((6-[4-(DifluoromethoxyV3.5-difluoroDhenyl]Dyrimidin-4- yl]aminoVI-phenylethanol trifluoroacetic acid salt.
  • Example 50 2-[4-(6-f ⁇ (2RV2-Hvdroxy-2-Dhenylethyt1aminotoyrimidin-4-yl)Dhenyt1- 2-methyiDroDanenitrile trifluoroacetic acid salt.
  • Example 51 1-r2-Fluoro-4-(6-ffl2RV2-h ⁇ roxy-2-phenylethyflamino)pyrimidin-4- yl)phenyl]ethanone trifluoroacetic acid salt.
  • Example 52 M Ry ⁇ -Ke-ra.S-DimethyM-M-methyiethoxytohenyl]pyrimidin ⁇ - vflaminoVI-phenylethanol trifluoroacetic acid salt.
  • Example 53 HRV2-f ⁇ 6-HH-lndol-6-yltoyrimidin-4-yriamino)-1-phenylethanol trifluoroacetic acid salt.
  • Example 54 MRV1-Phenyl-2-l ⁇ 6-(3.4.5-trifluorophenynpyrimidin-4- yl]aminotethanol trifluoroacetic acid salt.
  • Example 55 M RV2-f ⁇ 6-M -Methyl-1 H-indol-2-v»Pyrimidin-4-yl]amino ⁇ 1 - Dhenylethanol trifluoroacetic acid salt.
  • Example 56 M RV2-CT6-(5-Methy1-1 -benzothioDhen-2-yl ⁇ Dyrimkiin-4-v1laminoV-1 ⁇ phenyiethanol.
  • Example 57 r4-(64T(2RV2-Hvdroxy-2-Dhenylethynamino)Dyrimidin-4- yl)phenyl]fohenyl)methanone trifluoroacetic acid salt.
  • Example 58 M RV2-(f6-(3.5-Difluorophenyl ⁇ Dyrimidin-4-yl]aminoV1-Dheny1ethanol trifluoroacetic acid salt.
  • Example 59 M RV2-f ⁇ 6-(3.4-DifluoiOPhenyl)pyrimidin-4-yl]amino)-1-phenylethanol trifluoroacetic acid salt.
  • Example 60 MRV2-K6-r3-Chloro-4-(trifluoromethynphenyn-2- (methy1sulfany1k)yrimidin-4-yl]aminoV1-Dhenylethanol trifluoroacetic acid salt.
  • Example 61 M RV2- ⁇ 2-Amino-6-r3-chloro-4-t(rifluoromethyltohenynpyrimidin-4- vflaminoVI-phenylethanol trifluoroacetic acid salt.
  • Example 62 M RV2- ⁇ 6-r3-Chloro-4-(trif]uoromethyJ)DhenynDyrimklin-4-v1)aminoV- 1-(4-fluoroDheny1 Methanol.
  • Example 63 M RV2-f ⁇ 6-(6-Methoxypyridin-3-yltoyrimidin-4-vflamino)-1 - phenylethanol.
  • Example 64 M RV2-f ⁇ 6-(6-Ethoxypyridin-3-yl)pyrimidin-4-yl]amino ⁇ -1 - phenylethanol.
  • Example 65 HRV2-(f6-[4-(Dimethylaminotohenyl]pyrimk_in-4-yl)amino)-1- phenylethanol.
  • Example 66 M RV2-((6-[4-(Methylsulfonyl)DhenyflPyrimidin-4-vnaminoV1 - phenylethanol.
  • Example 68 MRV2-f ⁇ 6-(3-Chloro-4-ethoxyphenyltoyrimidin-4-yl]amino)-1- phenyiethanol.
  • Example 69 HRV2-K2'-Moroholin-4-yl-4.5'-biPyrimidin-6-yltamino1-1- phenylethanol.
  • Example 70 (1RV24r6-(6-Moroholin-4-viDyridin-3-v1 ⁇ Dyrimidin-4-vflaminoV1- phenylethanol.
  • Example 71 HRV2-l ⁇ 6-(3-Fluoro-4-methoxyphenyltoyrimidin-4-yl]amino)-1- phenylethanol.
  • Example 72 MRV2-f ⁇ 6-(2.3-Dihydro-1.4-benzodioxin-6-yl)pyrimidin-4-vt1amino)- 1-phenylethanol.
  • Example 73 M RV2-((6-r3-Chloro-4-(trifluoromethy»phenyn-2-methylPyrimidin-4- yl)amino>-1 -ohenylethanol.
  • Example 74 M RV2-l ⁇ 6-M -Benzyl- 1 H-Dyrazol-4-v1 ⁇ Dyrimidin-4-vJ1aminoV1 - phenylethanol.
  • Example 75 M Rl2-l ⁇ 6-(6-Fluoro-5-methylPyridin-3-yl)pyrimidin-4-yl]amino)-1- phenylethanol.
  • Example 76 4-(6-(K2RV2-Hvdroxy-2-phenylethyl]amino)pyrimidin-4-yl)-N.N- dimethylbenzenesulfonamide.
  • Example 77 5-(6-f ⁇ (2RV2-Hvdroxy-2-phendethyl]amino ⁇ pyrimidin-4-vQpyridine-2- carbonitrile.
  • Example 78 M RV2-W6-r6-(Dimethylaminotoyridin-3-vflpyrimidin-4-yl)aminoV1 - phenylethanol.
  • Example 79 M RV 1 -Phenyl-2-ffl>-[4-(piperidin-1 -ylsulfonyl)phenyl]pyrimidin-4- yllaminotethanol.
  • Example 80 (1 RM -Phenyt-2-((6-[4-( Dyrrolidin-1 -ylsulfonyltohenyl]Pyrimidin-4- yllaminotethanol.
  • Example 81 4-(6-ff(2RV2-Hvdroxy-2-phenylethynamino)pyrimk.in-4- yl)benzenesulfonamide.
  • Example 82 HRV2-l ⁇ 6-(4-Fluorophenyl)pyrimidin-4-yl]aminoM-ohenylethanol trifluoroacetic acid salt.
  • Example 83 M RV2- ⁇ r6-(3-Chloro-4-fluoroDhenyl)DVrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
  • Example 84 MRV2- ⁇ 6-r3-(MethylsulfanylbhenyJlDyrimiclin-4-v1)aminoV1- phenylethanol trifluoroacetic acid salt.
  • Example 85 M RV2-f ⁇ 6-M H-lndol-5-vQpyrimidin-4-yl]amino ⁇ -1 -phenylethanol trifluoroacetic acid salt.
  • Example 87 M R)-2-f ⁇ 6-(1 -Benzothk>Dhen-3-v1byrimidin-4-v1laminol-1 - phenylethanol trifluoroacetic acid salt.
  • Example 88 2-Fluoro-4-(6-f ⁇ (2RV2-hydroxy-2-phenylethyl]amino)pyrimidin-4- yl)benzonitrile trifluoroacetic acid salt.
  • Example 89 2-Fluoro-5-(6-f ⁇ (2RV2-hydroxy-2-phenylethyflamino)pyrimidin-4- yl)benzonitrile trifluoroacetic acid salt.
  • Example 90 M RV2-fl6-M -Methyl-1 H-indol-5-vQpyrimidin-4-yl]amino ⁇ -1 - Dhenylethanol trifluoroacetic acid salt.
  • Example 91 M RV2-K6-l4-r(1 -Methy1ethy1 ⁇ sulfanyliDhenyl)Dyrimidin-4-yl)aminol-1 ⁇ phenylethanoJ trifluoroacetic acid salt.
  • Example 92 r4-(6-ffl2RV2-HvdiOxy-2-phenylethyflamino)pyrimidin-4- ynohenyliacetonitrile trifluoroacetic acid salt.
  • Example 93 MRV2- ⁇ 6-r3-Chloro-4-(trifluoromethyl)Dhenyt1-2- (trifluoromethy»Dyrimidin-4-yl)aminoV1-Dhenylethanol trifluoroacetic acid salt.
  • Example 94 HRV2-f ⁇ 6-(3.4-DichloroDhenyiy2-methylDyrimidin-4-yl)amino)-1- phenylethanol.
  • Example 95 M RV2-l ⁇ 6-(3.4-Dichlorophenyl Vpyrimidin-4-yl)amino)-1 - phenvlethanol.
  • Example 96 (1 RV2-K6-[4-(EthylsulfanyltohenyliPyrimidin-4-yl)amino)-1 - phenylethanol.
  • Example 97 M RV2-f ⁇ 6-(3-Ethoxy])henyltoyrimidin-4-vflaminoM -phenylethanol.
  • Example 100 M RV2-l ⁇ 6-M -Benzothiophen-5-yl)pyrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
  • Example 101 M RV2- ⁇ 6-r3-Chloro-4-(trifluoromethyl)phenyn-2- fdimethylamino)pyrimidin-4-yl)aminoV1 -phenylethanol trifluoroacetic acid salt.
  • Example 102 MRl2- ⁇ 6-r3-Fluoro-4-t(rifluoromethynphenyl]-2- (methylsulfany ⁇ Dyrimidin-4-vJ)aminoV1-phenylethanol trifluoroacetic acid salt.
  • Examples 103-104 were prepared using methods analogous to those in Example 20, substituting the appropriate triazine in Step A, and the appropriate boronic acid in Step B.
  • Example 103 M RV1 -Phenyl-2- ⁇ 4-r4-(trifluoromethy ⁇ Dhenyn-1.3.5-triazin-2- yllaminotethanol trifluoroacetic acid salt.
  • Example 104 M RV2-((4-r3-Chloro-4-t(rifluoromethyl)phenyfl-1 ,3.5-triazin-2- vflaminoVI-phenylethanol trifluoroacetic acid salt.
  • Example 105 HRM-Phenyl-2-((6-r3-t(rifluoromethyl)phenyl]Pyrimidin-4- vftaminotethanol.
  • Example 106 MRV1-Phenyl-2-[(6-l4-r(trifluoromethylk3XylDheny1)Dyrimidin-4- ylteminoiethanol.
  • Step A 4-Chloro-6-(4-trifluoromethoxy-Dhenyl)-Dyrimidine.
  • DME dimethyl methacrylate
  • K 3 PO 4 6.24 g, 29.4 mmol
  • Pd(PPh 3 )4 0.51 g, 0.44 mmol
  • the reaction mixture was heated at 85 °C under N2 for 16 h.
  • the reaction mixture was cooled to rt and the organic layer separated, dried (MgSO 4 ), and concentrated.
  • the residue was purified (FCC) to give the title compound as a yellow solid (2.20 g, 54%).
  • Step B To a solution consisting of 4-chloro-6-(4- trifluoromethoxy)phenylpyrimidine (0.137 g, 0.5 mmol) and (R)-2-amino-1- phenylethanol (75 mg, 0.55 mmol) and dioxane (2 mL) was added NaHCO 3 (252 mg, 3.0 mmol) at rt. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to rt and the precipitate was isolated via filtration. The precipitate was purified (FCC) to give a white solid (63 mg, 34%). MS (ESI): mass calcd.
  • Examples 107-130 were synthesized in a similar manner to those described in Example 106, substituting the appropriate boronic acids and esters in Step A and amino alcohols (prepared analogously to Intermediate B or C) in Step B.
  • Example 107 1 -(4-Nitrophenyl V2-R644-[(trifluoiOmethyJ toxy1phenyl)Pyrimidin-4- ylt ⁇ minoiethanol.
  • Example 109 1 -(4-Chlorophenyl)-2-[(6- ⁇ 4-r(trifluoromethv ⁇ oxylphenyl)pyrimidin- 4-yl)aminolethanol.
  • Example 110 4-f1-Hvdroxy-2-f(6- ⁇ 4-f(trifluoromethv ⁇ oxylphenyl)pyrimidin-4- vOaminolethvDphenol.
  • Example 111 1 -r4-(Methyloxy)phenyll-2-r(6-(4-r(trifluoromethyltoxy1phenylV pyrimidin-4-yl)aminolethanol.
  • Example 112 441-Hvdroxy-2-r(6-l4-r(trifluoromethyl)oxyipheny1)Dyrimidin-4- yl)amino1ethyft-2-(methyioxytohenol.
  • Example 113 1-(4-FluoroDhenyJV2-r(6-/4-r(trifluoromethylk)xylpheny1)pyrimklin- 4-ylteminolethanol.
  • Example 114 1-(3.4-Dichloropheny1V2- ⁇ 644-r(trifluoronnethy1k)xylDhenyll- pyrimidin-4-yltaminolethanol.
  • Example 115 1-(2-Chlorophenyl)-2-r(6-(4-rftrifluoromethylk)xyiphenyftDyrimidin- 4-yl)aminoiethanol.
  • Example 116 1-(3-ChloroDhenyl)-2- ⁇ 644-r(trifluoro ⁇ nethy1V3xylDheny1)Dyrimidin- 4-yltaminolethanol.
  • Example 118 1-[2-(Methyloxy)Dhenyn-2-r(6-/4-r(trifluoromethylk?xylDhenyl)- pyrimidin-4-ylt ⁇ minolethanol.
  • Example 119 M R.2SV1 -PhenyJ-2-r(6-/4-[(trifluoromethylk)xylDhenyl)DyrimkJin-4- yltaminolpropan-1 -ol.
  • Example 120 MR.2RV2-rMethyl(6- ⁇ 4-r(trifluoromethyltoxyiDhenyl)pyrimidin-4- yltamino1-1-phenyipropan-1-ol. F 3 C 0 A ⁇ J '
  • Example 121 MR.2SV2-rMethyU6- ⁇ 4-Ktrifluoromethyltoxylphenyl)pyrimidin-4 ⁇ yl)amino1-1-DhenylproDan-1-ol.
  • Example 122 1-(2.2-Difluoro-1.3-benzodioxol-5-v1i-2-K6- ⁇ 4- rftrifluoromethylk)xylphenyl)pyrimidin-4-yltemino1ethanol.
  • Example 123 1-Pyridin-2-yl-2-r(6- ⁇ 4-rftrifluoromethyltoxyiphenyl)pyrimidin-4- vitaminoiethanol.
  • Example 124 1-Pyridin-3-yl-2-r(6-l4-r(trifluoromethyl)oxyiDhenyt ⁇ pyrimidin-4- yl)aminoiethanol.
  • Example 125 1-Pyridin-4-yl-2-rf6- ⁇ 4-r(trifluoromethyltoxyiphenyl)pyrimidin-4- yl)aminolethanol.
  • Example 126 1-(3.5-DichloroDheny1V2-r(644-r(t ⁇ fluoiOmethylk)xylDhenylV pyrimk.in-4-ylt ⁇ minolethanol.
  • Example 128 MSV-2-(f6-r3-Chloro-4-(trifluoromethylk)henynpyrimidin-4- vftaminoVI -phenyiethanol.
  • Example 129 MRV-2-(f6-[3-Fluoro-4-(1-hydroxyethylbhenynpyrimidin-4- v1)aminoV1-Dheny1ethanol trifluoroacetic acid salt.
  • Example 130 2- ⁇ 6-r3-Chloro-4-(trifluoromethyl)DhenyilDyrimidin-4-yl)aminoV1-r3- (trifluoromethoxytohenyliethanol trifluoroacetic acid salt.
  • the resultant mixture was allowed to gradually warm to rt with stirring for 21 h.
  • the reaction mixture was then re-cooled to 0°C and carefully treated with water (2.57 mL) followed by 15% aq. NaOH (2.57 mL) and lastly with water (7.7 mL).
  • the resultant mixture was stirred for 1 h, the solids removed by vacuum filtration and the filtrate concentrated.
  • the resulting crude product was purified by FCC (CH 2 Cl 2 ZMeOHZNH 3 ) to give the desired product.
  • Step B A vial containing a solution of 4-chloro-6-(3-chloro-4- trifluoromethyl-phenyl)-pyrimidine (59.9 mg, 0.204 mmol), 2-amino-1-(3- trifluoromethoxy-phenyl)-ethanol (72.4 mg, 0.327 mmol), ⁇ -BuOH (2 mL ) and DIPEA (0.15 mL, 0.86 mmol) was flushed with N 2 , capped and heated at 100 °C for 20 h. The reaction mixture was purified directly by reverse-phase HPLC. MS (ESI): mass calcd.
  • Examples 131-135 were prepared using methods analogous to those described in Example 130, using the appropriate aldehydes in Step A.
  • Example 131 2-((6-r3-Chloro-4-(trifluoiOmethyltohenyflDyrimidin-4-yl>aminoV1- (3-fluoroDhenyltethanol trifluoroacetic acid salt.
  • Example 132 2-r6-(3-Chloro-4-trifluoromethy1-Dhenyl)-Dyrimidin-4-ylamino1-1- (3.4-difluoro-phenyl)-ethanol trifluoroacetic acid salt.
  • Example 133 1-(4-Chloro-3-fluoro-Dhenyl)-2-r6-(3-chloro-4-trifluoromethyl- Dhenyl)-pyrimidin-4-ylaminol-ethanol trifluoroacetic acid salt.
  • Example 134 1-(3-Chloro-4-fluoroDhenyl)-2-((6-r3-chloro-4- ftrifluoromethy»phenyflDyrimiclin-4-yl)aminotethanol trifluoroacetic acid salt.
  • Example 135 2-((6-r3-Chloro-4-ftrifluoromethyltohenynpyrimidin-4-yl)aminoV143- ftrifluoromethynphenyl]ethanol trifluoroacetic acid salt.
  • Example 136 M RV2-ff2-Cvclopropyl-6-(3.4-dichlorophenyltoyrimidin-4-yl]amino ⁇ - 1-Dhenylethanol.
  • Step B 4-Chloro-2-cycloproDyl-6-(3.4-dichloro-Dhenyl)-Dyrimidine.
  • 2-cyclopropyl-6-(3,4-dichloro-phenyl)-pyrimidin-4-ol 131 mg, 0.467 mmol
  • POCI 3 0.13 mL, 1.42 mmol
  • the reaction mixture was heated at 80 °C for 105 min, cooled to rt, quenched with satd. aq. NaHCOa, and extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and concentrated.
  • the crude residue was purified (FCC) to give the title compound (113 mg, 81%).
  • Step C A mixture of 4-chloro-2-cyck>propyl-6-(3,4-dichloro-phenyl)- pyrimidine (108 mg, 0.364 mmol), (R)-(-)-2-amino-1-phenylethanol (67.2 mg, 0.490 mmol), and NaHCO 3 (190.1 mg, 2.26 mmol) and 1 ,4-dioxane was refluxed for 48 h. The mixture was poured into water and extracted with CH 2 Cb. The organic layer was dried (Na 2 SO 4 ) and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (119.4 mg, 82%). MS (ESI): mass calcd.
  • Example 137 MRl2-ff6-(3.4-Dichlorophenyl)-2-M-methylethyltoyrimidin-4- yl]aminoV 1 -ohenylethanol.
  • Example 138 M RV2-((6-r3-ChlorD-4-t(rifluoromethy ⁇ phenyt1-2- (methy1sutfonynDyrimkiin-4-yl)aminoV1-Dhenyiethanol.
  • Example 139 f1RV2-((6-r3-Chloro-4-t(rifluoromethyltohenyn-2- (methylsulfinyhPyrimidin-4-yl)aminoV1-phenylethanol.
  • Example 140 M RV2-ir6-(3-Methyl-1H-indazol-6-vibyrimidin-4-vt1amino)-1- phenylethanol trifluoroacetic acid salt.
  • Example 141 M R)-2M 6-r3-Chloro-4-t(rifluoromethy»phenyn-2- (methyJamino)Dyrimidin-4-v1)amino)-1-pheny1ethanol trifluoroacetic acid salt.
  • Example 142 M RV2-f ⁇ 6-(4-lodophenyltoyrimidin-4-yriamino ⁇ -1-phenylethanol.
  • Step A f4-(6-Chloro-Dyrimidin-4-vJ>-Dhenyn-carbamic acid tert-butyl ester.
  • the title compound was prepared analogously to that described in Example 20, Step B.
  • Step B 4-(6-Chloro-pyrimidin-4-yl)-phenylamine.
  • CH 2 Cl 2 (30 mL) and HCI (4 N in dioxane; 3.80 mL) was stirred overnight at rt and the solid isolated by filtration. The resultant solid was taken up in water, treated with satd. aq. NaHCO 3 and extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. The material was used directly in Step C.
  • Step C 4-Chloro-6-(4-iodo-phenyl)-pyrimidine.
  • Step D The title compound was prepared analogously to that described in Example 1, Step A.
  • Example 143 MSV2-r6-(3-Chloro-4-trifluoromethyl-phenyl)-Dyrim8din-4-ylamino1- 1 -(3.4-difluoro-Dhenvl Methanol.
  • Example 144 M RV2-[6-(3-Chloro-4-trifluoromethyl-phenyl)-Dyrimidin-4-ylaminol- 1-(3.4-difluoro-phenyl)-ethanol.
  • Example 145 MSV1-(4-Chloro-3-fluoro-phenyl)-2-r6-(3-chloro-4-trifluoromethyl- phenyl)-pyrimidin-4-ylamiriol-ethanol.
  • Example 146 M R)-1-(4-Chloro-3-fluoro-Phenyl)-2-r6-(3-chloro-4-trifluoromethyl- phenyl)-pyrimidin-4-ylaminol-ethanol.
  • Example 147 2-((644-(Methyloxytohenyl]Dyrimidin-4-yl ⁇ aminoi-1 -phenylethanol.
  • Example 148 2-l ⁇ 6-(3-Methylphenyl)pyrimidin-4-yl]amino ⁇ -1 -phenylethanol.
  • Example 149 1-Phenyl-2-K6-(3-rftrifluoromethyltoxyiphenyl)pyrimidin-4- yltaminolethanol.
  • Example 150 M S.2RV1 -Phenyl-2-K6-l4-rftrifluoromethylk)xyiPheny1)pyrimidin-4- ylteminoioropan-1 -ol.
  • Example 151 MSV1-Phenyl-2-K6- ⁇ 4-r(trifIuoromethyltoxyiphenyftpyrimidin-4- ylteminolethanol.
  • Example 152 M RV2-((6-r2.4-Bis(trifluoromethyl)phenyl]Pyrimidin-4-yl)aminoV1 ⁇ phenylethanol trifluoroacetic acid salt.
  • Example 153 MRV2-((6-r2-Methoxy-4-ftrifluoromethoxy)phenyl]Pyrimidin-4- vnaminoVI -phenylethanol trifluoroacetic acid salt.
  • Example 154 MRV2-f ⁇ 6-(4-Ethoxy-2-methylphenyltoyrimidin-4-yriamino ⁇ -1- DhenyJethanol trifluoroacetic acid salt.
  • Examples 155-156 were prepared using methods analogous to those described in Example 136.
  • Example 155 M RV2-ff6-(3.4-Dichlorophenyl V2-methylPyrimidin-4-v ⁇ amino)-1 - phenyiethanol.
  • Example 157-162 The compounds prepared in Example 157-162 were prepared using methods analogous to those described in Example 141.
  • Example 157 (1 R)-2-((2-r(2-Aminoethvnaminol-6-r3-chloro-4- (trifluoromethyl)phenvnpyrimidin-4-yl)amino)-1 -phenylethanol trifluoroacetic acid salt.
  • Example 158 (1 R)-2-f(6-r3-Chloro-4-(trifluoromethyl)phenyl1-2-(r2- (dimethylamino)ethyllamino)pyrimidin-4-yl)amino1-1 -phenylethanol trifluoroacetic acid salt.
  • Example 159 MRV2-a6-r3-Chloro-4-(trifluoromethy1)Dhenyfl-2- (ethylaminotoyrimidin-4-yl)aminoV1-phenylethanol trifluoroacetic acid salt.
  • Example 160 MRV-2-((6-r3-Chloro-4-(trifluoromethyltohenyl]-2-r(2- hydroxyethyl)aminolpyrimidin-4-yl)aminoV1-phenyiethanol trifluoroacetic acid salt.
  • Example 161 M Ri-2- ⁇ 2-Azetidin-1-yl-6-r3-chloro-4- ftrifluoromethyl)Dheny ⁇ Dyrimidin-4-yl)aminoV1-Dhenylethanol trifluoroacetic acid salt.
  • Example 162 (1RV2-((6-r3-Chloro-4-(trifluoiOmethyltohenyn-2- fcvclopropylaminotoyrimidin-4-yl)aminoH-phenylethanol trifluoroacetic acid salt.
  • Example 163 f1RV2-rf6-r3-Chloro-4-t(rifluoromethyl)phenyn-2-ir2- (methylaminotethyl)amino)pyrimidin-4-yltaminoM-phenylethanol hydrochloride salt.
  • Step A M RW2-[4-(3-Chloro-4-trifluoromethyl-Dhenyl>-6- ⁇ 2-hydroxy-2-Dhenyl- ethylaminoVpyrimidin-2-ylaminol-ethyl)-methyl-cart)amic acid tert-buM ester.
  • the title compound was prepared using methods analogous to those described in Example 141.
  • Step B To a solution consisting of (1 R)- ⁇ 2-[4-(3-chloro-4-trifluoromethyl-phenyl)- 6-(2-hydroxy-2-phenyl-ethylamino)-pyrimidin-2-ylamino]-ethyl ⁇ -methyl-carbamic acid tert-butyl ester (40 mg, 0.06 mmol) and CH 2 Cb (1.5 mL) was added HCI (2 M in Et 2 O, 0.15 mL). The reaction mixture was allowed to stir at rt for 18 h giving a white solid. The solid was isolated via vacuum filtration and then washed with Et 2 O to yield the title compound (18 mg, 63%). MS (ESI): mass calcd.
  • Example 164 MRV2-((6-r3-Chloro-4-(trifluoromethyl)Dhenyn-2-methoxy])yrimidin- 4-vDaminoH-phenylethanol trifluoroacetic acid salt.
  • Example 165 MRV2-f ⁇ 6-(3-Methyl-1.2-benzisQxazol-6-yl)pyrimidin-4-v1laminol-1- phenylethanol.
  • Example 166 1-(f6-r3-Chloro ⁇ -(trifluoromethyltohenyflpyrimidin-4-yl)aminoi-2- phenylpropan-2-ol.
  • Example 167 2-(f6-r3-Chloro-4-(trifluoromethyl)DhenynDyrimidin-4-yl)amino>-1 -F4- (methylsulfanyl)phenynethanol.
  • Step A 2-Azido-1-(4-methylsulfanyl-phenyl)-ethanone.
  • a solution consisting of 2- bromo-1-(4-methylsulfanyl-phenyl)-ethanone (2.00 g, 8.16 mmol) and DMF (7 mL) was cooled to 15 °C and treated portion-wise with sodium azide (583 mg, 8.98 mmol). Once addition was complete, the reaction mixture was stirred for 3 h with gradual warming to rt. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (25 mL x 2), NaHCOa (satd. ,25 mL x 2), and brine.
  • Step B 2-Azido-1-(4-methylsulfanyl-phenyl)-ethanol.
  • a solution consisting of 2- azido-1-(4-methylsulfanyl-phenyl)-ethanone (1.69 g, 8.15 mmol) and THF (8.15 mL) was cooled to 0 °C before slowly adding BH 3 -THF (1.0 M solution, 8.15 ml) over 10 min. The resulting solution was stirred at 0 °C for 2 h. The reaction was quenched by slow addition of MeOH (10 mL) at 0 °C 1 and then concentrating to dryness to yield the title compound (1.74 g, 100%).
  • Step C 2-Amino-1-(4-methylsulfanyl-phenyl)-ethanol.
  • 2-azido-1-(4-methylsulfanyl-phenyl)-ethanol 104.6 mg, 0.50 mmol
  • 10% Pd/C 100 mg, 0.10 mmol
  • MeOH 25 mL
  • ammonium formate 316 mg, 5.0 mmol
  • the resulting mixture was heated at 64 °C for 2 h.
  • the catalyst was removed by filtration through a pad of celite and the celite pad washed with MeOH. The filtrate was concentrated and purified (FCC) to yield the title compound (66 mg, 72%).
  • Step D Title compound was prepared using methods analogous to those in Example 106, Step B.
  • Example 168-169 The compounds in Example 168-169 were prepared using methods analogous to those described in Example 167.
  • Example 168 2-a6-r3-Chloro-4-rtrifluoromethy1)DhenyflDyrimidin-4-yl)aminoV1- thiophen-3-ylethanoJ.
  • Examples 170-172 were synthesized using methods analogous to those described in Example 20.
  • Example 170 M RV1-Phenyl-2-rf6-ouinolin-6-ylPyrimidin-4-yl)aminolethanol.
  • Example 171 N-tert-Butvt-4-(6-irf2RV2-hydroxy-2-Dhenytethyt1amino>Pyrimidin-4- yl)benzenesulfonamide.
  • Example 172 M RV1-Phenyl-2-((6-[4-(thiomorpholin-4-ylsulfonyltohenynpyrimidin- 4-vftaminotethanol.
  • Example 173-182 were prepared using methods analogous to those described in Example 20.
  • Example 173 MRH-(4-Fluorophenyl>-2-K6-r3-fluon>4- (trifluoromethyl)DhenyflPyrimidin-4-vi)amino)ethanol.
  • Example 174 (1R)-1-(4-Fluorophenyl)-2-K6-r3-fluoro-4- ftrifluorometrroxytohenyl]pyrimidin-4-vttaminotethanol trifluoroacetic acid salt.
  • Example 175 M RV2-(f6-r3-Chloro-4-t(rifluoromethoxy)phenynpyrimidin-4- vJ)aminoV1-(4-fluoroDheny1>ethanol trifluoroacetic acid salt.
  • Example 176 M R V1 -(4-fluoroDhenyi V2- ⁇ 6-r3-rDentafluoroethyJV1.2- benzisoxazol-6-yl]pyrimidin-4-vi)aminotethanol trifluoroacetic acid salt.
  • Example 177 M RV1-(4-FluoroDhenyl)-2- ⁇ 6-r3-(trifluoromethy1V1 ,2-benzisoxazol- 6-yl]DyrimkJin-4-vftaminotethanol trifluoroacetic acid salt.
  • Example 178 HRV2-W6-r3-Fluoro-4-(2.2.2-trifluoroethoxytohenyl]pyrimidin-4- yllaminoVI-phenylethanol trifluoroacetic acid salt.
  • Example 179 H R.2SV-2-K6-r3-chloro-4-(trifluoromethyltohenyl]Pyrimidin-4- vflaminoV 1 -phenylpropan-1 -ol.
  • Example 180 M RV1-Phenyl-2-r(644-r(trifluoromethynsulfany1lDheny1)pyrimidin-4- ylt ⁇ minolethanol.
  • Example 181 H RV2-(f6-r3-ChloiO-4-t(rifluoromethoxytohenyliPyrimidin-4- vDamino V1 -phenylethanol.
  • Example 182 (1 RM-Phenyl-2-(f6-r3-(trifluoromethyl)-1.2-benzisoxazol-6- ⁇ riiDyrimidin-4-ylteminotethanol.
  • Example 183 (1RV2-ir6-(2.2-Difluoro-1.3-penzodioxol-5-yl)pyrimidin-4-vflaminol- 1-phenylethanol.
  • Step B (1R)-2-[(6-Chloropyrimkiin-4-y1)amino]-1-phenylethanol (75 mg, 0.30 mmol), 2,2-difluoro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- benzo[1 ,3]dioxole (85 mg, 0.30 mmol), Pd(OAc) 2 (1.3 mg, 0.006 mmol, 2 mol%),.
  • Examples 184-187 were prepared using methods analogous to those described in Example 183.
  • Example 184 MRV1-Phenyl-2-((6-r5-t(rifluoromethyl)-1-benzothiophen-2- vf]pyrimidin-4-yl)aminotethal)ol trifluoroacetic acid salt.
  • Example 185 M RV1-Phenyl-2-((6-r5-(trifluoromethoxyV1-benzothiophen-2- vflpyrimidin-4-yl)aminotethanol trifluoroacetic acid salt.
  • Example 187 MRV2-f(6-[5-Fluoro-1-benzothioDhen-2-yltoyrimidin-4-yl]aminoV1- phenylethanol.
  • Example 188 MRV2-K6-r3-(pentafluomethyl)-1 ⁇ -benzisoxazol- ⁇ -yl)DyrimidirM- vftaminoVI-phenylethanol trifluoroacetlc acid salt.
  • Example 190 2- ⁇ 6-r3-Chloro-4-(trifluorOmethyl)phenynpyrimidin-4-yl)aminoV1-(4- fluorophen yl Methanol . OH
  • Step A 2-amino-1-(4-fluoro-phenyl)-ethanol.
  • 2-amino- 1-(4-fluoro-phenyl)-ethanone 150 mg, 0.9 mmol
  • MeOH 5 mL
  • NaBH 4 97 mg, 2.6 mmol
  • the mixture was stirred at rt for 45 min and then concentrated to dryness.
  • the residue was diluted with EtOAc and washed with a satd. NH 4 CI solution before drying (Na 2 SO 4 ), and concentrating to give 2-amino-1- (4-fluoro-phenyl)-ethanol (139 mg, 100%) which was used without further purification.
  • Step A 4-(2-Amino-1-hydroxy-ethyl)-benzonitrile.
  • BtVTHF 1-(2-bromo-acetyl)-benzonitrile 1 M in THF 1 5.4 mL) at 0°C.
  • MeOH 4 mL was added slowly to the reaction vessel and the reaction mixture stirred for an additional 30 min.
  • the reaction mixture was then concentrated dryness and re-dissolved in MeOH (10 mL) before treating with NH 4 OH (10mL).
  • the mixture was stirred at rt for 12 h and then concentrated.
  • the residue was dissolved in water and extracted with EtOAC.
  • the organic layer was dried (Na 2 SO4), and concentrated.
  • the crude residue was purified (FCC) to give the title compound (246 mg, 34%).
  • Example 192 2-a6-r3-Chloro-4-(trifluoromethyl ⁇ Dheny1lPyrimk.in-4-v1)aminoV1- naDhthalen-2-vlethanol.
  • Example 193 2-(f6-r3-Chloro-4-t(rifluoromethy»DhenynDyrimidin-4-vt)aminoV1-(4- Dyridin-2-ylDhenyi Methanol.
  • Step A 2-Nitro-1-(4-Dyridin-2-yl-DhenyJV-ethanol.
  • THF 5 ml.
  • NO 2 CH 3 0.3 mL
  • MeOH 2.5 mL
  • KOH 2.5 M, 1.13 mL
  • the reaction mixture was stirred at 0 °C for 30 min. and then quenched with a saturated NH4CI solution.
  • the aqueous mixture was extracted with EtOAC. The organic layer was dried (Na 2 SO.*) and concentrated.
  • Step B 2-Amino-1-(4-Dyridin-2-vJ-Dheny1V-ethanol.
  • NH 4 CI 900 mg, 16.9 mmol
  • Zn dust 1.10 g, 16.9 mmol
  • water 1 mL
  • the reaction mixture was stirred for 2 h at rt and then filtered.
  • the filtrate was washed with saturated NaHCO 3 and extracted with EtOAc.
  • the organic layer was dried (Na 2 SO 4 ) and concentrated.
  • Example 194 2-((6-[3-Chlorc>-4-(trifluoronnethylk)heny1lDyrimidin-4-yl)aminoV-1 -(4- thiophen-2-vlphenvltethanol.
  • Example 195 1 -Biphenyl-4-vt-2-K6-r3-chloro ⁇ -(trifluoromethyl tohenyl]Pyrimidin-4- vDaminotethanol.
  • Step A 2-Amino-1-bipheny1-4-yl-ethanol.
  • 1-biphenyl-4- yl-2-bromo-ethanone 412 mg. 1.5 mmol
  • EtOH 6 ml.
  • NaN 3 107 mg, 1.6 mmol
  • the mixture was stirred at rt for 2 h and then cooled to 0 °C.
  • NaBH 4 61 mg, 1.6 mmol
  • a mixture (black slurry) of CuSO 4 « 5H 2 O (37 mg)/NaBH 4 (28 mg) in MeOH 2 mL) was prepared by adding the NaBH 4 to CuSO 4 -5H 2 O in MeOH at 0 °C. This slurry was poured into the reaction mixture. The reaction vessel was allowed to gradually warm to rt. An additional amount of NaBH 4 (28 mg) was added 30 min after the addition of the slurry. 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, 80%).
  • Examples 196-218 were prepared using methods analogous to those described in Example 195.
  • Example 196 1-(1-Benzothiophen-2-yl)-2-K6-r3-chloro-4- l-vftaminotethanol.
  • Example 197 2-((6-r3-Chloro-4-t(rifluoromethy ⁇ Dhenynpyrimidin-4-yl>aminoV1 -[3- fluoro-4-t(rifluoromethyl)phenyl]ethanol.
  • Example 198 2-(l6-r3-chloro-4-(trifluoromethyl ⁇ p henynpyrimidin-4-vt)aminoV1 -13- rftrifluoromethvOsulfanvflphenvltethanol.
  • Example 199 2- ⁇ 6-r3-Chloro-4-(t ⁇ fluoromethy1)Dhenyl]Dyrimidin-4-v1)aminoV1- (2.3-dihydro-1.4-benzodioxin-6-v1 Methanol.
  • Example 200 2-((6-r3-Chloro-4-(trifluoromethy1)Dhenyl]DyrimkJin-4-yl)annino V1 -F4- M H-imkJazoH -vQphenyflethanol.
  • Example 201 1-M-benzothiophen-3-yl)-2-((6-r3-chloro-4- ftrifluoromethv ⁇ phenvliPvrimidin-4-vlteminotethanol.
  • Example 202 2-(f6-r3-Chloro-4-(trifluoromethyi)DhenyliDyrimidin-4-yl)aminoV1- (3.4-dimethoxy])henyl Methanol.
  • Example 203 1-(3-Chloro-4-metho ⁇ yphenyl)-2-((6-r3-chloro-4- ftrifluoromethyQphenyl]pyrimidin-4-yl)aminotethanol.
  • Example 204 2-(f6-r3-Chloro-4-t(rifluoromethy»Dhenyl]Dyrimidin-4-yl)aminoV1- (3.4-dihydro-2H-1.5-benzodioxepin-7-yl)ethanol.
  • Example 205 2-(f6-r3-Chloro-4-(trifluoromethyl)DhenynDyrimidin-4-vftaminoV1-r2- fluoro-5-(trifluoromethyl)phenyflethanol.
  • Example 206 3-r2-(f6-r3-Chloro-4-t(rifluoromethyl)phenyl]pyrimidin-4-yl)aminoV1- hydroxyethyflbenzonitrile.
  • Example 207 2-((6-r3-Chloro-4-(trifluoromethylbhenytiDyrimidin-4-vftamino)-1 -(3- phenylisoxazol-5-yl Methanol.
  • Example 208 2- ⁇ 6-r3-Chloro-4- ⁇ rifluoromethy1)DhenyflDyrimidin-4-v1 ⁇ aminoV1-(4- pyr ⁇ olidin-1 -ylphenyl)ethanol.
  • Example 209 2-((6-r3-Chloro-4-ftrifluoromethy1bhenyflDyrimidin-4-v1)aminoV1 -(5- pyridin-2-ylthiophen-2-vi Methanol.
  • Example 210 5-r2-((6-r3-Chloro-4-arifluoromethy1)Dhenyl]Dyrimidin-4-yl)aminoV1- hydroxyethyl]-2-fluorobenzonitrile.
  • Example 211 2-((6-r3-Chloro-4-t(rifluoromethy»DhenyfiDyrimidin-4-yl)aminoV1- f2.6-difluorophenyl Methanol.
  • Example 212 2- ⁇ 6-r3-Chloro-4-t(rifluoromethy»phenynpyrimidin-4-vftaminoV1 -12- fluorophenyl Methanol.
  • Example 213 2-r6-(3-Chloro-4-trifluoromethyl-phenylWpyrimidin-4-ylamino ' l-1 -I3- (3.4-dichloro-Dhenyl)-isoxa2 ⁇ l-5-vfl-ethanol.
  • Example 214 1-r3-(4-Chloro-Phenyl)-isoxazol-5-yl]-2-r6-(3-chloro-4- trifluoromethyl-phenyl)-pyrimidin-4-ylaminoi-ethanol.
  • Example 215 2-r6-(3-Chloro-4-trifluoromethyl-phenyl Vpyrimk.in-4-ylaminoi-i -F3- (2.4-dichloro-phenyl)-isoxazol-5-yl]-ethanol.
  • Example 216 1-Benzothiazol-2-yl-2-r6-(3-chloro-4-trifluoromethyl-phenyl)- pyrimidin-4-ylaminol-ethanol.
  • Example 217 1-r3.5-Bisftrifluoromethy»Dhenyn-2-(f6-r3-chloro-4- (trifluoromethy1)Dheny1lPyrir ⁇ idin-4-yl)amino ⁇ ethanol.
  • Example 218 1-(5-Bromo-1-benzothioprten-2-yl)-2-((6-r3-chloro-4- rtrifluoromethyl)pheny1iDyrimidin-4-v1)amino>ethanol.
  • Examples 219-221 were prepared using methods analogous to those described in Example 20.
  • Example 219 MRVPhenyl-2-l6-[4-(1.2.2.2-tetrafluoro-1-trifluoromethyl-ethyl)- Dhenyl]-Dyrimidin-4-ylaminoV-ethanol
  • Example 220 MRVPhenyl-2-l6-r3-M .2.2.2-tetrafluoro-1-trifluoromethyl-ethyl)- phenyn-pyrimidin-4-ylaminoV-ethanol
  • Example 221 HR)-Phenyl-2-r6-(3-trifluoromethyl-benzorblthiophen-6-yl)- pyrimidin-4-ethanol.
  • Example 222 can be prepared using methods analogous to those described in Example 141.
  • Example 222 4-(3-Chloro-4-trifluoromethyl-phenyl)- ⁇ (2-hydroxy-2-phenyl-MRV- ethylaminoVDyrimidine-2-carbonitrile.
  • Examples 223-245 were obtained by our employer from a third party as library compounds and therefore were known to us as compounds per so. We discovered that these compounds have FAAH- modulating activity, and that they therefore have utility in the therapeutic compositions and methods according to the invention, as reflected by the assay results for these compounds shown in Table 1.
  • Example 223 2-l ⁇ 6-(3.4-DimethylDhenyl)Dyrimidin-4-yl]amino)-1 -phem/lethanol.
  • Example 224 2-((6-f4-(1.1-Dimethylethyl)phenvnpyrimidin-4-yl)amino)-1- phenylethanol.
  • Example 225 2-r6-(4-Methylsulfanyl-phenyl)-pyrimidin-4-ylamino1-1 -phenyl ethanol.
  • Example 226 4-(6-r(2-Hvdroxy-2-phenylethyl)aminoipyrimidin-4-yl)benzonitrile.
  • Example 227 2-(6-Benzorblthiophen-2-yl-pyrimidin-4-ylamino)-1 -phenyl-ethanol.
  • Example 228 1 -(4-(6-r(2-Hvdroxy-2-phenylethyl)amino1pyrimidin-4- vDphenvPethanone.
  • Example 229 2-r6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-ylaminol-1 -phenyl- ethanol.
  • Example 230 2-/r6-(4-MethyJDhenylk ⁇ yrimidin-4-yl]amino)-1-Dheny1ethanol.

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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

ARYL-HYDROXYETHYLAMINO-PYRIMIDINES AND TRIAZINES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
Field of the Invention
Certain aryl-hydroxyethylamino-pyrimidine and triazine compounds, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity are provided. Certain methods of preparing the compounds are also disclosed.
Background of the Invention Medicinal benefits have been attributed to the cannabis plant for centuries.
The primary bioactive constituent of cannabis is Δ9-tetrahydro-cannabinol (THC). The discovery of THC eventually led to the identification of two endogenous cannabinoid receptors responsible for its pharmacological actions, namely CBi and CB2 (Goya, Exp. Opin. Ther. Patents 2000, 10, 1529). These discoveries not only established the site of action of THC, but also inspired inquiries into the endogenous agonists of these receptors, or "endocannabinoids". The first endocannabinokj identified was the fatty acid amide anandamide (AEA). AEA itself elicits many of the pharmacological effects of exogenous cannabinoids (Piomelli, Nat. Rev. Neurosci. 2003, 4(11), 873). The catabolism of AEA is primarily attributable to the integral membrane bound protein fatty acid amide hydrolase (FAAH), which hydrolyzes AEA to arachidonic acid. FAAH was characterized in 1996 by Cravatt and co-workers (Cravatt, Nature 1996, 384, 83). It was subsequently determined that FAAH is additionally responsible for the catabolism of a large number of important lipid signaling fatty acid amides including: another major endocannabinoid, 2- arachidonoylglycerol (2-AG) (Science 1992, 258, 1946-1949); the sleep-inducing substance, oleamide (OEA) (Science 1995, 268, 1506); the appetite-suppressing agent, N-oleoylethanolamine (Rodriguez de Fonesca, Nature 2001, 414, 209); and the anti-inflammatory agent, palmitoylethanolamide (PEA) (Lambert, Cum Med. Chem. 2002, 9(6), 663).
Small-molecule inhibitors of FAAH should elevate the concentrations of these endogenous signaling lipids and thereby produce their associated beneficial pharmacological effects. There have been some reports of the effects of various FAAH inhibitors in pre-clinical models.
In particular, two carbamate-based inhibitors of FAAH were reported to have analgesic properties in animal models. In rats, BMS-1 (see WO 02/087569), which has the structure shown below, was reported to have an analgesic effect in the Chung spinal nerve ligation model of neuropathic pain, and the Hargraves test of acute thermal nociception. URB-597 was reported to have efficacy in the zero plus maze model of anxiety in rats, as well as analgesic efficacy in the rat hot plate and formalin tests (Kathuria, Nat. Med. 2003, 9(1), 76). The sulfonylfluoridθ AM374 was also shown to significantly reduce spasticity in chronic relapsing experimental autoimmune encephalomyelitis (CREΞAE) mice, an animal model of multiple sclerosis (Baker, FASEB J. 2001 , 15(2), 300).
Figure imgf000003_0001
In addition, the oxazolopyridine ketone OL-135 is reported to be a potent inhibitor of FAAH, and has been reported to have analgesic activity in both the hot plate and tail emersion tests of thermal nociception in rats (WO 04/033652). o
35
Figure imgf000003_0002
Results of research on the effects of certain exogenous cannabinoids has elucidated that a FAAH inhibitor may be useful for treating various conditions, diseases, disorders, or symptoms. These include pain, nausea/emesis, anorexia,, spasticity, movement disorders, epilepsy and glaucoma. To date, approved therapeutic uses for cannabinoids include the relief of chemotherapy-induced nausea and emesis among patients with cancer and appetite enhancement in patients with HIV/A I Ds who experience anorexia as a result of wasting syndrome. Two products are commercially available in some countries for these indications, namely, dronabinol (Marinol®) and nabilone.
Apart from the approved indications, a therapeutic field that has received much attention for cannabinoid use is analgesia, i.e., the treatment of pain. Five- small randomized controlled trials showed that THC is superior to placebo, producing dose-related analgesia (Robson, Br. J. Psychiatry 2001 , 178, 107-115). Atlantic Pharmaceuticals is reported to be developing a synthetic cannabinoid, CT-3, a 1,1 -dimethyl heptyl derivative of the carboxylic metabolite of tetrahydrocannabinol, as an orally active analgesic and anti-inflammatory agent. A pilot phase Il trial in chronic neuropathic pain with CT-3 was reportedly initiated in Germany in May 2002.
A number of individuals with locomotor activity-related diseases, such as multiple sclerosis have claimed a benefit from cannabis for both disease-related pain and spasticity, with support from small controlled trials (Croxford et el., J. Neuroimmunol, 2008, 193, 120-9; Svendsen, Br. Med. J. 2004, 329, 253). Likewise, various victims of spinal cord injuries, such as paraplegia, have reported that their painful spasms are alleviated after smoking marijuana. A report showing that cannabinoids appear to control spasticity and tremor in the CREAE model of multiple sclerosis demonstrated that these effects are mediated by CBi and CB2 receptors (Baker, Nature 2000, 404, 84-87). Phase 3 clinical trials have been undertaken in multiple sclerosis and spinal cord injury patients with a narrow ratio mixture of tetrahydrocannabinol/cannabidiol (THC/CBD). It has been reported that FAAH knockout mice consistently recover to a better clinical score than wild type controls, and this improvement is not a result of anti-inflammatory activity, but rather may reflect some neuroprotection or remyelination promoting effect of lack of the enzyme (Webb et al, Neυrosci Lett., 2008, vol. 439, 106-110).
Reports of small-scale controlled trials to investigate other potential commercial uses of cannabinoids have been made. Trials in volunteers have been reported to have confirmed that oral, injected, and smoked cannabinoids produced dose-related reductions in intraocular pressure (lOP) and therefore may relieve glaucoma symptoms. Ophthalmologists have prescribed cannabis for patients with glaucoma in whom other drugs have failed to adequately control intraocular pressure (Robson, 2001 , supra).
Inhibition of FAAH using a small-molecule inhibitor may be advantageous compared to treatment with a direct-acting CBi agonist. Administration of exogenous CBi agonists may produce a range of responses, including reduced nociception, catalepsy, hypothermia, and increased feeding behavior. These four in particular are termed the "cannabinoid tetrad." Experiments with FAAH -/- mice show reduced responses in tests of nociception, but did not show catalepsy, hypothermia, or increased feeding behavior (Cravatt, Proc. Natl. Acad. Sci. USA 2001 , 98(16), 9371 ). Fasting caused levels of AEA to increase in rat limbic forebrain, but not in other brain areas, providing evidence that stimulation of AEA biosynthesis may be anatomically regionalized to targeted CNS pathways (Kirkham, Br. J. Pharmacol. 2002, 136, 550). The finding that AEA increases are localized within the brain, rather than systemic, suggests that FAAH inhibition with a small molecule could enhance the actions of AEA and other fatty acid amides in tissue regions where synthesis and release of these signaling molecules is occurring in a given pathophysiological condition (Piomelli, 2003, supra).
In addition to the effects of a FAAH inhibitor on AEA and other endocannabinoids, inhibitors of FAAhTs catabolism of other lipid mediators may be used in treating certain other therapeutic indications. For example, PEA has demonstrated biological effects in animal models of inflammation (Holt, et al. Br. J. Pharmacol. 2005, 146, 467-476), immunosuppression, analgesia, and neuroprotection (Ueda, J. BIoI. Chem. 2001 , 276(38), 35552). Oleamide, another substrate of FAAH, induces sleep (Boger, Proc. Natl. Acad. Sci. USA 2000, 97(10), 5044; Mendelson, Nθuropsychopharmacology 2001 , 25, S36). Inhibition of FAAH has also been implicated in cognition (Varvel et al., J. Pharmacol. Exp. Ther. 2006, 317(1), 251-257) and depression (Gobbi et al., Proc. Natl. Acad. Sci. USA 2005, 102(51), 18620-18625).
Two additional indications for FAAH are supported by recent data indicating that FAAH substrate activated receptors are important in energy metabolism, and in bone homeostasis (Overton et al., Br. J. Pharmacol. 2008, in press; and Plutzky, Diab. Vase. Dis. Res. 2007, 4 Suppl3, S 12-4). It has been shown that the previously mentioned lipid signaling fatty acid amides catabolized by FAAH1 oleoylethanolamkje (OEA), is one of the most active agonists of the recently de-orphanised GPCR 119 (GPR119) (also termed glucose dependent insulinotropic receptor). This receptor is expressed predominantly in the pancreas in humans and activation improves glucose homeostasis via glucose- dependent insulin release in pancreatic beta-cells. GPR119 agonists can suppress glucose excursions when administered during oral glucose tolerance tests, and OEA has also been shown independently to regulate food intake and body weight gain when administered to rodents, indicating a probable benefit energy metabolism disorders, such as insulin resistance and diabetes. The FAAH substrate palmitoylethanolamide (PEA) is an agonist at the PPARα receptor. Evidence from surrogate markers in human studies with the PPARα agonist fenofibrate is supportive of the concept that PPARα agonism offers the potential for inducing a coordinated PPARα response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes. The FAAH substrate anandamkde (AEA) is an agonist at the PPARγ receptor. Anandamide treatment induces 3T3-L1 differentiation into adipocytes, as well as triglyceride droplet accumulation and expression of adiponectin (Bouaboula et al., E. J. Pharmacol. 2005, 517, 174- 181 ). Low dose cannabinokJ therapy has been shown to reduce atherosclerosis in mice, further suggesting a therapeutic benefit of FAAH inhibition in dyslipidemia, liver steatosis, steatohepatitis, obesity, and metabolic syndrome (Steffens et al., Nature, 2005, 434, 782-6).
Osteoporosis is one of the most common degenerative diseases. It is characterized by reduced bone mineral density (BMD) with an increased risk for bone fractures. CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion. A CBrselective agonism enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis and attenuates ovariβctomy-induced bone loss (Ofek et al., Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 696-701). There is a substantial genetic contribution to BMD, although the genetic factors involved in the pathogenesis of human osteoporosis are largely unknown. The applicability to human BMD is suggested by genetic studies in which a significant association of single polymorphisms and haplotypes was found encompassing the CNR2 gene on human chromosome 1 p36, demonstrating a role for the peripherally expressed CB2 receptor in the etiology of osteoporosis (Karsak et al., Hum. MoI. Genet, 2005, 14, 3389-96). Research also demonstrates a role in osteoarthritis.
Thus, small-molecule FAAH inhibitors should be useful in treating pain of various etiologies, anxiety, multiple sclerosis, Parkinson's disease and other movement disorders, nausea/emesis, eating disorders, epilepsy, glaucoma, inflammation, itch, immunosuppression, neuroprotection, depression, cognition enhancement, and sleep disorders, and potentially with fewer side effects than treatment with an exogenous cannabinokj. Certain amino-substituted pyrimidine compounds have been described in the literature. Certain 2,6-substituted-4-monosubstituted pyrimidines were disclosed as prostaglandin D2 receptor antagonists (PCT Pat. Appl. Publ. No. WO 2006/044732). Certain 2,4-Pyrimidinediamine compounds appear in U.S. Pat. Appl. Publ. No. US 2006/0058525. U.S. Pat. Appl. Publ. No. US 2003/0187026 describes certain heterocyclic compounds as kinase inhibitors. Certain arylalkyl heterocyclic compounds are shown as pharmaceutical agents in U.S. Pat. No. 6,881 ,740. Certain piperazinyl and piperidinyl ureas, heteroaryl piperazinyl ureas, and heteroaryl-substituted ureas were disclosed as inhibitors of FAAH in U.S. Pat. Appl. Publ. No. US 2006/0173184, U.S. Pat. Appl. Publ. No. US 2007/0004741, respectively. Certain α-keto-oxazole and oxazolyl piperidine compounds were disclosed as inhibitors of FAAH in PCT Pat. Appl. Publ. No. WO 2007/061862 and WO 2007/14005, respectively. Certain α -keto heterocyclic compounds were disclosed as inhibitors of FAAH in U.S. Patent Nos. 6,462,054 and 6,891 ,043, U.S. Pat. Appl. Publ. Nos. US 2005/0239785 and US 2006/0111359, and PCT Pat. Appl. Publ. No. WO 2004/033652. Certain oxadiazole ketone compounds were disclosed as inhibitors of FAAH in U.S. Pat. Appl. Publ. No. US 2006/0100212, and PCT Pat. Appl. Publ. No. WO 2006/044617. Certain oxazole ketone compounds were disclosed as inhibitors of FAAH in U.S. Pat. Appl. Publ. No. US 2007/0203156, and PCT Pat. Appl. Publ. No. WO 2007/098142, and references cited therein for all of the publications referenced in this paragraph. Still further, certain compounds were obtained from from a third party. The compounds are identified herein as Examples 223-245 and Comparative Examples 1-8.
Despite the progress that has been achieved, there remains a desire for potent FAAH modulators with suitable pharmaceutical properties.
Summary of the Invention
Certain aryl-hydroxyethylamino-pyrimidine and triazine derivatives are herein described, which have been found to have FAAH-modulating activity. The invention is directed to the general and preferred embodiments defined, respectively, by the independent and dependent claims appended hereto, which are incorporated by reference herein.
In one general aspect, the invention is directed to compounds of Formula (I-A):
R1
N^N
_-AAVvAA.tlJL. AArr11 (I-A)
R3 OH wherein:
R1 is -H, -C^alkyl, -OC^alkyl, -S(O)o-2Ci.»alkyl, -CF3, -CN1 -N(Ra)Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H , -Ci^alkyl optionally substituted with -OH, N(Rm)Rn, where Rm and Rn are -H, C1-4alky1; or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered tricyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
(i) one, two, or three Rc moieties, where each Rc moiety is independently -d^alkyl, -d^alkyl-OH, -Ci^alkyl- CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2. -OCH2CF3, -S(O)o.2Ci-»alkyl, -SCF3, -SO2CF3, -CHO1 -COC^alkyl, -CO2C1-»alkyl, -CO2H1 -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, -phenyl, pyridyl, or halo.where Rd and R* are each independently -H or -d^alkyl, or taken together Rd and Rβ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring; or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)i-3O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -C-Malkyl, -C1. 4alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2Ci^alkyl, -SCF3, -SO2CF3, -CHO, -COCi^alkyl, -CO2Ci. 4alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, or halo, where Rd and Rβ are each independently -H or -C^alkyl; X is N or C(Rf), where Rf is -H or methyl; Ar2 Is: (i) a phenyl group substituted with: (a) one, two, or three R0 moieties each at a meta or para position, and optionally with one or two additional R° moieties at an ortho position; where each R° moiety is independently -Ci^alkyl, -C-Mβlkyl-OH, -Ci^alkyl-
CN, perhaloalkyl, perhaloalkoxy, -OC^alkyl, -OC1^alkyl-(monocyclic cycloalkyl). -S(O)o.2Ci^alkyl. -SCF3, -SO2CF3, -CHO. -COC1^alkyl, -CO2Ci-»alkyl, -CO2H, -N(Rh)R', -SO2NRiRk, -NRhSO2R', -C(O)NRjRk, -NO2, -CN, or halo; or a phenoxy, benzyl, p hen ethyl, or benzoyl group unsubstituted or substituted with -d^alkyl, -OC1^alkyl, perhaloalkyl, perhaloalkoxy, -NO2, -CN, or halo; where Rh is -H or -C^alkyl;
R1 is -C-Malkyl or monoyclic cycloalkyl group; or Rh and R* taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R1 is -H or -Ci^alkyl; and Rk is -H, -C^alkyl or monoyclic cycloalkyl group; or R1 and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or (b) two adjacent R° moieties together form -O(CH2)i-2O- unsubstituted or substituted with one or two fluoro groups;
(ii) a monocyclic heteroaryl group substituted with: one, two, or three R0 moieties, where each R° moiety is independently or two adjacent R° moieties together form -O(CH2)i-2O- unsubstituted or substituted with one or two fluoro groups; or
(iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties, where each R1 moiety is independently -Chalky], -OCi^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo;
R2 is -H or methyl; and R3 is -H or methyl; provided, however, that Ar2 is not -CHO or para substituted -OCFa when Ar1 is unsubstituted phenyl; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
In another general aspect, the invention is directed to compounds of Formula (I-B):
R1
N^N
A^ .ϊΛ^AXΛA^.N.^λY.^Ar11 (I-B)
R3 OH wherein:
R1 is -d^alkyl, -OC1-4alky1, -S^^C^alkyl, -CN, -CF3, -N(Ra)Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H, -Chalkyl optionally substituted with -OH, N(Rm)Rπ, where Rm and Rn are -H, C^alkyl; or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
(i) one, two, or three Rc moieties, where each Rc moiety is independently -d^alkyl, -Ci^alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OCi-»alkyl, -OCF3, -OCHF2. -OCH2CF3, -S(O)o.2C1^alkyl, -SCF3, -SO2CF3, -CHO, -COC^alkyl, -CO∑C^alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, phenyl, pyridyl, or halo, where Rd and Rβ are each independently -H or -d^alkyl, or taken together Rd and Rβ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring; or (ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)i^O- un substituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -d^alkyl, -C1- 4alkyl-OH, -Ci-»alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -SfOXwC1-4βlkyl, -SCF3, -SO2CF3, -CHO1 -COC^alkyl, -CO2Ci. 4alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN1 or halo, where Rd and Rβ are each independently -H or -d^alkyi;
X is N or C(Rf), where Rf is -H or methyl; Ar2 Is:
(i) a phenyl group substituted with: (a) one, two, or three R8 moieties each at a meta or para position, and optionally with one or two additional R° moieties at an ortho position; where each R0 moiety is independently -Chalkyl, -Ci^alkyl-OH, -Ci^alkyl- CN, peitialoalkyl, perhaloalkoxy , -OC^alkyl, -OCi^alkyl-(monocyclic cycloalkyl), -S(O)o.2Ci^alkyl, -SCF3, -SO2CF3, -CHO, -COC1-4alky1, -CO2Ci-*alkyl, -CO2H, -N(Rh)R', -SO2NRiRk, -NRhSO2R', -C(O)NRiRk, -NO2, -CN, or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -C^alkyl, -OC^alkyl, pertialoalkyl, perhaloalkoxy , -NO2, -CN1 or halo; where Rh is -H or -Chalkyl; R1 is -C1^alkyl or monoyclic cycloalkyl group; or Rh and R1 taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R1 is -H or -C^alkyl; and Rk is -H1 -C-Malkyl or monoyclic cycloalkyl group; or R1 and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or
(b) two adjacent R° moieties together form -O(CH2)i-2O- unsubstituted or substituted with one or two fluoro groups;
(ii) a monocyclic heteroaryl group substituted with one, two, or three Rg moieties, where each R° moiety is independently or two adjacent R° moieties together form -O(CH2)i-2O- unsubstituted or substituted with one or two fluoro groups; or (Hi) a naphthyl or tricyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties, where each R1 moiety is independently -C-Malkyl, -OC-Malkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo; R2 is -H or methyl; 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 is directed to compounds of Formula (I-C):
R"
Figure imgf000012_0001
wherein:
R1 is -H, -Chalkyl, -OCi-»alkyl, -S(O)o-2Ci^alkyl, -CN, -CF3, -N(R')Rb, or a monocyclic cycloalkyl group, where R" and Rb are each independently -H1 -C-Malkyl optionally substituted with -OH, N(Rm)Rn, where Rm and Rπ are -H1 C1-4alkyl; or taken together with the nitrogen of attachment R" and Rb form a 4-7 membered heterocycloalkyl;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with; (i) one, two, or three Rc moieties, where each Rc moiety is independently -Ci-4alkyl, -Ci-4alkyl-OH, -d^alkyl-CN, -CF3, -OH, -OC1-4alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o-2C1-4alkyl,
-SCF3, -SO2CF3, -CHO, -COC^alkyl, -CO2C1-4alkyl, -CO2H, -N(Rd)Re, -SO2NRdRe, -NRdSO2Re, -C(O)NRdRe, -NO2, -CN, phenyl, pyridyl, or halo, where Rd and Re are each independently -H or -Ci^alkyl, or taken together
Rd and Re with the nitrogen of attachment form a 4-7 membered heterocycloalkyl; or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)i-3O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -Ci^alkyl, -Ci- 4alkyl-OH, -C1-4alkyl-CN, -CF3, -OH, -OC1-4alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o-2C1-4alkyl, -SCF3, -SO2CF3, -CHO, -COC1-4alkyl, -CO2C1..
4alkyl, -CO2H, -N(Rd)Re, -SO2NRdRe, -NRdSO2Re, -C(O)NRdRe, -NO2, -CN, or halo, where Rd and Re are each independently -H or -Ci-4alkyl; X is N or C(Rf), where Rf is -H or methyl;
RXl Ry, and Rz are each independently a) - c): a) Rx and R2 are each -H, and Ry is -NO2, -C2-3alkyl, -OC2-4alkyl, or phenoxy; b) Rx and R2 are each -H, Ry is -OCF3, and Ar1 is a substituted phenyl group or an unsubstituted or substituted pyridyl group; or c) one of Rx, Ry, and R7 is -Cl, -F, or -CF3, and the other two are: (i) independently -H or an R9 moiety, provided that when Ry is -H then Rx and Rz are not -CF3; where each R9 moiety is -C1-4alkyl, -C-ι-4alkyl-OH, -C1-4alkyl-CN, perhaloalkyl, perhaloalkoxy , -OCi-4alkyl, -OC1-4alkyl-(monocyclic cycloalkyl), -S(O)0- 2Ci-4alkyl, -SCF3, -SO2CF3, -CHO, -COCi-4alkyl, -CO2Ci-4alkyl, -CO2H,
-N(R11JR1, -SO2NRjRk, -NR^1SO2R1, -C(O)NRjRk, -NO2, -CN, or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -Ci^alkyl, -OC1-4alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN1 or halo; where Rh is -H or-Ci^alkyl; R* is -C1-4alkyl or monoyclic cycloalkyl group; or Rh and R* taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R1 is -H or-Ci-4alky1; and Rk is -H, -Ci^alkyi or monoyclic cycloalkyl group; or R1 and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or
(ii) two adjacent R° moieties that together form -O(CH2)L2O- unsubstituted or substituted with one or two fluoro groups; or (iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R* moieties; where each R1 moiety is independently -Chalkyl, -OC1^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN1 or halo; R2 is -H or methyl; and R3 is -H or methyl; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.
In especially preferred embodiments, the invention is directed to compounds described or exemplified in the detailed description below and their pharmaceutically acceptable salts.
In a further general aspect, the invention relates to pharmaceutical compositions each comprising: (a) an effective amount of at least one agent selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of Formula (I):
R1
N^-N
,,..AAAA-.JO A*r11 (l)
R3 OH wherein: R1 is -H, -C^alkyl, -OC^alkyl, -S(O)o.2Ci.4alkyl, -CN1 -CF3, -N(Ra)Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H, -Ci^alkyl optionally substituted with -OH, N(Rm)Rn, where Rm and Rn are -H, Ci^alkyl; or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
(i) one, two, or three Rc moieties, where each Rc moiety is independently -C1^alkyl, -C^alkyl-OH, -d^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2C1-*alkyl, -SCF3, -SO2CF3, -CHO, -COC^alkyl, -CO2C^alkyl, -CO2H, -N(Rd)R", -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, phenyl, pyridyl, or halo, where Rd and R* are each independently -H or -C-Malkyl, or taken together Rd and R* with the nitrogen of attachment form a 4-7 membered heterocycloalkyl group; or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)^O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -C^alkyl, -Ci. 4alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -SfO)o^C^alkyl, -SCF3, -SO2CF3, -CHO, -COCi-»alkyl, -CO2Ci. 4alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, or halo, where Rd and Rβ are each independently -H or -C^alkyi; X is N or C(Rf), where Rf is -H or methyl; Ar2 Js: (i) a phenyl group substituted with: (a) one, two, or three R° moieties each at a meta or para position, and optionally with one or two additional R° moieties at an ortho position; where each Rg moiety is independently -Ci^alkyl, -Ci^alkyl-OH, -C^alkyl- CN1 perhaloalkyl, perhaloalkoxy , -OC1^alkyl, -OCi^alkyl-(monocyclic cycloalkyl), -S(O)04Ci^aIkyI1 -SCF3, -SO2CF3, -CHO, -COC1^alkyl, -CO2Ci^alkyl. -CO2H, -N(Rh)R', -SO2NR1^1 -NR11SO2R1, -C(O)NRjRk, -NO2, -CN1 or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -d^alkyl, -OCi^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo; where Rh is -H or-Ci^alkyl; R* is -C^alkyl or monoyclic cycloalkyl group; or Rh and R* taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R1 is -H or -C1-4alkyl; and Rk is -H1 -C^alkyl or monoyclic cycloalkyl group; or R1 and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or
(b) two adjacent R0 moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups;
(ii) a monocyclic heteroaryl group substituted with one, two, or three R° moieties, where each R8 moiety is independently or two adjacent R0 moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups; or
(iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties, where each R1 moiety is independently -Chalkyl, -OCi^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo;
R2 is -H or methyl; and R3 is -H or methyl; and (b) a pharmaceutically acceptable excipient.
In another general aspect, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by FAAH activity, comprising administering to the subject in need of such treatment an effective amount of at least one agent selected from compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically active prodrugs, and pharmaceutically active metabolites. In preferred embodiments of the inventive method, the disease, disorder, or medical condition is selected from: anxiety, depression, pain, sleep disorders, eating disorders, inflammation, multiple sclerosis and other movement disorders, HIV wasting syndrome, closed head injury, stroke, learning and memory disorders, Alzheimer's disease, epilepsy, Tourette's syndrome, Niemann-Pick disease, Parkinson's disease, Huntington's chorea, optic neuritis, autoimmune uveitis, symptoms of drug or alcohol withdrawal, nausea, emesis, sexual dysfunction, post-traumatic stress disorder, cerebral vasospasm, glaucoma, irritable bowel syndrome, inflammatory bowel disease, immunosuppression, itch, gastroesophageal reflux disease, paralytic ileus, secretory diarrhea, gastric ulcer, rheumatoid arthritis, unwanted pregnancy, hypertension, cancer, hepatitis, allergic airway disease, auto-immune diabetes, intractable pruritis, neuroinflammation, diabetes, metabolic syndrome, and osteoporosis. Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.
Detailed Description of Invention and Its Preferred Embodiments The invention may be more fully appreciated by reference to the following detailed description, including the following glossary of terms and the concluding examples. For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.
As used herein, the terms "including", "containing" and "comprising" are used in their open, non-limiting sense. The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by / symbol), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and so on. The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties: >. D. o. O. . . o. .0.
Figure imgf000018_0001
CO. CO.00. CO. CO. <J
Figure imgf000018_0002
and
Figure imgf000018_0004
Figure imgf000018_0003
A "heterocycloalkyl" refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative examples of heterocycloalkyl groups include the following entities, in the form of properly bonded moieties:
H H fco. d1 H . r L?i . VJ. Λ VJ ■ W. H ^N-NH. ό ^-S . ό ^- N . ό \— N> . O ^NH . ^NH .
O
X
(S) O HN^O
^NR . ^NH . ^NR ' VJ . VJ . HN V1-/NH . AVJ H . AVJ . <A vu .
H CL J) O. X) H H H H C . . . Cr . . . .
Figure imgf000018_0005
Th e term ".he teroa ryl" refers to. a monOocycl.ic, fused or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of property bonded moieties:
ύ.ύ. ύ. .ύ. . ύ. .ύ. r
Figure imgf000019_0001
The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.
The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
The terms "para", "meta", and "ortho" have the meanings as understood in the art. Thus, for example, a fully substituted phenyl group has substituents at both "ortho"(o) positions adjacent to the point of attachment of the phenyl ring, both "meta" (m) positions, and the one "para" (p) position across from the point of attachment as illustrated below.
Figure imgf000019_0002
In one general embodiment, the invention relates to compounds that are encompassed by Formulae (I-A), (I-B), and (I-C) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds. In another general embodiment, the invention relates to pharmaceutical compositions each comprising a therapeutically effective amount of a FAAH-modulating agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds.Compounds encompassed by Formulae (I), (I-A), (1-B)1 and (I-C) having asymmetric or chiral centers may exist in different enantiomeric forms. All stereoisomers of the compounds of the general formula and racemates or mixtures of various combinations thereof, are intended to be represented by the formula. Thus, except where a stereocenter is shown as having a specific stereoisomeric form, a general formula shown herein is intended to represent all racemates, enantiomerically pure forms, diastereomeric forms, atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers, which are intended to be encompassed by a structural formula. Additionally, a formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof. A structural formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C1 14C, 15N, 18O, 17O, 32P, 33P, 35S, 18F, 38CI, and 125I, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with 14C)1 reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F- or 11C-labeled compound may be preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words, where a formula variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula.
In preferred embodiments of Formula (I), (I-A) or (1-C)1 R1 is -H, methyl, isopropyl, trifluoromethyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl. In still other embodiments of Formula (I)1 (I-A) or (I-C), R1 is amino. In still other embodiments of Formula (I), (I-A) or (I-C), R1 is -H. In preferred embodiments of Formula (I-B), R1 is methyl, isopropyl, trifluoromethyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl. In still other embodiments of Formula (I-B), R1 is amino.
In preferred embodiments of Formula (I)1 (I-A), (I-B) or (I-C), Ar1 is a phenyl group, each unsubstituted or substituted with one, two, or three Rc moieties. In preferred embodiments of Formula (I), (I-A), (I-B), or (I-C), each Rc moiety is independently fluoro, chloro, nitro, trifluoromethyl, methoxy, hydroxy, or trifluoromethoxy, or two adjacent Rc moieties together form -O(CH2)i-2O- or -O(CF2)O-. In some embodiments of Formula (I), (I-A), (I-B), or (I-C), Ar1 is phenyl, 4-fluorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4- hydroxyphenyl, 4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3,4- dichlorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 2-methoxy phenyl, 3,5-dichlorophenyl, 3-trifluoromethoxyphenyl, 3-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3- trifluoromethylphenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1 ,3-benzodioxolyl, or 2,2- difluoro-1,3-benzodk>xolyl. In still other embodiments of Formula (I), (I-A), (I-B), or (I-C), Ar1 is unsubstituted phenyl, 4-fluorophenyl, or 4-trifluoromethoxyphenyi. In preferred embodiments of Formula (I), (I-A), (I-B), or (I-C), X is C(Rf). In further preferred embodiments of Formula (I), (I-A), (I-B), or (I-C), Rf is -H. In preferred embodiments of Formula (I)1 (I-A) or (I-B), Ar2 is a phenyl substituted at either or both of the meta and para positions with one, two or three R0 moieties. In some embodiments of Formula (I), (i-A) or (I-B), Ar2 is a thiophenyl, pyridinyl, pyrimidinyl, or pyrazolyl group, each substituted with one, two, or three Rs moieties. In some embodiments of Formula (I), (I-A) or (I-B), each R° moiety is independently methyl, ethyl, i so propyl, tert- butyl, hydroxymethyl, 1-hydroxyethyl, cyanomethyl, cyano-dimethy1-methyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, cyclopropylmethoxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, methylsulfonyl, formyl, acetyl, dimethylamino, morpholin-4-yl, sulfamoyl, dimethylsulfamoyl, cyclopropylsulfamoyl, piperidine-1-sulfonyl, pyrrolidine-1-sulfonyl, nitro, cyano, ... chloro, fluoro, iodo, phenoxy, benzyl, benzoyl, or phenethyl, or two adjacent R° moieties together form -O(CH2)i-2O- or -O(CF2)O-. In further preferred embodiments of Formula (I), (I-A) or (I-B), Ar2 is 3,4-dimethylphenyl, 4-tert- butylphenyl, 4-cyanophenyl, 4-acetylphenyl, 4-methylphenyl, 4-chlorophenyl, 4- fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 3- methylphenyl, 3-trifluoromethoxyphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3,4- dichlorophenyl, 3-chlorophenyl, 3-chloro-4-trifluoromethylphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-phenoxy-phenyl, 3-chloro-4-ethoxyphenyl, 3-chloro-4- isopropoxyphenyl, 3-fluoro-4-methylphenyl, 4-hydroxymethylphenyl, 4- formylphenyl, 3-formylphenyl, 4-trifluoroethoxyphenyl, 3-trif)uoroethoxyphenyl, 4- chloro-3-methylphenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-trifluoromethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 4-ethoxy-3-fluorophenyl, 4-ethoxy-3- methylphenyl, 4-cyclopropylmethoxyphenyl, 4-butoxy-3-fluoro phenyl, 4- butoxyphenyl, 3-fluoro-4-propoxyphenyl, 3-fluoro-4-isopropoxyphenyl, 4- isobutoxyphenyl, 4-methoxy-3-methylphenyl, 3-chloro-4-methylphenyl, 3,5- dimethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 3-chloro-5-fluorophenyl, 4-propoxyphenyl, 4-isopropoxy-3-methyl phenyl, 4- difluoromethoxy-3,5-difluorophenyl, 4-{cyano-dimethy1-methyl)phenyl, 4-acetyl-3- fluorophenyl, 3,5-dimethyl-4-isopropoxyphenyl, 3,4,5-trifluorophenyl, 4- benzoyl phenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 4-dimethylaminophenyl, 4- methylsulfonylphenyl, 4-cyclopropylsulfamoylphenyl, 3-fluoro-4-methoxyphenyl, 1,4-benzodioxin-6-y1, 4-dimethytsulfamoylphenyt, 4-piperidine-1-sulfonyiphenyl, 4- pyrrolidine-1-sulfonylphenyl, 3-chloro-4-fluoiOphenyl, 4-methylsulfanyiphenyl, 4- cyano-3-fluorophenyl, 3-cyano-4-fluoro phenyl, 4-isopropylsulfanylphenyl, 4- cyanomethylphenyl, 4-ethylsulfanylphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 3- butoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-(2-o-tolyl- ethyl)phenyl, 3-fluoro-4-(1-hydroxy-ethyl)phenyl, 4-iodophenyl, 4-ethoxy-3- trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl, 2,4- bis(trifluoromethyl)phenyl, 2-methoxy-4-(trifluoromethoxy)phenyl, 4-ethoxy-2- methylphenyl, 2,2-difluoro-i ,3-benzodk)xol-5-yl, 1 ,3-benzodioxol-5-yl, 5-acetyl- thiophen-2-yl, β-methoxypyridin-3-yl, 6-ethoxypyridin-3-yl, 6-morpholin-4-ylpyridin- 3-yl, 6-fluoro-5-methyl-pyridin-3-yl, 6-cyanopyridin-3-yl, 6-(dimethylamino)pyridine- 3-yl, 2-morpholin-4-ylpyrimidin-5-yl, or i-benzyl-1H-pyrazol-4-yl.
In other preferred embodiments of Formula (I), (I-A) or (I-B), Ar2 is a naphthyl, benzoxadiazolyl, indolyl, benzothiophenyl, quinolinyl, or indazolyl, each unsubstituted or substituted with one, two, or three R1 moieties. In some embodiments of Formula (I), (I-A) or (I-B), each R1 moiety is independently methyl. In further preferred embodiments of Formula (I), (I-A) or (I-B), Ar2 is naphthyl, 2,1 ,3-benzoxadiazol-5-yl, 1 H-indol-5-yl, 1 H-indol-6-yl, 1-methyl-1H-indol-2-yl, 1- methyl-1H-indol-5-yl, 5-methyl-1-benzothk}phen-2-yl, benzothiophen-3-yl, benzothiophen-5-yl, quinolin-3-yl, or 3-methyl-1 H-indazol-6-yl.
In preferred embodiments of Formula (I-C), Rx is -Cl or -F, Rz is -H, and Ry is -H or R0. In further preferred embodiments of Formula (I-C), Rx is -Cl or -F, Rz is -H, and Ry is -d^alkyl, -CF3, -OCi^alkyl, -OCF3, or halo. In other embodiments of Formula (I-C), Ar2 is 4-nitrophenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-ethoxyphenyl, 4-pro poxy phenyl, 4-isopropxy phenyl, 4- butoxyphenyl, 4-isobutoxyphenyl, or 4-phenoxyphenyl. In other embodiments of Formula (I-C), Ar2 is 4-trifluoromethoxyphenyl. In other embodiments of Formula (I-C), Ar2 is 4-chlorophenyl, 4-fluorophenyl, 4-trifluorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-chloro-4-trifluoromethylphenyl, 3-chloro-4-ethoxy phenyl, 3- chloro-4-isopropoxyphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3-methylphenyl, 4- chloro-3-trifluoiOmethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 4-butoxy-3- fluorophenyl, 3-fluoro-4-propoxyphenyl, 3-fluoro-4-isopropoxyphenyl, 3-chloro-4- methylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 3- chloro-5-fluorophenyl, 4-acetyl-3-fluorophenyl, 3,4,5-trifluorophenyl, 3,5- difluorophenyl, 3,4-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4- fluorophenyl, 4-cya no-3-fluo raphe nyl, 3-cyano-4-fluorophenyl, 3- trifl uo ro methyl phenyl, 3-fluoro-4-{1-hydroxy-ethyl)phenyl, or 4-ethoxy-3- trifluoromethylphenyi.
In preferred embodiments of Formula (I), (I-A), (1-B)1 or (1-C)1 R2 is -H. In preferred embodiments of Formula (I), (I-A), (I-B), or (I-C), R3 is -H. In certain embodiments of Formula (I)1 (I-A), (I-B), or (I-C), Rs and/or R1 is perhaloalkyl or perhaloalkoxy. The term "perhaloalkyT refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain optionally substituting hydrogens with halogens. Examples of perhaloalkyl groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCFa), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (-CF(CFa)2), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. The term "perhaloalkoxy" refers to a straight- or branched-chain alkoxy group having from 1 to 4 carbon atoms in the chain optionally substituting hydrogens with halogens. Examples of perhaloalkoxy groups include trifluoromethoxy (OCF3), difluoromethoxy (OCF2H), monofluoromethoxy (OCH2F), pentafluoroethoxy (OCF2CF3), tetrafluoroethoxy (OCHFCF3), trifluoroethoxy (OCH2CF3), tetrafluorotrifluoromethylethoxy (- OCF(CFs)2), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. In preferred embodiments of Formulae (I), (I-B) or (I-C), the secondary hydroxyl group adjacent to Ar1 is in the configuration as shown below:
/γAr1 OH .
Further preferred embodiments of Formulae (I), (I-A), (I-B), or (I-C) encompass combinations of two or more of the preferred embodiments for each of R1-3, X, Ar1 , Ar2, R*1, and Rx z listed above.
The invention also relates to pharmaceutically acceptable salts of the free acids or bases represented by Formulae (I), (I-A), (I-B), or (I-C), preferably of the preferred embodiments described above and of the specific compounds exemplified herein. A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by Formulae (I), (I-A), (1-B)1 or (I-C) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. ScL1 1977, 66:1-19, and Handbook of Pharmaceutical SaHs, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formulae (I), (I-A), (I-B), or (I-C) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts: include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hyϋroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phθnylbutyratθs, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene- 2-sulfonates, and mandelates.
If a compound of Formulae (I), (I-A), (I-B), or (I-C) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic add, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like; or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid; a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid; or any compatible mixture of acids such as those given as examples herein.
If a compound of Formulae (I), (I-A), (I-B), or (I-C) is an acid such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, or any compatible mixture of bases such as those given as examples herein. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formulae (I), (I-A), (I-B), or (I-C). The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formulae (I), (I-A), (I-B), or (I-C)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Examples of prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formulae (I), (I-A), (I-B), or (I- C). Examples of amino acid residues include the twenty naturally occurring amino adds, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone.
Additional types of prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formulae (I), (I-A), (I-B), or (I-C) as amides or alkyl esters. Examples of amides include those derived from ammonia, primary C1^alkyl amines and secondary di(Ci^alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that are derived from ammonia, C1^alkyl primary amines, and di(C1-2alkyl)amines. Examples of esters of the invention include Cwalkyl, Cs- 7cycloalkyl, phenyl, and phenyl(Ci^alkyl) esters. Preferred esters include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs. Prodrugs of this type may be prepared as described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamkJes. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities. The present invention also relates to pharmaceutically active metabolites of compounds of Formulae (I), (I-A), (I-B), or (I-C). A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formulae (I), (I-A), (I-B), or (I-C) or a salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.1997, 86 (J), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 224-331 ; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
The compounds of Formulae (I), (I-A), (I-B), and (I-C), and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites (collectively, "active agents") of the present invention are useful as FAAH inhibitors in the methods of the invention. The active agents may be used in the inventive methods for the treatment of medical conditions, diseases, or disorders mediated through inhibition or modulation of FAAH, such as those described herein. Active agents according to the invention may therefore be used as an analgesic, anti-depressant, cognition enhancer, neuroprotectant, sedative, appetite stimulant, or contraceptive.
Exemplary medical conditions, diseases, and disorders mediated by FAAH activity include anxiety, depression, pain, sleep disorders, eating disorders, inflammation, multiple sclerosis and other movement disorders, HIV wasting syndrome, closed head injury, stroke, learning and memory disorders,
Alzheimer's disease, epilepsy, Tourette's syndrome, epilepsy, Niemann-Pick disease, Parkinson's disease, Huntington's chorea, optic neuritis, autoimmune uveitis, symptoms of drug or alcohol withdrawal, nausea, emesis, sexual dysfunction, post-traumatic stress disorder, cerebral vasospasm, diabetes, metabolic syndrome, osteoarthritis and osteoporosis.
Thus, the active agents may be used to treat subjects diagnosed with or suffering from such a disease, disorder, or condition. The term "treat" or "treating" as used herein is intended to refer to administration of an agent or composition of the invention to a subject for the purpose of effecting a therapeutic benefit through modulation of FAAH activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, reducing the incidence of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of FAAH activity. The term "subject" refers to a mammalian patient in need of such treatment, such as a human. "Modulators" include both inhibitors and activators, where "inhibitors" refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate FAAH expression or activity, and "activators" are compounds that increase, activate, facilitate, sensitize, or up- regulate FAAH expression or activity.
Accordingly, the invention relates to methods of using the active agents described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through FAAH activity, such as: anxiety, pain, sleep disorders, eating disorders, inflammation, movement disorders (e.g., multiple sclerosis), glucose and lipid metabolism (e.g. diabetes) and bone homeostasis (e.g. osteoporosis).
Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases." For example, pain may be associated with various diseases, disorders, or conditions, and may include various etiologies. Illustrative types of pain treatable with a FAAH-modulating agent, in one example herein a FAAH-inhibiting agent, according to the invention include cancer pain, postoperative pain, Gl tract pain, spinal cord injury pain, visceral hyperalgesia, thalamic pain, headache (including stress headache and migraine), low back pain, neck pain, musculoskeletal pain, peripheral neuropathic pain, central neuropathic pain, neurogenerative disorder related pain, and menstrual pain. HIV wasting syndrome includes associated symptoms such as appetite loss and nausea. Parkinson's disease includes, for example, levodopa- induced dyskinesia. Treatment of multiple sclerosis may include treatment of symptoms such as spasticity, neurogenic pain, central pain, or bladder dysfunction. Symptoms of drug withdrawal may be caused by, for example, addiction to opiates or nicotine. Nausea or emesis may be due to chemotherapy, postoperative, or opioid related causes. Treatment of sexual dysfunction may include improving libido or delaying ejaculation. Treatment of cancer may include treatment of glioma. Sleep disorders include, for example, sleep apnea, insomnia, and disorders calling for treatment with an agent having a sedative or narcotic-type effect. Eating disorders include, for example, anorexia or appetite loss associated with a disease such as cancer or HIV infection/AIDS. In treatment methods according to the invention, an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. A "therapeutically effective amount" or "effective amount" means an amount or dose of a FAAH-modulating agent sufficient to generally bring about a desired therapeutic benefit in patients in need of treatment for a disease, disorder, or condition mediated by FAAH activity. Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day. Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
In addition, the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with an active agent of Formulae (I), (I-A), (I-B), and (I-C) or included with such an agent in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by FAAH activity, such as another FAAH modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention. In one illustrative embodiment, a composition according to the invention may contain one or more additional active ingredients selected from opioids, NSAIDs (e.g., ibuprofen, cyclooxygenase-2 (COX-2) inhibitors, and naproxen), gabapentin, pregabalin, tramadol, acetaminophen, and aspirin. The active agents of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, earner, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration. For oral administration, the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be formulated to yield a dosage of, e.g., from about 5 mg to 5 g daily, or from about 50 mg to 5 g daily, in single or divided doses. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP)1 sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
The active agents of this invention may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery. Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
Exemplary active agents useful in methods of the invention will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formulae (I), (I-A), (I-B), and (I-C). For clarity, since compounds of Formulae (I- A), (1-B)1 and (I-C) are embodiments of compounds of Formula (I), compounds of Formulae (I-A), (I-B), and (I-C) are depicted in the following schemes collectively as compounds of Formula (I).
Figure imgf000034_0001
Referring to Scheme A, compounds of Formulae (I), (I-A), (I-B), and (I-C) are prepared from pyrimidines or triazines (II), where Z is halo or another suitable substituent. Various substituted pyrimidines and triazines are commercially available or are prepared using known methods. Pyrimidines of formula (III) are obtained via palladium-mediated cross-coupling of reagents (II) with suitable boronic acids. Preferably, pyrimidines of formula (II) are treated with the desired boronic acid in the presence of a base such as K3PO4 or KF, in a suitable polar solvent such as CH3CN, 1 ,2-dimethoxyethane (DME)1 tetrahydrofuran (THF), water, or a mixture thereof, at a temperature from about 50 °C to about 180 °C using conventional heating or a microwave reactor. Pyrimidines (III) are converted to compounds of Formulae (I-A), (I-B), and (I-C) via nucleophilic aromatic substitution (SNAΓ) with aryl-substituted amino alcohols in the presence of a suitable base such as NaHCO3, (JPr)2EtN1 Et3N, or a mixture thereof, either neat or in a solvent such as 1 ,4-dioxane, THF, t-amyl alcohol, n-BuOH, or a mixture thereof, at a temperature from about 80 °C to about 150 °C. Alternatively, pyrimidines or triazines of Formulae (I-A), (I-B), and (I-C) are obtained by SNAT displacement of compounds (II) with amino alcohols, followed by palladium- mediated cross-coupling using known procedures. Compounds of Formulae (I)1 (1-A)1 (1-B)1 and (I-C) are additionally prepared in a one-pot fashion by nucleophilic aromatic substitution (Sr4Ar) displacement of compounds (II) with amino alcohols in the presence of a suitable base such as NaHCO3, in a suitable polar solvent such as CH3CN at a temperature from about 50 °C to about 180 °C; followed by a palladium-mediated cross-coupling reaction with a suitable boronic acid in the presence of a base such as K3PO4, and palladium-mediated cross-coupling reagents such as Pd(dppf)Cl2* CH2CI2 and Pd(OAc)2 at a temperature from about 50 °C to about 180 °C.
Figure imgf000035_0001
Referring to Scheme B, thioethers (V), obtained as described in Scheme A, are oxidized using generally known methods to provide sulfones (Vl). Those skilled in the art will recognize that compounds (V) and (Vl) are embodiments of Formulae (I), (I-A), (I-B), and (I-C). To prepare further embodiments of Formulae (I), (I-A), (I-B), and (I-C), the sulfone substituent is displaced by reaction with a suitable amine or alcohol in a solvent such as MeOH, EtOH1 n-BuOH, t-amyl alcohol, THF, N,N-dimethylformamide (DMF)1 dimethylsulfoxide (DMSO), toluene, or a mixture thereof, with or without the presence of a base such as NaOMe, NaOEt, KOtBu1 Et3N, (1'Pr)2EtN, pyridine, or a mixture thereof, at a temperature from about room temperature to the reflux temperature of the solvent. Preferably, displacement with a suitable amine is performed by heating a sulfone (Vl) in t- amyl alcohol at 130 °C in a sealed tube.
Figure imgf000036_0001
Referring to Scheme C, compounds of Formulae (I), (1-A)1 (I-B), and (I-C), where X is C(Rf), are prepared from β-ketoesters (VII), which are commercially available or are prepared according to general techniques known in the art. β- Ketoesters (VII) are reacted with amidines or carboximidamides (XII) or with ureas or thioureas (XIII) where Y is O, S, or NR", for example, in the presence of a base : such as NaOEt or KOtBu1 in a solvent such as EtOH1 t-BuOH, or a mixture thereof, at a temperatures between about room temperature and the the reflux temperature of the solvent, to form hydroxy-pyrimidines (VIII). Hydroxy- pyrimidines (VIII) are then activated for use in the SNAΓ displacement by general procedures known in the art. For example, treatment with POCb, PBr3, or POBr3 affords the corresponding halopyrimidines (IX) where Z2 is a chloride or bromide. Alternatively, treatment of hydroxy-pyrimidines (VIII) with trifluoromethane-sulfonic anhydride or N-phenyl-bis(trifluoromethanesulfonimide) in 1 ,2-dichloroethane, CH2CI2, THF, or a mixture thereof, in the presence of a base such as pyridine, Et3N1 (JPr)2EtN, KOtBu1 or a mixture thereof, provides triflates where Z2 is -OSO2CF3. Preferably, hydroxy-pyrimidines (VIM) are treated with POCI3 in CH3CN at a temperature from about 80 °C to about 100 °C. Chloropyrimidines (IX) are processed to compounds of Formulae (I-A), (I-B), and (I-C) via Sn-aryl • displacement as described in Scheme A.
Figure imgf000036_0002
Racemic or enantio-enriched amino-alcohols (X) are commercially available or are prepared using generally known procedures. For example, in certain embodiments, amino-alcohols (X), where R2 and R3 are both -H, are prepared as shown in Scheme D. To form racemic amino-alcohols, aldehydes (Xl) are treated with trimethylsilylcyanide (TMSCN) in the presence of a catalyst such as Znl2, neat or in a solvent such as diethyl ether (Et2O), THF1 1 ,4-dioxane, or a mixture thereof, to provide cyanohydrins (XII). To form enantio-enriched amino-alcohols (X), reactions are are run in the presence of a chiral ligand, such as S-(-)-1 ,1'-bi-2-naphthol. Preferably, the resulting cyanohydrin is formed as the trimethylsilyl ether. Reduction of the nitrile using known general procedures, such as LiAIH4, or a borane complex (such as borane complexed with THF (BH3-THF), dimethylsulfide (BH3OMS)1 or N-ethyl-N-isopropylaniline (BACH-EI)), in solvent such as THF or Et2O, provides amino-alcohols (X). Where a trimethylsilyl ether was formed, it is deprotected using standard acidic or basic conditions to give racemic or enantio-enriched amino-alcohols (X). Where racemic and non- racemic mixtures of enantiomers are obtainied, single enantiomers may be isolated using known methods, such as chiral chromatography and recrystallization.
Alternatively, amino-alcohols (X) are accessed through the addition of azldθ anion to a suitable α-haloketone and subsequent reduction of the azido group and the ketone. In another embodiment, reduction of a suitable α- haloketone to the corresponding halohydrin and displacement with ammonia, methylamine, or dimethylamine, provides amino-alcohols (X).
Enantio-enriched amino-alcohols (X) are accessed through other stereoselective syntheses or chiral separation methods. For example, the reduction shown in Scheme D is optionally performed with a borane complex in the presence of a chiral catalyst such as (R)-2-methyl-CBS-oxazaborolidine (CBS) to generate chiral product. Stereoselective reductions of α-haloketones, α- azidoketones, or α-aminoketones, are also useful in preparing chiral reagents. Scheme E
R2 R2
H Ar1 JL Ar1 JL Δr1
Y Addition u O2N^y Reduction L HN^γ
O OH R3 OH
(Xl) (XVII) (X) Alternatively, racemic amino-alcohols (X)1 where R2 can be either -H or alkyl and R3 is -H1 are accessed via nitro-aldol addition as shown is Scheme E. Aldehydes (Xl) are treated with nitromethane (CH3NO2) in the presence of base, such as NaOH, KOH, KOtBu1 NaOtBu, TBAF, and NaH, in solvents such as THF and MeOH, at temperatures between 0 °C and the reflux temperature of the solvent, to form nitro-alcohols (XVII). Amino alcohols (X) are obtained by reduction of the nitro group using generally known methods such as Pd-catalyzed hydrogenation using a hydrogen source such as H2, cyclohexadiene, or NH4HCO2 in the presence of Zn, in solvents such as MeOH and EtOH at temperatures between room temperature and the reflux temperature of the solvent. Where racemic and non-racemic mixtures of enantiomers are obtainied, single enantiomers may be isolated using known methods, such as chiral chromatography and recrystallization.
Figure imgf000038_0001
In certain embodiments, amino alcohols (X)1 where R2 and R3 are both -H may be prepared from α-halo ketones (XIII) shown in Scheme F. To prepared achiral amino-alcohols, α-halo ketones (XIII), where Y = Br or Cl1 are treated with sodium azide (NaN3) in solvents such as DMF, THF, MeOH, EtOH or a mixture thereof at temperatures between room temperature and the reflux temperature of the solvent to provide azido-ketones (XIV). Reduction of the azido-ketone using known methods, such as treatment with borane complex (BH3 »THF and BH3OMS) or NaBH4, in solvent such as THF, MeOH and EtOH at temperatures between 0 °C and room temperature provide azido-alcohols (XVI). Alternatively, azido-alcohols (XVI) are prepared by reduction of the α-halo ketone (XIII) to give α-halo-alcohols (XV) which are converted to azido-alcohols (XVI) by addition of NaN3. To form enantio-enriched amino-alcohols (X), α-halo ketones (XIII) or azido-ketones (XIV) are reduced using a borane complex in the presence of either (S) or (R)-2-methyl-CBS oxazaborolkJine (CBS) in THF at temperatures between 0 °C and room temperature. Reduction of azido-alcohols (XVI) via known methods such as Pd-catalyzed hydrogentation using a hydrogen source such as H2, and cyclohexadiene or NH4HCO2 in the presence of Zn, in solvents such as MeOH1 EtOH or a mixture thereof, at temperatures between room temperature and the reflux temperature of the solvent, and at pressures ranging from 0-50 psi. provide amino-alcohols (X). Additionally, azido-alcohols (XVI) are reduced to amino-alcohols (X) using NaBH4 in the presence of CuSθ4#5H2O in solvents such as EtOH1 MeOH1 or a mixture thereof at temperatures between 0 °C and reflux temperature of the solvent. Preferably, α-halo ketones (XIII), where X = Br1 are treated with NaNa in EtOH at room temperature followed by reduction using NaBH4 in EtOH at 0 °C to provide azido-alcohols (XVI) which is subsequently reduced using a mixture of NaBH4 and CuSO4 »5H2O in MeOH at temperatures from about 0 °C to 80 °C to provide amino alcohols (X). Where racemic and non-racemic mixtures of enantiomers are obtainied, single enantiomers may be isolated using known methods, such as chiral chromatography and recrystallization.
Compounds of Formulae (I), (I-A), (I-B), and (I-C) may be converted to their corresponding salts by applying general techniques described in the art. For example, a compound of Formulae (I), (I-A), (I-B), and (I-C) may be treated with trifluoroacetic acid, HCI, or citric acid in a solvent such as Et2O1 CH2Cl2, THF1 or MeOH to provide the corresponding salt forms.
Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regio-specific synthesis, or by resolution. Compounds prepared according to the schemes above may alternatively be obtained as racemic (1 :1 ) or non-racemic (not 1 :1) mixtures or as mixtures of diastereomers or regioisomers. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.
The following specific examples are provided to further illustrate the invention and various preferred embodiments. EXAMPLES
Chemistry:
In obtaining the characterization data described in the examples below, the following analytical protocols were followed unless otherwise indicated.
Unless otherwise specified, reaction mixtures were stirred under a nitrogen atmosphere at room temperature (rt). Where solutions were "concentrated", they were concentrated using a rotary evaporator under reduced pressure. Where solutions are dried, they are typically dried over a drying agent such as MgSO4 or Na2SO4.
Microwave reactions were carried out in either a CEM Discover® or a Biotage Initiator™ Microwave at specified temperatures.
Thin-layer chromatography was performed using Merck silica gel 60 F2** 2.5 cm x 7.5 cm 250 μm or 5.0 cm x 10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM Science silica gel 60 F254 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone.
Normal phase purification was typically done by normal phase flash column chromatography (FCC) with RediSep® silica gel columns using EtOAc/hexanes or CH2Cl2ZMeOH as eluent unless otherwise specified.
Reverse phase high performance liquid chromatography (HPLC) was performed under the following conditions: 1 ) Instrument, Shimadzu; Column, Phenomenex Gemini column 5 μm C18 (150 x 21.2 mm) or Waters Xterra RP18 OBD 5 μm (100 x 30 mm); Gradient, 95:5 to 0:100 water (0.05% trifluoroacetic acid (TFA))ZCH3CN (0.05% TFA); Flow rate, 30-80 mL/min; Detection, UV at λ = 220-254 nM. 2) Instrument, Gilson; Column, Phenomenex LUNA column 5 μm C18 (250 x 50 mm) or Waters XBridge Prep C18 OBD 5 μm (30 x 150 mm); Gradient, 95:5 to 0:100 water (0.05% TFAyCH3CN (0.05% TFA); Flow rate, 30-80 mL/min; Detection, UV at λ = 220-254 nM. Analytical chiral HPLC was performed under the following conditions:
Stationary phase, Chiralpak AS (250 x 4.6 mm) at 25 °C; Mobile Phase, 10% MeOH containing 0.2% triethylamine, 90% CO2; Flow Rate, 2mL/min; Back Pressure, 150 bar.
Preparative chiral HPLC was performed under the following conditions: Stationary Phase, Chiralpak AS-H SFC 250 x 21 mm (L x I.D.); Mobile Phase, 10% MeOH containing 0.2% triethylamine, 90% CO2; Flow Rate, 31.5 mL/min; Back Pressure, 150 bar.
Hydrochloride salts were obtained by treating the corresponding free bases with HCI (4 N in dioxane, 2 M in Et2O, or 1.25 N in MeOH) at rt. The mixtures were either concentrated to obtain the HCI salt, or the resulting solid was isolated by filtration.
Trifluoroacetic acid salts were obtained by purification of the crude reaction product by preparative reverse phase HPLC.
Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of 1H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).
Mass spectra were obtainied on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass corresponds to the exact mass.
Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoft Corp., Cambridge, MA) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).
Intermediate A: (ffl-2-Amino-1-(4-fluoro-Dhenyl)-ethanol hydrochloride.
Figure imgf000041_0001
A mixture of (SH-M , 1'-bi-2-naphthol ((S)-BINOL) (573 mg, 2.0 mmol) and lithium isopropoxide (132 mg, 2.0 mmol) was treated with toluene (40 mL). After 40 min, 4-fluorobenzaldehyde (2.15 mL, 20.0 mmol) was added. The resulting yellow solution was placed in a dry ice/acetone bath. After 10 min, trimethylsilyl cyanide (TMSCN; 2.5 mL, 20.0 mmol) was added. After 75 min, the resulting mixture was treated with methanolic HCI (10% 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 (2x100 mL). The combined extracts were dried (MgSO4), and concentrated, giving a mixture of green oil and a crystalline solid. The oil was decanted yielding 2.24 g of product (75%). A solution of this oil (1.0 g, 6.6 mmol) in THF (6.6 mL) was treated dropwise with BH3-THF (1.0 M in THF; 13.2 mL, 13.2 mmol). The resulting mixture was heated to reflux for 1 h, stirred at rt for 16 h, and quenched by slow addition of MeOH (2.5 mL). Volatiles were removed in vacuo. MeOH (3 mL) was added, and the resulting solution was treated with HCI (2 M in Et2O; 6 mL). Et2O (30 mL) was added, resulting in the formation of a solid, which was filtered and dried in vacuo, giving the title compound (564 mg, 45%).
Intermediate B: (R)-2-(6-Chloro-Dyrimidin-4-ylaminoV1-(4-fluoro-Dhenyl)-ethanol.
Figure imgf000042_0001
H OH
A suspension of (R)-2-amino-1-(4-fluoro-pheny1)-ethanol hydrochloride (500 mg, 2.61 mmol), 4,6-dichloropyrimidine (353 mg, 2.37 mmol), and NaHCO3 (1.39 g, 16.6 mmol) in dioxane (10 mL) was heated in a 100 °C bath for 19 h and cooled to rt. Water (10 mL) was added, and the mixture, containing solid, was extracted with CH2Cl2 (3x10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound as a white solid (415 mg, 59%) in 90% enantiomeric excess (Chiralcel AD-H column, supercritical CO2).
Intermediate C: 2-Amino-1-(3.4-dichloro-DhenylWethanol. H2N
Figure imgf000043_0001
To a mixture of 3,4-dichlorobenzaldehyde (3.50 g, 20.2 mmol) and ZnI2 (19 mg, 0.06 mmol) at 0 °C was added TMSCN (2.2 g, 2.2 mmol). The reaction mixture was stirred at 0 °C for 10 min and then warmed to rt and stirred for an additional 1 h. The mixture was concentrated to afford an orange-brown colored oil. The oil was dissolved in THF (20 mL) and BH3-THF (1 M in THF; 25 mL, 25 mmol) was added at 0 °C. The reaction mixture was warmed to rt and stirred overnight. The mixture was cooled to 0 °C and MeOH (6 mL) was added with continued stirring for 2 h. After being warmed to rt, the mixture was concentrated. The residue was dissolved in MeOH (10 mL) and HCI (2 M in Et2O; 25 mL) was added at 0 °C. After 30 min, Et2O (100 mL) was added and the resulting white solid was filtered and washed with Et2O (2x50 mL) to give a white solid (3.5 g, 72%).
Intermediate D: 4-Chloro-6-(3-chloro-4-trifluorOmethyl-DhenylW)yrimidine.
F3C
Figure imgf000043_0002
Cl
To a solution of CH3CN and water (75:25 mL) that has been degassed by bubbling N2 into the solvent were added 4,6-dichloro-pyrimidine (3.63 g, 22.7 mmol) and Ph3P (840 mg, 2.2 mmol). De-gassing was continued for an additional 15 min before adding 3-chloro-4-trifluoromethylphenyl boronic acid (5 g, 22 mmol), Pd (OAc)2 (250 mg, 1.11 mmol) and K3PO4 (9.4 g, 44.3 mmol). The resulting mixture was stirred at rt for 2 h before diluting with water and extracting with EtOAc. The organic layer was dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (2.3 g, 35%).
Intermediate E: 2,2-Difluoro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-y1)- benzo[1 ,3]dk>xole.
Figure imgf000044_0001
To an 80 mL microwave vessel were added 5-bromo-2,2-difluoro- benzo[1,3]dioxole (2.0g, 8.44 mmol), bis(pinocolato)diboron (2.36 g, 9.28 mmol), potassium acetate (1.66 g, 16.9 mmol), Pd(ClPPf)Cl2OH2Cl2 (689 mg, 0.84 mmol) and 1 ,4-dk>xane (25 mL). The vessel was purged with N2 and then heated via microwave irradiation for 45 min at 140 °C. The reaction mixture was diluted, filtered through a pad of celite and then filtered through a 0.45 μM nylon filter to remove residual palladium particulates, dried (Na2SO.*) and concentrated. The crude material was purified (FCC) to yield the title compound as a green oil (1.41 g, 59%).
Intermediate F: 4.4.5.5-TetramethyJ-2-(5-trifluoromethyl-benzorb1thioDhen-2-ylV- H .3.2Tdioxaborolane.
Figure imgf000044_0002
Step A: 5-Trifluoromethyl-benzorbithioDhene. A mixture of 5-trifluoromethyl- benzo[b]thiophene-2-carboxylic acid (2.00 g, 8.12 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (5.0 mL, 34 mmol) in DMA (13 mL) was heated via microwave irradiation at 200 °C for 1 h. The reaction was cooled to rt, diluted with HCI (1 N aq., 20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and concentrated. The residue was taken up in Et2O (25 mL) and washed with water (25 mL). The aqueous layer was extracted with Et2O (10 mL x 2). The combined Et2O layers were dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (1.22 g, 74%). Step B. To a 2-necked round bottom flask were added [lr(OMeχCOD)]2 (19 mg, 0.03 mmol) and 4,4'-di-tert-butyl-2,2l-bipyridine (dtbpy) (15.0 mg, 0.06 mmol) and the flask was evacuated and refilled with N2. The flask was charged with a solution consisting of 5-trifluoromethyl-benzo[b]thiophene (380 mg, 1.88 mmol) in hexane (12 mL), followed by pinacolborane (0.35 mL, 2.44 mmol). The reaction mixture was allowed to stir at rt for 4 h before diluting with CH2Cl2 (20 mL) and washing with water (10 mL). The organic layer was dried (Na2SO4), concentrated, and purified (FCC) to yield the title compound (405 mg, 66%).
Intermediate G: 4-trifluoromethylsulfanyl-benzene boronic acid.
Figure imgf000045_0001
Step A: 4.4.5.5-Tetramethy1-2-(4-trifluorOmethyJsulfanyl-Dhenyl)--
H .3.21dioxaborolane. Title compound was prepared analogously to Intermediate
E. Step B. To a round-bottomed flask were added 4,4,5,5-tetramethyl-2-(4- trifluoromethylsulfanyl-phenyl)-[1 ,3,2]dioxaborolane (960 mg, 3.16 mmol) and sodium periodate (2.03 g, 9.48 mmol) in THF and water (4:1 , 26 mL). The resulting suspension was stirred at rt for 30 min. HCI (1 N aq., 2.21 mL) was added to the suspension and the reaction mixture was stirred at rt for 18 h. The resulting precipitate was removed by filtration and washed with hexanes. The filtrate was diluted with water (25 mL) and extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (10 mL x 2), and the combined organic layers dried (Na2SO-J) and concentrated to yield the title compound (512 mg, 73%).
Intermediate H. Routel: 3-Trifluoromethvl-benzordlisoxazole-6-boronic acid.
Figure imgf000045_0002
Step A: 1-(4-Bromo-2-hydroxy-Dhenyl>-2.2.2-trifluoro-ethanone. To a pre-cooled (0 °C) solution of 3-bromophenol (4.93 ml, 46.2 mmol) and dichloroethane (185 mL), was added trifluoroacetic anhydride (9.3 mL, 67 mmol) over 10 min.
Aluminum chloride (20.1 g, 150.7 mmol) was then added portion-wise over 15 min. The reaction mixture was gradually warmed to rt over 2 h and then heated at 40 °C for 19 h. The reaction mixture was cooled to rt and poured over ice water. The resultant mixture was extracted with CH2Cl2 (50 mL x 2) the combined organic layers were washed with a satd. NaHCO3 solution (150 mL), followed by a brine solution (150 mL), dried (Na2SO4) and concentrated to dryness. The crude material was dissolved in Et∑O (100 ml.) and extracted with NaHCO3 (10% aq., 100 mL x 4). The pH of the combined aqueous extracts was lowered to 7 by careful addition of HCI (6 N aq.) and the resultant mixture extracted with Et2O (200 mL). The Et2O layer was dried (Na2SO^ and concentrated. The residue, containing 95% product and 5% 3-bromophenol by NMR analysis, was purified (FCC) to yield the title compound (5.55 g, 45%).
Step B: 1-(4-Bromo-2-hydroxy-phenyl)-2.2.2-trifluoro-ethanone oxime. To a round bottom flask were added sodium acetate (9.46 g, 115 mmol), hydroxylamine hydrochloride (7.09 g, 102 mmol) and MeOH (10 mL). To this mixture was added a solution consisting of 1-(4-bromo-2-hydroxy-phenyl)-2,2,2- trifluoro-ethanone (2.5 g, 9.3 mmol) and MeOH (62 mL). The reaction vessel was heated at 64 °C for 7 h before cooling to rt and pouring the reaction mixture into ice water (100 mL). The aqueous solution was then extracted with EtOAc (75 mL x 2) and the organic layers dried (Na2SO-O an<J concentrated to yield the title compound as a mixture of the two possible oxime isomers (2.64 g, 100%).
Step C: 6-Bromo-3-trifluoromethyl-benzord1isoxazole. To a flask containing 1-(4- bromo-2-hydroxy-phenyl)-2l2l2-trifluoro-ethanone oxime (2.64 g, 9.29 mmol) was added acetic anhydride (14 mL) and the reaction mixture stirred for 18 h at rt. The reaction mixture was concentrated and taken up in toluene and again concentrated to yield the acylated intermediate. This intermediate was dissolved in pyridine (15 mL) and triethylamine (3.2 mL) and heated at 112 °C for 4.5 h. The reaction mixture was concentrated and the residue was taken up in toluene and again concentrated the residue was then partitioned between EtOAc (25 mL) and HCI (1 N aq., 25 mL). The layers were separated and the organic layer washed with HCI (1 N aq., 25 mL). The combined water layers were then extracted with EtOAc (25 mL x 2) and the combined organic layers were washed with brine (15 mL), dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (44 mg, 17%).
Step D. Title compound was prepared using methods similar to those described in Intermediate G. Intermediate H1 Route 2: 3-Trifluoromethyl-benzo[d]isoxazole-6-boronic acid
Figure imgf000047_0001
Step A: 1-(4-Bromo-2-fluoro-phenylV2.2.2-trifluoro-ethanol. A mixture of 4- bromo-2-fluoro-benzaldehyde (8.12 g, 40.0 mmol) and
(trifluoromethyl)trimethylsilane (7.50 mL, 48.0 mmol) in THF (40 mL) was cooled to 0 °C before treating with TBAF (1 M in THF1 0.6 mL) and warming to rt. After 3 h, an additional portion of TBAF (1 M in THF1 8.0 mL) was added. The resultant mixture was allowed to stir for 10 min before adding HCI (1 N aq., 40 mL) and extracting with Et2O (40 mL). The Et2O layer was dried (MgSO4) and concentrated to yield the title compound (10.7 g, 98%).
Step B: 1-(4-Bromo-2-fluoro-Dheny1V2.2.2-trifluoro-ethanone. Dess-Martin period inane (16.57 g, 39.06 mmol) was added to a solution consisting of 1-(4- bromo-2-fluoro-phenyl)-2,2l2-trifluoro-ethanol (10.66 g, 39.06 mmol) and DCM (100 mL) and the resultant mixture was stirred at rt for 1.5 h. Na2S2O3 (10% aq., 100 mL) was added and the resulting mixture extracted with CH2Cl2 (100 mL). The organic layer was washed with Na2S2O3 (50 mL x 2), NaHCO3 (satd. aq., 100 mL x 2), and brine (100 mL x 2). The organic layer was dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (3.20 g, 30%).
Step C: 1-(4-Bromo-2-fluoro-DhenylV2.2.2-trifluoro-ethanone oxime. To a solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (3.12 g, 11.5 mmol) and MeOH (50 mL) were added hydroxylamine hydrochloride (4.00 g, 57.5 mmol) and sodium acetate (5.90 g, 71.9 mmol). The resulting mixture was heated at 64 °C for 19 h, at which time additional hydroxylamine hydrochloride (2.40 g, 34.5 mmol) and sodium acetate (3.54 g, 43.1 mmol) were added. Heating was continued for 24 h and the mixture was cool to rt and the mixture was filtered to remove solids. The filtrate was diluted with EtOAc (150 mL), washed with water (150 mL), dried (Na2SO4) and concentrated. The title compound was obtained as a 70:30 ratio of the E and Z oxime isomers (3.28 g, 100%). Step D: 6-Bromo-3-trffluoromethyl-benzordlisoxazole. A solution consisting of 1- (4-bromo-2-fluoro-phenyl)-2l2l2-trifluoro-ethanone oxime (3.2 g, 11.2 mmol) 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (1.1 mL, 7.4 mmol) and THF (42 mL) was heated at 150 °C via microwave irradiation for 30 min. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with HCI (1 N aq., 25 mL). The organic layer was then dried (Na2SO4), concentrated, and purified (FCC) to yield the title compound (1.97 g, 66%).
Step E. Title compound was prepared using methods analogous to those described in Intermediate G.
Intermediate 1: 3-Chloro-4-trifluoromethoxy-benzene boronic acid.
Figure imgf000048_0001
Step A: 4-Bromo-2-chloro-1-trifluoromethoxy-benzene. To a 0 βC solution consisting of 3-chloro-4-trifluoromethoxy-aniline (2.12 g, 10.0 mmol) and HBr (48% aq , 50 mL) was added NaNO2 (2 M aq., 917.7 mg, 13.3 mmol) dropwise at a rate such that the reaction temperature remained below 5 °C. After stirring for 1.75 h, urea (330 mg, 5.5 mmol) was added and the mixture stirred for 20 min. A solution consisting of Cu(I)Br (2.96 g, 20.6 mmol) and HBr (48% aq., 13.1 mL) was then added while keeping the reaction temperature in the range of 0-5 °C. Upon complete addition, the reaction mixture was heated to 85 °C for 2.5 h. After cooling to rt, the reaction mixture was poured into ice water (150 mL) and extracted with hexanes (100 mL). The aqueous layer was washed with CH2Cl2 (100 mL) and the combined organic phases washed with satd. aq. NaHCO3 (150 mL x 2), dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (806 mg, 29%).
Step B. Title compound was prepared using methods similar to those described in Intermediate G. Intermediate J: 3-Pentafluoroethy1-benzo[d]isoxazole-6-boronic acid.
OH
Figure imgf000049_0001
Title compound was prepared using methods similar to those described in Intermediate H, Route 2.
Intermediate K: (1R)-2-Amino-1-(4-fluoro-phenyl)-ethanol hydrochloride salt.
H2N
Figure imgf000049_0002
OH
Step A: (1 RV2-Chloro-1-(4-fluoro-pheny1Vethanol. To a solution consisting of BH3-THF (1 M1 150 mL) and (R)-(+)-2-methyl-CBS-oxazaborolidine (1 M in THF) (2.14 mL) was added a second solution consisting of 2-chloro-4'-fluoro- acetophenone (37.0 g, 214 mmol) and THF (100 ml) over 1 h at rt. The resultant colorless reaction mixture was stirred for 45 min and then quenched with MeOH (75 mL). The solvent was removed in vacuo leaving the title compound as pale yellow oil, which was used without further purification (37 g, 100%) Step B: (1 RV2-Azido-1-(4-fluoro-Dhenyl)--ethanol. Sodium azide (41.8 g, 642 mmol) was added to a solution consisting of (1R)-2-chloro-1-(4-fluoro-phenyl)- ethanol (37.4 g, 214 mmol) and DMF (214 mL) at rt. The reaction mixture was heated to 100 °C for 3 h, diluted with water (500 mL), and extracted with EtOAc (700 mL). The organic layer was washed with brine (500 mL), and the organic layer dried (MgSO4), filtered, and concentrated, giving the title compound as a yellow liquid, which was used without further purification (39 g, 100%).
Step C: To a solution consisting of (1 R)-2-azido-1-(4-fluoro-phenyl)-ethanol (38.8 g, 214. mmol) and EtOH (250 mL) was added 5% Pd/C (60% water, 38 g). The reaction mixture was subjected to 50 psi of hydrogen at rt for 1 h. The reaction mixture was filtered through a 0.45 μM nylon filter giving a black filtrate. HPLC analysis showed that the reaction was incomplete. Fresh Pd/C was added (38 g) and the reaction mixture re-subjected to hydrogenation at 50 psi and rt for 2 h. The reaction mixture was filtered again through a 0.45 μM nylon filter giving a black filtrate. The solvent was removed under vacuum and the residue dissolved in EtOH (215 nriL). The ethanolic solution was then treated with HCI (2 M in Et2O1 107 imL), followed by Et2O (250 ml). The precipitated title compound was isolated via vacuum filtration (20.8 g, 51%). A solution consisting of (R)-(-)-2-amino-1-(4-fluoro-phenyl)-ethanol (22.3g, 116 mmol) was dissolved and ethanol (225 ml.) was heated at 70 °C to give a homogeneous solution. Heptane (115 mL) was slowly added and the solution was allowed to stir for 10 min before allowing the solution to slowly cool to rt. Upon cooling, crystals formed. After cooling to rt, the solution was placed at -20 °C for 18 h. The mother liquor in the flask was decanted and the remaining crystals were washed twice with heptane (-50 ml) and dried under vacuum leaving the title compound (18.29 g, 81%). The ee of the recrystallized material and the crude material were determined by preparing [2-(4-fluoro-phenyl)-2- hydroxy-ethylj-carbamic acid tert-butyl ester using known methods. HPLC conditions: OD-H column, 95% hexanes/5% EtOH (0.1% DEA)1 0.8 ml/min flow. The ee of the crude material and recrystallized material was 94% and 97-98% respectfully.
Intermediate M: (R^-fβ-Chloro-pyrimidin^-ylamino^i-^-fluoro-phenyl^thanol.
Figure imgf000050_0001
H OH
Title compound was prepared analogously to the methods described in Example 1 , Step A.
Intermediate N: 4-(1.2.2.2-Tetrafluoro-1-trifluoromethyl-ethyl) -benzene boronic acid and 2-r3-M .2.2.2-tetrafluoiO-1-trifluoromethyl-ethyl) -benzene boronic acid.
F F
HO \ £~F
B- J~ Λ -/
H
Figure imgf000050_0003
O Λ= =/ F ) rF
Figure imgf000050_0002
Step A: 4.4.5.5-Tetramethyl-2-[4-(1.2.2.2-tetrafluoro-1 -trifluoromethyl-ethyl)-- phenyn-π ,3.21dioxaborolane and 4.4.5.5-Tetramethyl-2-r3-(1.2.2.2-tetrafluoro-1- trifluoromethyl-ethyl)-phenyfl-ri.3.21dioxaborolane. Title compounds was obtained as a mixtureusing methods analogous to those described in Intermediate F.
Step B: Title compounds were obtained as a mixture using methods analogous to those described in Intermediate G.
Intermediate O: 3-Trifluoromethyl-benzorbTthiophen-6-yl-benzene boronic acid.
Figure imgf000051_0001
Step A: 4.4.5.5-Tetramethy1-2-(3-trifluoronriethyl-benzorb]thiophen-6-v1V- H .3.21dioxaborolane. Title compound was prepared using methods analogous to those described in Intermediate E. (6-bromo-3-trifluoromethyl-benzo[b]thiophene was prepared as described in TeL Lett., 2003, 44, 7147). Step B: Title compound was prepared using methods analogous to those described in Intermediate G.
Example 1 : M RV2-((6-[4-(Ethy1oxyV3-(trifluoromethyhphenyl]Dyrimidin-4- ynaminoV 1 -ohenylethanol.
Figure imgf000051_0002
H OH ^XT
Step A: M RV2-K6-Chloropyrimidin-4-yltaminol-1-phenylethanol. To a solution consisting of (R)-(-)-2-amino-1-phenyletharιol (4.80 g, 35.0 mmol) in and 1 ,4-dioxane (150 mL) at rt was added dropwise a solution consisting of 4,6- dichloropyrimidine (5.21 g, 35.0 mmol) and 1 ,4-dioxane (75 mL). Upon complete addition, NaHCO3 (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 (60 mL) and the pH was adjusted to 12 by the addition of a 1 N NaOH (25 mL). The solution was extracted with CH2Cl2 (75 mL), washed with satd. aq. NaCI (50 mL), and the organic extract was dried (Na2SO4) and concentrated. The crude material (8.2 g) was suspended in CH2Cl2 (40 mL) and warmed to 50 °C to give a homogeneous solution. The solution was cooled to 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 calcd. for C2IH20F3N3O2, 403.2; m/z found, 404.2 [M+H]*. 1H NMR (CD3OD): 8.44 (s, 1H)1 8.15 (s, 1H), 8.09 (dd, J = 8.8, 2.2 Hz, 1H), 7.43 (d, J = 7.7 Hz1 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)1 3.58 (dd, J = 13.7, 7.7 Hz1 1H), 1.45 (t, J = 7.1 Hz, 3H).
Step B. 2-[(6-Chloropyrimidin-4-yl)amino]-1-phenylethanol (62.4 mg, 0.25 mmol), 3-chloro-4-ethoxyphenyl boronic acid (100 mg, 0.5 mmol), Pd(PPh3)4 (14.4 mg. 0.0125 mmol), and K3PO4 (106 mg, 0.50 mmol) were placed in a two-necked round bottom flask and the flask evacuated. The flask was backfilled with N2 and then charged with DME (2.0 mL) and degassed water (0.5 mL). The reaction mixture was heated at reflux (85 °C) for 17 h. The reaction mixture was then cooled, diluted with water (10 mL x 2). extracted with EtOAc (10 mL x 2), and the organic layer dried (Na2SO4) and concentrated. The crude residue was purified (FCC followed by reverse-phase HPLC) to yield the desired product (90.1 mg, 97%). MS (ESI): mass calcd. for C20H2OCIN3O2, 369.1 ; m/z found, 370.2 [M-I-H]+. 1H NMR (CD3OD): 8.42 (s, 1 H), 7.94 (d, J = 2.3 Hz. 1 H)1 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.43 (d, J = 7.1 Hz, 2H), 7.36-7.32 (m, 2H), 7.27-7.24 (m, 1H)1 7.14 (d, J = 8.6 Hz1 1H)1 6.82 (s, 1H)1 4.92-4.89 (m, 1H), 4.19 (q, J = 6.8 Hz, 2H)1 3.75-3.67 (m, 1H)1 3.58 (dd, J = 13.9, 7.8 Hz, 1 H), 1.46 (t. J = 6.8 Hz, 3H).
The compounds in Examples 2-19 were prepared using methods analogous to those described in Example 1 , using either enantiomerically pure or racemic amino alcohols in Step A and substituting the appropriate boronic acids or esters in Step B. Final compounds were purified by FCC. Example 2: 2-f{6-(4-ChlorophenyQpyrimidin-4-yl)amino)-1-phenylethanol.
Figure imgf000052_0001
MS (ESI): mass calcd. for C18Hi6CIN3O, 325.1 ; m/z found, 326.2 [M+H]+. 1H NMR (CD3OD): 8.45 (s, 1H)1 7.88 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.35-7.32 (m, 2H)1 7.27-7.24 (m, 1 H), 6.88 (s, 1H), 4.89 (dd, J = 7.7, 4.9 Hz1 1H), 3.77-3.67 (m, 1H), 3.59 (dd, J = 13.7, 7.7 Hz, 1H).
Example 3: 2-f{6-(4-Fluorophenyltoyrimidin-4-vπamino)-1-phenylethanol.
Figure imgf000053_0001
MS (ESI): mass calcd. for C18H16FN3O, 309.1 ; m/z found, 310.2 [M+H]+. 1H NMR (CD3OD): 8.45 (s, 1H), 7.94 (dd, J = 8.8, 5.5 Hz, 2H), 7.42 (d, J = 7.1 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.26 (t, J = 7.1 Hz, 1H), 7.22-7.19 (m, 2H), 6.86 (s, 1H), 4.89 (dd, J = 7.1 , 4.9 Hz, 1H), 3.78-3.67 (m, 1H), 3.58 (dd, J = 13.7, 7.7 Hz, 1H).
Example 4: 1 -Phenyl-2-(f6-[4-(trifluoromethy»phenynpyrimidin-4-yl)amino)ethanol trifluoroacetic acid salt.
Figure imgf000053_0002
MS (ESI): mass calcd. for C19Hi6F3N3O, 359.1 ; m/z found, 360.2 [M+H]*. 1H NMR (CD3OD): 8.68 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 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)1 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-l{6-(4-NitrophenyQpyrimidin-4-yl]amino)-1-phenylethanol trifluoroacetic acid salt.
Figure imgf000053_0003
MS (ESI): mass calcd. for C18Hi6N4O3, 336.1; m/z found, 337.2 [M+H]*. 1H NMR (CD3OD): 8.68 (s, 1H), 8.44 (d, J = 9.1 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 7.3 Hz1 2H)1 7.38-7.34 (m. 2H)1 7.30-7.26 (m, 1H), 7.06 (s, 1H)1 4.96- 4.92 (m. 1H)1 3.95-3.86 (m. 1H)1 3.77 (dd. J = 13.6. 7.8 Hz, 1 H).
Example 6: 2-f{6-(4-EthyiDhenyltoyrimidin-4-vt1amino)-1-Dhenylethanol.
Figure imgf000054_0001
MS (ESI): mass calcd. for C20H2IN3O1 319.2; m/z found, 320.2 [M+H]*. 1H NMR (CD3OD): 8.44 (s. 1H)1 7.80 (d. J = 8.3 Hz1 2H), 7.43 (d. J = 7.6 Hz, 2H), 7.37-7.31 (m, 4H), 7.28-7.24 (m, 1 H), 6.86 (s, 1H)1 4.91-4.90 (m, 1H)1 3.77-3.67 (m. 1 H)1 3.58 (dd, J = 13.9. 7.8 Hz1 1 H), 2.70 (q, J = 7.6 Hz1 2H)1 1.26 (t, J = 7.6 Hz1 3H).
Example 7: 2-((6-[4-(1-Methy1ethyltohenyfloyrimktin^yl)aminoV1-phenylethanol.
Figure imgf000054_0002
MS (ESI): mass calcd. for C21H23N3O1 333.2; m/z found. 334.2 [M +H]+. 1H 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, 1 H), 6.86 (m, 1H), 4.91-4.90 (m, 1H), 3.76-3.68 (m, 1 H)1 3.58 (dd. J = 13.9, 7.8 Hz. 1 H). 2.97 (septet. J - 6.8 Hz. 1 H), 1.28 (d, J = 6.8 Hz1 6H).
Example 8: 2-f{6-(3.4-Dichlorophenyl)pyrimidin-4-vπamlno)-1 -phenylethanol.
Figure imgf000054_0003
MS (ESI): mass calcd. for C18H15Cl2N3O, 359.1 ; m/z found, 360.1 [M+H]*. 1H NMR (CD3OD): 8.46 (s, 1 H), 8.09-8.08 (m, 1H)1 7.82 (dd. J = 8.2. 2.2 Hz. 1H). 7.63 (d, J - 8.2 Hz, 1H), 7.43 (d, J - 7.7 Hz, 2H), 7.35-7.32 (m, 2H), 7.27-7.24 (m, 1 H), 6.89 (S, 1H), 4.89 (dd, J =7.1 , 4.9 Hz, 1H), 3.78-3.67 (m, 1H), 3.58 (dd, J = 13.7, 7.7 Hz, 1H). Example 9: 2-f{6-(3-ChloiOPhenyl)pyrimidin-4-yl)amino)-1-phenylethanol.
Cl
Figure imgf000055_0001
MS (ESI): mass calcd. for C18Hi6CIN3O, 325.1 ; m/z found, 326.1 [M+H]*. 1H NMR (CD3OD): 8.46 (s, 1H), 7.92 (s, 1H), 7.82-7.81 (m, 1 H)1 7.47-7.46 (m, 2H)1 7.43 (d, J = 7.7 Hz, 2H), 7.34 (t, J = 7.7 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-r3-Chloro-4-t(rifluoromethyl)DhenyiiDyrimidin-4-yl)aminoV1- phenylethanol.
Figure imgf000055_0002
MS (ESI): mass calcd. for Ci9Hi5CIF3N3O, 393.1 ; m/z found, 394.1 [M+H]*. 1H NMR (CD3OD): 8.50 (s, 1 H)1 8.16 (s, 1H), 8.00 (d, J = 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 (S1 1 H), 4.91 -4.89 (m, 1 H)1 3.79-3.70 (m, 1 H), 3.60 (dd, J = 13.7, 7.7 Hz, 1 H).
Example 11 : 2-K6-[4-(Ethyloxytohenynpyrimidin-4-yl)amino)-1-phenylethanol.
Figure imgf000055_0003
MS (ESI): mass calcd. for C20H2IN3O2, 335.2; m/z found, 336.2 [M+H]*. 1H NMR (CD3OD): 8.41 (s, 1 H), 7.84 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 7.27-7.25 (m. 1H)1 7.00 (d. J = 8.8 Hz, 2H), 6.81 (s, 1H), 4.91- 4.88 (m, 1H), 4.09 (q, J - 7.1 Hz, 2H), 3.75-3.67 (m, 1H), 3.57 (dd, J = 13.7, 7.7 Hz, 1H), 1.41 (t, J = 7.1 Hz, 3H).
Example 12: 2-[(6-(4-[(1-Methy1ethy1)oxy]phenyl)pyrimidin-4-yl)aminol-1- phenylethanol.
Figure imgf000056_0001
MS (ESI): mass calcd. for C2IH23N3O2, 349.2; m/z found, 350.2 [M+H]*. 1H NMR (CD3OD): 8.40 (s, 1 H), 7.83 (d, J = 9.3 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.26 (t, J = 7.1 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 2H)1 6.81 (s, 1 H), 4.89 (dd, J = 7.7, 4.4 Hz, 1 H), 4.68 (septet, J = 6.0 Hz, 1 H), 3.75-3.67 (m, 1 H)1 3.57 (dd, J = 13.7, 7.7 Hz, 1 H)1 1.33 (d, J - 6.0 Hz, 6H).
Example 13: 1-Phenyl-2-α6-[4-(Dhenyloxy^DhenyflDyrimidin-4-yl)amino Methanol.
Figure imgf000056_0002
MS (ESI): mass calcd. for C24H21N3O2, 383.2; m/z found, 384.2 [M+H]*. 1H
NMR (CD3OD): 8.43 (s, 1H)1 7.90-7.88 (m. 2H)1 7.44-7.38 (m. 4H); 7.36-7.32 (m. 2H), 7.27-7.24 (m, 1H), 7.19-7.15 (m, 1H), 7.07-7.03 (m, 4H), 6.85 (s. 1H)1 4.91- 4.89 (m. 1H)1 3.75-3.67 (m, 1H), 3.59 (dd, J = 13.9, 7.8 Hz, 1 H).
Example 14: 2-((6-r3-Chloro-4-(ethyloxytohenyl]pyrimldin-4-yl}aminoV1- phenyiethanol.
Figure imgf000056_0003
^0XJ H OH
MS (ESI): mass calcd. for C12Hi2CIN3O, 249.1 ; m/z found, 250.2 [M+H]+. 1H NMR (CD3OD): 8.21 (s, 1 H), 7.40 (d, J = 7.1 Hz1 2H)1 7.35-7.32 (m, 2H)1 7.27- 7.24 (m, 1 H)1 6.52 (s. 1 H)1 4.84 (dd, J = 7.7, 4.9 Hz1 1 H), 3.74-3.66 (m, 1 H), 3.56- 3.54 (m, 1 H).
Example 15: MRV1-Phenyl-2-^6-[4-ftrifluoromethyltohenynpyrimidin-4- yl)ami no Methanol.
Figure imgf000056_0004
MS (ESI): mass calcd. for Ci9Hi6F3N3O, 359.1; m/z found, 360.2 [M+H]+. 1H NMR (CD3OD): 8.50 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 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, J - 13.6, 7.8 Hz, 1 H).
Example 16: MRV2-f(6-r3-Chloro-4-(trifluoromethylbhenyπDyrimidin-4-yl)aminoV 1-phenylethanol.
Figure imgf000057_0001
MS (ESI): mass calcd. for C19Hi5CIF3N3O, 393.1 ; m/z found, 394.1 [M+H]*. 1H 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).
The title compound was also prepared in a manner similar to Example 1 , with modifications to combine steps A and B as follows:
To a solution of 4,6-dichloropyrimidine (50 g, 0.34 mol, 1.0 equiv) in CH3CN (1.2 L), was added NaHCO3 (34 g, 0.40 mol, 1.2 equiv) and (R)-(-)-2- amino-1-phenyl-ethanol (48.3 g, 0.35 mol, 1.05 equiv) sequentially. The reaction mixture was stirred at reflux temperature under N2 for 3 hours then cooled to rt. HPLC analysis of the crude reaction mixture indicated that the reaction was complete, to afford the intermediate (1R)-2-[(6-chloropyrimidin-4-yl)amino]-1- phenylethanol. In the same flask, without purification or work-up, was added a solution of K3PO4 (85 g, 0.40 mol, 1.2 equiv) in H2O (750 mL), 3-chloro-4- (trifluoromethyl)phenylboronic acid (79.4 g, 0.35 mol, 1.05 equiv), Pd^pPf)Cl2* CH2Cl2 (2.4 g, 2.9 mmol, 0.009 equiv) and Pd(OAc)2 (68 mg, 0.29 mmol, 0.0009 equiv) sequentially under N2 at rt. The reaction solution was degassed with N2 (3X) and was stirred at reflux temperature for 16 hours then cooled to rt. The layers were separated and the CH3CN phase was dried (MgSO4) and filtered. The filtrate solution was stirred with Si-Thiol (8.8 g, 1.5 mmol/g loading, 4 equiv of Pd added) at rt for 1 hour. Si-Thiol is commercially available through SiliCycle (230-400 mesh, 40-63 μm). The Si-Thiol was removed by filtration and washed with EtOAc. The organics were combined and concentrated under reduced pressure. The crude residue was recrystallized from hot EtOH (~250 mL) with stirring to afford the title compound (83 g). Further concentration of the mother liquor followed by a second recrystallization from hot EtOH with stirring provided an additional crop of the title compound (23 g). The combined recrystallized yield of the title compound was 80% (106 g, >99% ee). MS (ESI): mass calcd. for Ci9Hi5CIF3N3O, 393.1; m/z found, 394.1 [M+H]*. 1H NMR (CDCI3, 500 MHz): 8.69 (S, 1H)1 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, 1 H). 5.42 (br s, 1H), 5.10-4.98 (m, 1H), 3.92 (br s, 1H), 3.70-3.58 (m, 1H).
Example 16A: MRV2-((6-r3-Chloro-4-t(rifluoromethy»Dhenyl]Pyrimidin-4- vDaminoH-Dhenylethanol hydrochloride salt.
1H NMR (CD3OD): 8.72 (s, 1 H), 8.11 (s, 1 H), 8.04 (d. J = 8.3, 1 H), 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, 1 H), 4.95 (dd, J = 4.1 , 7.8, 1H), 3.94 (dd, J = 4.2, 13.6 Hz1 1H), 3.60 (dd. J = 13.6, 7.6 Hz, 1H).
Example 17: 1-[4-(6-ffl2RV2-Hvdroxy-2-Phenylethyflamino)pyrimidin-4- vQphenyflethanone.
Figure imgf000058_0001
MS (ESI): mass calcd. for C20Hi9N3O2, 333.2; m/z found, 334.2 [M+H]*. 1H NMR (CD3OD): 8.49 (s, 1H). 8.10 (d, J = 8.6. 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 7.3 Hz, 2H), 7.36-7.32 (m, 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).
Example 18: H RV2-α6-[4-(1-Methylethy1tohenyl]pyrimidin-4-yl)aminoV1- phenylethanol.
Figure imgf000059_0001
MS (ESI): mass calcd. for C21H23N3O, 333.2; m/z found, 334.2 [M+H]*. 1H NMR (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^.89 (m, 1H), 3.77-3.68 (m, 1H)1 3.59 (dd, J = 13.6, 7.6 Hz, 1 H), 2.96 (septet, J - 6.8 Hz, 1 H), 1.28 (d, J = 6.8 Hz, 6H).
Example 19: HRV2-r(6-l3-Chloro-4-rH-methylethylκ)xyiphenyl)pyrimidin-4- ylteminoi-1 -phenylethanol.
Cl
Figure imgf000059_0002
MS (ESI): mass calcd. for C2IH22CIN3O2, 383.1 ; m/z found, 384.2 [M+H]+. 1H 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, 1 H), 6.82 (s, 1H), 4.91-4.89 (m, 1 H), 4.73 (septet, J = 6.1 Hz, 1H), 3.75-3.66 (m, 1 H), 3.58 (dd, J = 13.6, 7.6 Hz, 1H), 1.37 (d, J = 6.1 Hz, 6H).
Example 20: HRV2-f{6-(3-Fluoro-4-methylphenyltoyrimidin-4-yl]amino)-1- phenylethanol trifluoroacetic acid salt.
Figure imgf000059_0003
The title compound was synthesized in a manner similar to Example 1 with modifications to Step B as follows:
Step B. (1 R)-2-[(6-Chloropyτimidin-4-y1)amino]-1-phenylethanol (62.4 mg, 0.3 mmol), 3-fluoro-4-methyl-phenyl boronic acid (42 mg, 0.30 mmol), Pd(PPh3)4 (2.9 mg, 0.0025 mmol), and K3PO4 (106 mg, 0.50 mmol) were placed in a microwave vial and the vial evacuated. The vial was then backfilled with N2 and charged with DME (2.0 mL) and degassed water (0.5 mL). The reaction mixture was heated in the microwave for 21 min at 180 °C. The crude reaction mixture was diluted with CH2Cl2 and filtered through a plug of MgSO4. The filtrate was concentrated and the residue purified using reverse phase chromatography (Gilson) to yield the title compound (87.4 mg, 80%). MS (ESI): mass calcd. for Ci9H18FN3O, 323.1; m/z found, 324.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55-7.48 (m, 3H), 7.43 (d, J = 7.1 Hz1 2H), 7.37-7.34 (m, 2H), 7.29-7.27 (m, 1 H)1 6.98 (s, 1 H), 4.95-4.92 (m, 1H), 3.93-3.87 (m, 1H)1 3.79 (dd. J = 13.7, 7.7 Hz1 1H)1 2.38 (S. 3H).
The compounds in Examples 21-102 were prepared using methods analogous to those described in Example 20, using either enantiomerically pure or racemic amino alcohols and appropriately substituted 4,6-dichloropyrimidines in Step A and substituting the appropriate boronic acids or esters in Step B. Example 21: MRV2-(f6-[4-(Hvdroxymethyl)phenynpyrimidin-4-vftamino>-1- phenylethanol.
Figure imgf000060_0001
MS (ESI): mass calcd. for C19H19N3O2, 321.2; m/z found. 322.2 [M+H]*. 1H NMR (CD3OD): 8.45 (s. 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.43 (d, J - 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 7.27-7.24 (m, 1 H)1 6.88 (s, 1H)1 4.90 (dd, J = 7.7, 4.4 Hz1 1 H), 4.67 (s, 2H), 3.76-3.68 (m, 1 H), 3.60 (dd, J = 13.7, 7.7 Hz, 1H).
Example 22: 4-(6-f{f2RV2-Hvdroxy-2-phenylethynamino)pyrimldin-4- yl)benzaldehyde.
Figure imgf000060_0003
Figure imgf000060_0002
MS (ESI): mass calcd. for C19Hi7N3O2, 319.1 ; m/z found, 320.2 [M+H]*. 1H
NMR (CDCI3): 10.09 (s, 1H), 8.70 (s, 1 H), 8.12 (d, J = 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)1 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-{K2RV2-Hvdroxy-2-phenylethyπamino)pyrimidin-4- yl)benzaldehyde.
Figure imgf000061_0001
MS (ESI): mass calcd. for C19Hi7N3O2, 319.1 ; m/z found, 320.2 [M+Hf. 1H NMR (CDCI3): 10.10 (s, 1H)1 8.69 (s, 1 H), 8.45-8.44 (m, 1H), 8.20-8.25 (m, 1H)1 7.99-7.97 (m, 1H), 7.66-7.63 (m, 1H), 7.44-7.37 (m, 4H), 7.34-7.30 (m, 1 H), 6.80 (S, 1H)1 5.33 (br s, 1H), 5.01 (dd. J = 7.3, 3.3Hz, 1H)1 3.93-3.85 (m, 1 H)1 3.66-3.60 (m. 1H).
Example 24: M RV1-Phenyl-2-K6-(4-K2.2.2-trifluoroethyltoxyiphenyl)pyrimidin-4- ylteminoiethanol.
Figure imgf000061_0002
F3C^
MS (ESI): mass calcd. for C20H18F3N3O2, 389.1 ; m/z found, 390.2 [M+H]+. 1H NMR (CD3OD): 8.43 (s, 1H), 7.90 (d. J = 8.8 Hz, 2H)1 7.43 (d, J = 7.7 Hz, 2H), 7.36-7.33 (m, 2H), 1.21-1. TA (m, 1H)1 7.12 (d. J = 8.8 Hz1 2H)1 6.84 (s, 1H), 4.91- 4.87 (m, 1H), 4.61 (q. J = 8.2 Hz1 2H), 3.73-3.69 (m. 1H)1 3.59 (dd, J = 14.38.2 Hz, 1H).
Example 25: M RV1 -Pheny1-2-r(6-/3-r(2.2.2-trifluoroethy1)oxy]Dheny1)Dyrimidin-4- yltaminolethanol.
F3C
Figure imgf000061_0003
MS (ESI): mass calcd. for C20Hi8F3N3O21 389.1 ; m/z found, 390.2 [M+H]*. 1H NMR (CD3OD): 8.46 (s, 1H)1 7.57-7.54 (m, 2H)1 7.46-7.42 (m, 3H)1 7.36-7.32 (m, 2H)1 7.27-7.23 (m, 1H)1 7.14-7.11 (m. 1H)1 6.89 (s. 1H)1 4.91-4.88 (m. 1H)1 4.63-4.57 (m. 2H)1 3.77-3.69 (m, 1H)1 3.62-3.58 (m. 1H). Example 26: HRV2-f{6-(4-Chloro-3-methylPhenyltoyrimidin-4-vflamino)-1- phenylethanol trifluoroacetic acid salt.
Figure imgf000062_0001
MS (ESI): mass calcd. for C19Hi8CIN3O, 339.1; m/z found, 340.1 [M-I-H]+. 1H NMR (CD3OD): 8.64 (s, 1H)1 7.74 (s, 1H), 7.61-7.59 (m, 2H)1 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: H RV2-f{6-M-Chloro-3-fluorophenynpyrimidin-4-yl]amino)-1- phenylethanol trifluoroacetic acid salt.
Figure imgf000062_0002
MS (ESI): mass calcd. for Ci8H15CIFN3O, 343.1 m/z found, 344.1 [M+H]*. 1H 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)1 7.29-7.28 (m, 1H), 7.01 (s, 1 H), 4.95-4.93 (m, 1H), 3.93-3.90 (m, 1H), 3.79 (dd, J = 13.7, 8.2 Hz. 1H).
Example 28: M RV2-f(6-[4-Chloro-3-ftrifluoromethyitohenyl]Dyrimidin-4-vi)aminoV 1-phenylethanol trifluoroacetic acid salt.
Figure imgf000062_0003
MS (ESI): mass calcd. for C19Hi5CIF3N3O, 393.1; m/z found, 394.1 [M+H]+. 1H NMR (CD3OD): 8.65 (s, 1H), 8.24 (s, 1H), 8.04 (dd, J = 8.2, 2.2 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 7.1 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.29-7.26 (m, 1H), 7.03 (s, 1H)1 4.95-4.93 (m, 1H), 3.93-3.87 (m, 1H), 3.78 (dd, J = 13.2, 7.7 Hz, 1H). Example 29: 11 RV2-((6-r3-Fluoro-4-(trifluoromethoxy)DhenynDyrimidin-4- yl)amino)-1-phenylethanol trifluoroacetic acid salt.
Figure imgf000063_0002
Figure imgf000063_0001
MS (ESI): mass calcd. for Ci9H15F4N3O2, 393.1 ; m/z found, 394.1 [M+H]*. 1H NMR (CD3OD): 8.64 (s, 1H)1 7.88-7.85 (m, 1H)1 7.75-7.73 (m, 1H), 7.69-7.65 (m, 1 H), 7.44 (d, J = 7.7 Hz1 2H), 7.36 (t, J = 7.7 Hz1 2H)1 7.29-7.27 (m, 1 H)1 7.00 (s, 1H)1 4.95-4.92 (m, 1H), 3.93-3.84 (m, 1H), 3.77 (dd. J = 13.7, 7.7 Hz, 1H).
Example 30: (1RV2-ff6-(4-Ethoxy-3-fluorophenylbyrimidin-4-yl]amino)-1- phenylethanol trifluoroacetic acid salt.
Figure imgf000063_0003
MS (ESI): mass calcd. for C20H20FN3O2, 353.2; m/z found, 354.2 [M+H]*. 1H 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)1 6.94 (s, 1H)1 4.94-4.92 (m, 1 H), 4.23 (q, J = 7.1 Hz1 2H), 3.93-3.88 (m, 1 H)1 3.79 (dd, J = 13.7, 8.2 Hz, 1 H)1 1.47 (t, J = 7.1 Hz1 3H).
Example 31 : M RV2-f{6-(4-Ethoxy-3-methylPhenyltoyrim8din-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000063_0004
MS (ESI): mass calcd. for C2IH23N3O2, 349.2; m/z found, 350.2 [M+H]+. 1H NMR (CD3OD): 8.58 (s, 1 H)1 7.64-7.62 (m, 1H)1 7.60 (s. 1H)1 7.44-7.43 (m, 2H)1 7.37-7.34 (m, 2H)1 7.30 -7.27 (m, 1H), 7.11-7.10 (m. 1H)1 6.93 (s, 1 H)1 4.94-4.92 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H)1 3.91 (dd, J = 13.2, 4.4 Hz, 1H), 3.79 (dd, J = 13.7, 7.7 Hz1 1 H)1 2.30 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). Example 32: M RV2-((6-[4-(Cvdopropylmethoxytohenyl]Pyrimidin-4-yl)amino)-1 - phenylethanol trifluoroacetic acid salt.
p^o
Figure imgf000064_0001
Figure imgf000064_0002
MS (ESI): mass calcd. for C22H23N3O2, 361.2; m/z found, 362.2 [M+H]*. 1H NMR (CD3OD): 8.58 (s, 1H)1 7.74 (d, J = 8.8 Hz1 2H)1 7.45 (d, J = 7.7 Hz, 2H)1 7.37-7.34 (m, 2H)1 7.30 -7.26 (m, 1H)1 7.14 (d, J = 8.8 Hz, 2H)1 6.92 (s, 1H)1 4.94- 4.92 (m. 1H)1 3.95 (d, J = 7.1 Hz1 2H)1 3.91-3.87 (m, 1 H)1 3.80-3.76 (m, 1H)1 1.32- 1.26 (m, 1 H)1 0.67-0.63 (m, 2H), 0.40-0.37 (m, 2H).
Example 33: M RV2-f{6-(4-Butoxy-3-fluorophenynpyrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000064_0003
MS (ESI): mass calcd. for C22H24FN3O2, 381.2; m/z found, 382.2 [M+H]*. 1H NMR (CD3OD): 8.59 (s, 1 H)1 7.63-7.59 (m. 2H)1 7.43 (d, J = 7.7 Hz, 2H), 7.37- 7.34 (m. 2H)1 7.31 (t, J - 8.8 Hz, 1 H)1 7.29-7.28 (m. 1 H)1 6.93 (s, 1H)1 4.94-4.92 (m, 1H)1 4.17 (t, J = 6.6 Hz1 2H)1 3.94-3.86 (m. 1H)1 3.78 (dd. J = 13.7, 7.7 Hz, 1H), 1.86-1.81 (m. 2H)1 1.54 (sextet. J = 7.7 Hz1 2H)1 1.01 (t, J = 7.7 Hz1 3H).
Example 34: M RV2-f{6-(4-Butoxyphenyl)pyrimidin-4-yl]amino)-1 -phenylethanol trifluoroacetic acid salt.
Figure imgf000064_0004
MS (ESI): mass calcd. for C22H25N3O2, 363.2; m/z found. 364.2 [M+H]+. 1H NMR (CD3OD): 8.59 (s. 1H)1 7.75 (d, J = 8.8 Hz1 2H)1 7.45 (d, J - 7.7 Hz1 2H). 7.37-7.34 (m. 2H), 7.29-7.27 (m. 1 H), 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 (sextet, J = 7.7 Hz, 2H), 1.00 (t, J = 7.7 Hz, 3H).
Example 35: M RV2-f{6-(3-Fluoro-4-propoxyphenyltoyrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000065_0001
MS (ESI): mass calcd. for C2IH22FN3O2, 367.2; m/z found, 368.2 [M+H]+. 1H NMR (CD3OD): 8.61 (s, 1 H), 7.63-7.59 (m, 2H), 7.45-7.43 (m, 2H)1 7.37-7.26 (m, 4H), 6.94 (m, 1H), 4.94-4.92 (m, 1H), 4.13 (t, J = 6.6 Hz, 2H)1 3.93-3.90 (m, 1H), 3.82-3.77 (m, 1H), 1.87 (sextet, J = 7.1 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H).
Example 36: (1RV2-(f6-r3-Fluoro-4-M-methylethoxytohenynpyrimidin-4-yl)aminoV 1 -phenylethanol trifluoroacetic acid salt.
Figure imgf000065_0002
MS (ESI): mass calcd. for C2IH22FN3O2. 367.2; m/z found, 368.2 [M+H]+.
1H NMR (CD3OD): 8.60 (s, 1H)1 7.63-7.58 (m, 2H), 7.45-7.43 (m, 2H)1 7.37-7.27 (m, 4H), 6.93 (s, 1H), 4.94-4.92 (m, 1 H)1 4.81-4.74 (m, 1H), 3.94-3.88 (m, 1 H)1 3.81-3.77 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H).
Example 37: HRV2-K6-[4-(2-Methylpropoxytohenyl]pyrimidin-4-yl)aminoV1- phenylethanol trifluoroacetic acid salt.
Figure imgf000065_0003
MS (ESI): mass calcd. for C22H25N3O2, 363.2; m/z found, 364.2 [M +H]+. 1H NMR (CD3OD): 8.60 (s, 1 H), 7.74 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 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)1 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, 1 H), 2.11 (heptet, J = 6.6 Hz, 1H), 1.05 (d, J = 7.1 Hz, 6H).
Example 38: MRV2-f{6-(4-Methoxy-3-methylphenylk)yrimidin-4-yl]amino)-1- phenvlethanol trifluoroacetic acid salt.
Figure imgf000066_0001
MS (ESI): mass calcd. for C20H2IN3O2. 335.2; m/z found, 336.2 [M+H]*. 1H NMR (CD3OD): 8.58 (s, 1H), 7.66 (dd, J = 8.8, 2.7 Hz1 1 H)1 7.60-7.59 (m, 1H), 7.44 (d, J = 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, J - 13.7, 7.7 Hz, 1H)1 2.29 (s, 3H).
Example 39: M RV2-=fr6-(3-Chloro-4-methylphenyl)pyrimidln-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000066_0002
MS (ESI): mass calcd. for Ci9Hi8CIN3O1 339.1; m/z found, 340.1 [M+H]*. 1H NMR (CD3OD): 8.62 (s, 1H)1 7.85-7.84 (m, 1H), 7.63 (dd, J = 8.2, 1.7 Hz1 1H)1 7.54 (d. J = 8.2 Hz, 1 H), 7.44 (d, J = 7.1 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.98 (S1 1H)1 4.95-4.92 (m, 1H), 3.94-3.89 (m, 1H), 3.80 (dd, J - 13.7, 7.7 Hz, 1H), 2.48 (s, 3H).
Example 40: M RV2-f{6-(3.5-Dimethylphenynpyrimidin-4-yl)amino)-1 - phenvlethanol trifluoroacetic acid salt.
Figure imgf000066_0003
MS (ESI): mass calcd. for C20H2IN3O1 319.2; m/z found, 320.2 [M+H]*. 1H
NMR (CD3OD): 8.61 (s, 1 H), 7.45-7.43 (m, 2H), 7.39 (s, 2H)1 7.38-7.33 (m, 3H)1 7.30-7.27 (m, 1H)1 6.96 (s, 1H)1 4.95-4.93 (m, 1 H), 3.94-3.91 (m, 1H)1 3.80 (dd, J = 13.2, 7.7 Hz1 1H), 2.42 (s, 6H).
Example 41 : M RV2-((6-r3-Fluoro-4-t(rifluoromethyltohenynDyrimidin-4-vt)aminoV 1-Dhenylethanol trifluoroacetic acid salt.
Figure imgf000067_0001
MS (ESI): mass calcd. for Ci9Hi5F4N3O, 377.1 ; m/z found, 378.1 [M+H]*. 1H NMR (CD3OD): 8.63 (s, 1H), 7.93-7.90 (m, 1H), 7.86-7.81 (m, 2H), 7.45-7.44 (m, 2H)1 7.37-7.34 (m, 2H), 7.29-7.26 (m, 1 H), 7.04 (s, 1H), 4.95-4.92 (m, 1H), 3.90-3.83 (m, 1H), 3.78-3.73 (m, 1H).
Example 42: M RV2-((6-r3-Fluoro-5-(trifluoromethyltohenynpyrimidin-4-yl)aminoV 1-DhenylethanoJ trifluoroacetic acid salt.
Figure imgf000067_0002
MS (ESI): mass calcd. for Ci9Hi5F4N3O, 377.1 ; m/z found, 378.1 [M+H]+.
1H NMR (CD3OD): 8.64 (s, 1 H), 8.01 (s, 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 Hz1 2H)1 7.29-7.26 (m, 1H), 7.04 (s, 1H), 4.95-4.93 (m, 1H), 3.92-3.84 (m, 1 H), 3.77 (dd, J = 13.7, 7.7 Hz1 1H).
Example 43: M RV24f6-(3-Chloro-5-fluoroDheny1^Dyrimidin-4-yl]aminol-1 - phenyiethanol trifluoroacetic acid salt.
Figure imgf000067_0003
MS (ESI): mass calcd. for CI0H15CIFN3O1 343.1 ; m/z found, 344.2 [M+H]+. 1H 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)1 7.37-7.34 (m, 2H), 7.29-7.26 (m, 1H)1 7.00 (s, 1H), 4.95-4.92 (m, 1H), 3.93-3.86 (m, 1 H), 3.77 (dd, J = 13.7, 7.7 Hz, 1 H).
Example 44: H RV1-Phenyl-2-{r6-(4-propoxyphenyl)pyrimidin-4-yl]aminotethanol trifluoroacetic acid salt.
Figure imgf000068_0001
MS (ESI): mass calcd. for C2IH23N3O2, 349.2; m/z found, 350.2 [M+H]+. 1H NMR (CD3OD): 8.58 (s, 1H), 7.76-7.74 (m, 2H), 7.43 (d, J = 7.1 Hz1 2H), 7.37- 7.34 (m, 2H), 7.30-7.25 (m, 1H)1 7.15-7.13 (m. 2H)1 6.93 (s, 1H)1 4.94-4.92 (m. 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.94-3.86 (m, 1 H), 3.80-3.75 (m, 1H), 1.88-1.81 (m, 2H), 1.07 (t, J = 7.7 Hz, 3H).
Example 45: f 1 RV2-f{6-(2.1.3-Benzoxadiazol-5-v1byrimidin-4-v1laminoV1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000068_0002
MS (ESI): mass calcd. for C18Hi5N5O2. 333.1; m/z found, 334.2 [M+H]+. 1H NMR (CD3OD): 8.70 (s, 1H), 8.49-8.48 (m, 1H), 8.14 (d, J = 9.3 Hz, 1H), 7.88 (dd, J = 9.3 Hz, 1.7 Hz1 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.30- 7.27 (m, 1H)1 7.13 (s, 1 H), 4.97-4.94 (m, 1 H), 3.96-3.90 (m, 1 H), 3.79 (dd, J = 13.7, 8.2 Hz1 1H).
Example 46: M RV2-((6-r3-Methyl-4-(1 -methylethoxytohenyl]pyrimidin-4- vDamino V 1 -phenylethanol.
Figure imgf000068_0003
MS (ESI): mass calcd. for C22H25N3O2, 363.2; m/z found, 364.2 [M+H]*. 1H
NMR (CD3OD): 8.40 (s, 1H), 7.70-7.69 (m, 2H), 7.42 (d, J = 7.7 Hz1 2H), 7.36- 7.33 (m, 2H), 7.27-7.24 (m, 1H), 6.98 (d, J = 9.3 Hz, 1H), 6.80 (s, 1 H), 4.91-4.88 (m, 1H)1 4.68 (septet, J = 6.0 Hz1 1H)1 3.74-3.68 (m. 1H)1 3.57 (dd, J = 13.7, 7.7 Hz, 1 H), 2.24 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H).
Example 47: M RV2-({6-r3-Chloro-4-(trifluoromethyl)phenyl]-5-methylPyrimidin-4- yl)aminoVI-Dhenylethanol trifluoroacetic acid salt.
Figure imgf000069_0001
MS (ESI): mass calcd. for C20Hi7CIF3N3O, 407.1; m/z found, 408.1 [M+H]*. 1H NMR (CD3OD): 8.66 (s, 1H)1 8.04 (d, J = 8.2 Hz1 1H)1 7.89 (s, 1 H), 7.69 (d, J = 7.7 Hz1 1 H), 7.49 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.31-7.28 (m, 1 H)1 5.02 (dd, J = 7.7, 4.9 Hz, 1 H), 3.97-3.88 (m, 2H), 2.09 (s, 3H).
Example 48: MRV2-((6-r3-Fluoro-4-(trifluoiOmethy»phenyl]-5-methylPyrimidin-4- yl)aminoV1-phenylethanol trifluoroacetic acid salt.
Figure imgf000069_0002
MS (ESI): mass calcd. for C20Hi7F4N3O, 391.1 ; m/z found, 392.1 [M+H]*.
1H NMR (CD3OD): 8.66 (s, 1H), 7.97 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 10.4 Hz1 1H), 7.56 (d, J = 7.7 Hz1 1 H), 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: MRV2-((6-[4-(DifluoromethoxyV3.5-difluoroDhenyl]Dyrimidin-4- yl]aminoVI-phenylethanol trifluoroacetic acid salt.
Figure imgf000069_0004
Figure imgf000069_0003
MS (ESI): mass calcd. for C19Hi5F4N3O2, 393.1; m/z found, 394.1 [M+H]*. 1H 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), 7.30-7.26 (m, 1H), 6.99 (t, JH÷ = 72.0 Hz, 1H), 7.00 (s, 1H), 4.94-4.91 (m, 1H)1 3.92-3.85 (m, 1H), 3.79-3.74 (m, 1H). Example 50: 2-[4-(6-f{(2RV2-Hvdroxy-2-Dhenylethyt1aminotoyrimidin-4-yl)Dhenyt1- 2-methyiDroDanenitrile trifluoroacetic acid salt.
Figure imgf000070_0001
MS (ESI): mass calcd. for C22H22N4O, 358.2; m/z found, 359.2 [M+H]+. 1H NMR (CD3OD): 8.67 (s, 1H)1 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)1 4.93 (dd, J = 7.3, 4.3 Hz, 1H), 3.94 (dd, J = 13.6, 4.3 Hz, 1H)1 3.80 (dd, J = 13.9, 7.8 Hz, 1H), 1.78 (S, 6H).
Example 51: 1-r2-Fluoro-4-(6-ffl2RV2-h^roxy-2-phenylethyflamino)pyrimidin-4- yl)phenyl]ethanone trifluoroacetic acid salt.
Figure imgf000070_0002
MS (ESI): mass calcd. for C20Hi8FN3O2, 351.1 ; m/z found, 352.2 [M+H]*. 1H NMR (CD3OD): 8.69 (s, 1 H), 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, J = 7.2 Hz, 2H), 7.30-7.28 (m, 1 H), 7.06 (S, 1H), 4.95-4.93 (m, 1H), 3.92 (dd, J = 13.5, 3.6 Hz, 1H), 3.79 (dd, J = 13.8, 7.9 Hz, 1H), 2.67 (d, J = 4.3 Hz, 3H).
Example 52: M Ry∑-Ke-ra.S-DimethyM-M-methyiethoxytohenyl]pyrimidin^- vflaminoVI-phenylethanol trifluoroacetic acid salt.
Figure imgf000070_0003
MS (ESI): mass calcd. for C23H27N3O2, 377.2; m/z found, 378.2 [M+H]*. 1H NMR (CD3OD): 8.60 (s, 1H), 7.48 (s, 2H)1 7.43 (d, J = 7.2 Hz, 2H), 7.37-7.35 (m, 2H), 7.30-7.27 (m, 1 H), 6.93 (s, 1 H), 4.94-4.92 (m, 1 H), 4.37 (septet, J = 6.3 Hz, 1 H), 3.91 (dd, J = 13.5, 4.3 Hz, 1 H), 3.78 (dd, J = 13.8, 8.2 Hz1 1 H), 2.36 (s, 6H), 1.31 (d. J = 6.3 Hz, 6H).
Example 53: HRV2-f{6-HH-lndol-6-yltoyrimidin-4-yriamino)-1-phenylethanol trifluoroacetic acid salt.
Figure imgf000071_0001
MS (ESI): mass calcd. for C20Hi8N4O, 330.2; m/z found, 331.2 [M+H]*. 1H NMR (CD3OD): 8.60 (s, 1H)1 7.88 (s. 1H)1 7.77 (d. J = 8.2 Hz, 1 H), 7.50 (d, J = 2.7 Hz, 1H), 7.46-7.44 (m, 2H)1 7.43 (dd. J = 8.2. 1.7 Hz1 1H)1 7.36 (t, J = 7.7 Hz1 2H)1 7.30-7.27 (m. 1 H)1 7.03 (s, 1H), 6.59 (d, J = 3.3 Hz1 1H)1 4.95-4.93 (m. 1H)1 3.94- 3.91 (m, 1 H), 3.82-3.78 (m, 1H).
Example 54: MRV1-Phenyl-2-l{6-(3.4.5-trifluorophenynpyrimidin-4- yl]aminotethanol trifluoroacetic acid salt.
Figure imgf000071_0002
MS (ESI): mass calcd. for CI8HUF3N3O, 345.1; m/z found. 346.1 [M+H]*. 1H NMR (CD3OD): 8.61 (s, 1H)1 7.70-7.68 (m, 2H)1 7.43 (d. J = 7.7 Hz1 2H)1 7.37- 7.33 (m. 2H)1 7.28-7.26 (m. 1H)1 6.97 (s, 1 H)1 4.94-4.92 (m, 1H)1 3.91-3.83 (m. 1H)1 3.77 (dd, J = 13.7. 7.7 Hz1 1H).
Example 55: M RV2-f{6-M -Methyl-1 H-indol-2-v»Pyrimidin-4-yl]amino^1 - Dhenylethanol trifluoroacetic acid salt.
Figure imgf000071_0003
MS (ESI): mass calcd. for C2IH20N4O1 344.2; m/z found. 345.2 [M+H]+. 1H NMR (CD3OD): 8.65 (s. 1 H)1 7.68 (d. J = 7.7 Hz1 1 H)1 7.54 (d, J = 8.2 Hz1 1 H)1 7.45 (d, J = 7.1 Hz1 2H)1 7.41-7.35 (m, 3H)1 7.31-7.28 (m, 1 H), 7.20-7.17 (m, 1H), 7.09 (S1 1H), 6.96 (S1 1H), 4.96-4.90 (m, 1H)1 3.98-3.88 (m. 1H), 3.91 (s, 3H), 3.83-3.77 (m, 1H).
Example 56: M RV2-CT6-(5-Methy1-1 -benzothioDhen-2-yl^Dyrimkiin-4-v1laminoV-1 ■ phenyiethanol.
Figure imgf000072_0001
MS (ESI): mass calcd. for C2IH19N3OS, 361.1 ; m/z found, 362.2 [M+H]+. 1H NMR (CD3OD): 8.39 (S1 1H), 7.92 (s, 1 H), 7.75 (d, J = 8.2 Hz, 1H)1 7.66 (s, 1H), 7.43 (d, J = 7.1 Hz, 2H), 7.35 (t. J = 7.7 Hz1 2H), 7.27-7.23 (m, 2H), 6.94 (s, 1 H), 4.92-4.89 (m, 1H), 3.76-3.71 (m, 1H)1 3.59 (dd, J = 13.7, 7.7 Hz, 1H)1 2.46 (s. 3H).
Example 57: r4-(64T(2RV2-Hvdroxy-2-Dhenylethynamino)Dyrimidin-4- yl)phenyl]fohenyl)methanone trifluoroacetic acid salt.
Figure imgf000072_0002
MS (ESI): mass calcd. for C25H2IN3O2. 395.2; m/z found, 396.3 [M +H]+. 1H NMR (CD3OD): 8.69 (s. 1 H), 7.98-7.94 (m, 4H), 7.82-7.81 (m, 2H), 7.71-7.68 (m, 1 H), 7.57 (t, J - 7.7 Hz, 2H)1 7.44 (d, J = 7.1 Hz1 2H), 7.36 (t, J = 7.1 Hz, 2H)1 7.30-7.27 (m. 1 H), 7.08 (s, 1H), 4.96-4.94 (m, 1H)1 3.96-3.90 (m. 1H), 3.82 (dd, J = 13.7. 8.2 Hz1 1H).
Example 58: M RV2-(f6-(3.5-Difluorophenyl^Dyrimidin-4-yl]aminoV1-Dheny1ethanol trifluoroacetic acid salt.
Figure imgf000072_0003
MS (ESI): mass calcd. for Ci8Hi5F2N3O, 327.1; m/z found, 328.3 [M+H]*. 1H NMR (CD3OD): 8.64 (s, 1 H), 7.49-7.43 (m, 4H), 7.37-7.34 (m, 2H), 7.31-7.27 (m, 2H), 7.00 (s, 1H)1 4.95-4.92 (m, 1H), 3.93-3.85 (m, 1H), 3.78 (dd, J = 13.7, 7.7 Hz1 1H).
Example 59: M RV2-f{6-(3.4-DifluoiOPhenyl)pyrimidin-4-yl]amino)-1-phenylethanol trifluoroacetic acid salt.
Figure imgf000073_0001
MS (ESI): mass calcd. for Ci8Hi5F2N3O, 327.1 ; m/z found. 328.3 [M+H]*. 1H NMR (CD3OD): 8.64 (s, 1 H), 7.82-7.78 (m, 1 H), 7.67-7.63 (m, 1 H)1 7.56-7.51 (m, 1 H), 7.43 (d, J = 7.7 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.24 (m, 1H), 6.97 (s, 1H), 4.95^.92 (m, 1 H), 3.94-3.87 (m, 1H), 3.78 (dd, J = 13.7, 7.7 Hz, 1H).
Example 60: MRV2-K6-r3-Chloro-4-(trifluoromethynphenyn-2- (methy1sulfany1k)yrimidin-4-yl]aminoV1-Dhenylethanol trifluoroacetic acid salt.
Figure imgf000073_0002
MS (ESI): mass calcd. for C2OHi7CIF3N3OS, 439.1 ; m/z found, 440.1 [M+H]*. 1H NMR (CD3OD): 8.09 (s, 1H)1 7.95 (d, J = 8.1 Hz, 1 H)1 7.90 (d, J - 8.1 Hz1 1H)1 7.44 (d, J - 7.6 Hz, 2H)1 7.37-7.33 (m, 2H), 7.29-7.25 (m. 1H)1 6.69 (s. 1H), 4.96-4.93 (m, 1H), 3.91-3.85 (m, 1H)1 3.78-3.73 (m. 1 H)1 2.65 (s, 3H).
Example 61: M RV2-α2-Amino-6-r3-chloro-4-t(rifluoromethyltohenynpyrimidin-4- vflaminoVI-phenylethanol trifluoroacetic acid salt.
Figure imgf000073_0003
MS (ESI): mass calcd. for Ci9H16CIF3N4O, 408.1 ; m/z found, 409.1 [M+H]*. 1H NMR (CD3OD): 8.00-7.98 (m, 2H), 7.83-7.80 (m, 1 H), 7.45-7.43 (m, 2H), 7.38- 7.34 (m, 2H)1 7.30-7.26 (m, 1 H), 6.44 (s, 1 H)1 4.92-4.89 (m, 1 H), 3.84 (dd, J = 13.6, 4.5 Hz1 1H), 3.65 (dd, J = 13.6, 8.3 Hz, 1H).
Example 62: M RV2-α6-r3-Chloro-4-(trif]uoromethyJ)DhenynDyrimklin-4-v1)aminoV- 1-(4-fluoroDheny1 Methanol.
Figure imgf000074_0001
MS (ESI): mass calcd. for Ci9H14CIF4N3O, 411.1; m/z found, 412.1 [M+H]\ 1H NMR (CD3OD): 8.50 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 8.3 Hz1 1 H), 7.88 (d, J = 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)1 3.76-3.70 (m, 1H), 3.63-3.57 (m, 1H).
Example 63: M RV2-f{6-(6-Methoxypyridin-3-yltoyrimidin-4-vflamino)-1 - phenylethanol.
Figure imgf000074_0002
MS (ESI): mass calcd. for C18H18N4O2, 322.1 ; m/z found, 323.2 [M+H]+. 1H NMR (CD3OD): 8.90-8.83 (m, 1H), 8.62 (s, 1H), 8.35 (dd, J = 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, 1 H), 4.15 (s, 3H), 3.96-3.85 (m, 1H), 3.76 (dd, J = 7.7, 13.7 Hz1 1H).
Example 64: M RV2-f{6-(6-Ethoxypyridin-3-yl)pyrimidin-4-yl]amino}-1 - phenylethanol.
Figure imgf000074_0004
Figure imgf000074_0003
MS (ESI): mass calcd. for C19H20N4O2, 336.2; m/z found, 337.2 [M+H]*. 1H
NMR (CD3OD): 8.43 (d, J = 2.5 Hz, 1H), 8.21 (s, 1H), 7.93 (dd, J = 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)1 4.15 (q, J = 7.1 Hz, 2H), 3.54-3.43 (m, 1H), 3.35 (dd, J = 7.7, 13.7 Hz, 1H), 1.17 (t, J = 7.1 Hz1 3H).
Example 65: HRV2-(f6-[4-(Dimethylaminotohenyl]pyrimk_in-4-yl)amino)-1- phenylethanol.
Figure imgf000075_0001
MS (ESI): mass calcd. for C20H22N4O, 334.2; m/z found, 335.2 [M+H]*. 1H 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, 1 H), 6.85-6.79 (m, 2H), 6.79-6.76 (m, 1H), 4.95-4.87 (m, 1H), 3.78-3.65 (m, 1H)1 3.58 (dd, J = 13.7, 7.6 Hz, 1H)1 3.03 (s, 6H).
Example 66: M RV2-((6-[4-(Methylsulfonyl)DhenyflPyrimidin-4-vnaminoV1 - phenylethanol.
Figure imgf000075_0002
MS (ESI): mass calcd. for C19Hi9N3O3S, 369.1; m/z found, 370.1 [M+H]*.
1H NMR (CD3OD): 8.53 (s, 1H)1 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).
Example 67: N-Cvdopropyl-4-(6-{K2RV2-hydrOxy-2-phenylethyl]amino)pyrimidin- 4-vhbenzenesulfonamide.
Figure imgf000075_0003
MS (ESI): mass calcd. for C2IH22N4O3S, 410.1 ; m/z found, 411.2 [M+H]+. 1H 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)1 4.97-4.86 (m, 1H)1 3.86-3.67 (m, 1H)1 3.63 (dd, J = 13.7, 7.7 Hz, 1H), 2.30-2.12 (m, 1H), 0.63- 0.41 (m, 4H).
Example 68: MRV2-f{6-(3-Chloro-4-ethoxyphenyltoyrimidin-4-yl]amino)-1- phenyiethanol.
Figure imgf000076_0001
MS (ESI): mass calcd. for C2OH20CIN3O2, 369.1 ; m/z found. 370.2 [M+H]*. . 1H NMR (CD3OD): 8.43 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.7, 2.2 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 2H), 7.38-7.32 (m, 2H), 7.30-7.25 (m, 1H)1 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, J = 13.8, 7.7 Hz, 1H), 1.47 (t, J = 7.0 Hz, 3H).
Example 69: HRV2-K2'-Moroholin-4-yl-4.5'-biPyrimidin-6-yltamino1-1- phenylethanol.
Figure imgf000076_0002
MS (ESI): mass calcd. for C20H22N6O2, 378.2; m/z found, 379.2 [M+H]+. 1H NMR (CD3OD): 8.87 (d, J = 2.9 Hz, 2H), 8.43 (s, 1 H), 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, J = 13.8, 7.7 Hz, 1H).
Example 70: (1RV24r6-(6-Moroholin-4-viDyridin-3-v1^Dyrimidin-4-vflaminoV1- phenylethanol.
Figure imgf000076_0003
MS (ESI): mass calcd. for C2IH23N5O2, 377.2; m/z found, 378.2 [M+H]+. 1H NMR (CD3OD): 8.74-8.64 (m, 1 H), 8.42 (s, 1 H), 8.09 (dd, J = 9.0, 2.5 Hz, 1 H), 7.50-7.39 (m, 2H)1 7.38-7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.93-6.85 (m, 1 H), 6.83- 6.80 (m, 1H), 4.94-4.87 (m, 1 H), 3.86-3.76 (m, 4H)1 3.76-3.68 (m, 1H), 3.64-3.56 (m, 5H).
Example 71 : HRV2-l{6-(3-Fluoro-4-methoxyphenyltoyrimidin-4-yl]amino)-1- phenylethanol.
Figure imgf000077_0001
MS (ESI): mass calcd. for C19H16FN3O2, 339.1 ; m/z found, 340.2 [M+H]*.
1H NMR (CD3OD): 8.33 (s, 1H)1 7.65-7.52 (m, 2H), 7.37-7.29 (m, 2H), 7.27-7.22 (m, 2H), 7.19-7.13 (m, 1 H)1 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. J = 13.8, 7.7 Hz, 1 H).
Example 72: MRV2-f{6-(2.3-Dihydro-1.4-benzodioxin-6-yl)pyrimidin-4-vt1amino)- 1-phenylethanol.
Figure imgf000077_0002
MS (ESI): mass calcd. for C20Hi9N3O3, 349.1; m/z found, 350.2 [M+H]+. 1H NMR (CD3OD): 8.41 (s, 1 H), 7.47-7.42 (m, 3H), 7.42-7.37 (m, 1H), 7.37-7.33 (m, 2H), 7.30-7.24 (m, 1 H), 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).
Example 73: M RV2-((6-r3-Chloro-4-(trifluoromethy»phenyn-2-methylPyrimidin-4- yl)amino>-1 -ohenylethanol.
Figure imgf000077_0003
MS (ESI): mass calcd. for C20Hi7CIF3N3O, 407.1 ; m/z found, 408.1 [M+H]*. 1H NMR (CD3OD): 8.15 (s, 1H), 8.00-7.94 (m, 1H), 7.89-7.85 (m, 1H), 7.48-7.39 (m, 2H), 7.39-7.32 (m, 2H), 7.29-7.24 (m, 1H), 6.81-6.70 (m, 1 H), 4.97-4.85 (m, 1H)1 3.87-3.67 (m, 1H), 3.66-3.58 (m, 1 H)1 2.52 (s, 3H).
Example 74: M RV2-l{6-M -Benzyl- 1 H-Dyrazol-4-v1^Dyrimidin-4-vJ1aminoV1 - phenylethanol.
Figure imgf000078_0001
MS (ESI): mass calcd. for C22H2IN5O, 371.2; m/z found, 372.2 [M+H]*. 1H NMR (CD3OD): 8.34 (s, 1 H), 8.20 (s, 1 H), 8.02 (s, 1 H), 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, 1 H), 3.77-3.61 (m, 1H), 3.62-3.52 (m, 1H).
Example 75: M Rl2-l{6-(6-Fluoro-5-methylPyridin-3-yl)pyrimidin-4-yl]amino)-1- phenylethanol.
Figure imgf000078_0002
MS (ESI): mass calcd. for Ci8H17FN4O1 324.1; m/z found, 325.2 [IvHH]+. 1H 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)1 7.07-7.01 (m, 1H), 6.60 (s, 1H), 5.04-4.84 (m, 1H)1 3.86- 3.67 (m, 1 H)1 3.67-3.56 (m, 1 H)1 2.43 (s, 3H).
Example 76: 4-(6-(K2RV2-Hvdroxy-2-phenylethyl]amino)pyrimidin-4-yl)-N.N- dimethylbenzenesulfonamide.
Figure imgf000078_0003
MS (ESI): mass calcd. for C20H22N4O3S1 398.1 ; m/z found, 399.2 [M+H]*.
1H NMR (CD3OD): 8.57-8.46 (m. 1H), 8.19-8.11 (m, 2H)1 7.93-7.88 (m, 2H), 7.49- 7.42 (m, 2H), 7.39-7.33 (m, 2H)1 7.30-7.24 (m, 1 H)1 7.03-6.94 (m, 1H)1 5.00-4.84 (m. 1H), 3.84-3.68 (m, 1H)1 3.67-3.57 (m, 1 H)1 2.82-2.61 (m, 6H).
Example 77: 5-(6-f{(2RV2-Hvdroxy-2-phendethyl]amino}pyrimidin-4-vQpyridine-2- carbonitrile.
Figure imgf000079_0001
MS (ESI): mass calcd. for Ci8Hi5N5O, 317.1 ; m/z found, 318.2 [M+H]*. 1H NMR (CD3OD): 9.32-9.12 (m, 1H)1 8.60-8.43 (m, 2H), 8.04-7.93 (m. 1H)1 7.49- 7.41 (m, 2H), 7.39-7.33 (m, 2H), 7.30-7.25 (m. 1 H)1 7.08-7.00 (m. 1 H)1 5.00-4.84 (m, 1 H)1 3.86-3.68 (m, 1 H)1 3.68-3.58 (m, 1 H).
Example 78: M RV2-W6-r6-(Dimethylaminotoyridin-3-vflpyrimidin-4-yl)aminoV1 - phenylethanol.
Figure imgf000079_0002
MS (ESI): mass calcd. for C19H2iN5O, 335.2; m/z found, 336.2 [M+H]+. 1H
NMR (CD3OD): 8.78-8.67 (m, 1H)1 8.52-8.46 (m, 1H), 8.14 (dd, J = 9.1 , 2.5 Hz, 1H)1 7.58-7.49 (m, 2H)1 7.48-7.41 (m. 2H)1 7.40-7.33 (m, 1H), 6.94-6.77 (m, 2H), 4.94-4.86 (m, 1 H), 3.92-3.73 (m, 1 H), 3.72-3.62 (m, 1 H)1 3.25 (s. 6H).
Example 79: M RV 1 -Phenyl-2-ffl>-[4-(piperidin-1 -ylsulfonyl)phenyl]pyrimidin-4- yllaminotethanol.
MS (ESI): mass calcd. for C23H26N4O3S, 438.2; m/z found, 439.2 [M+H]*. 1H NMR (CD3OD): 8.52 (s, 1H)1 8.17-8.09 (m, 2H), 7.90-7.85 (m, 2H), 7.48-7.41 (m. 2H), 7.39-7.33 (m, 2H), 7.30-7.23 (m, 1 H), 7.02-6.93 (m. 1 H)1 5.04-4.87 (m, . 1H)1 3.87-3.66 (m, 1H)1 3.66-3.59 (m, 1H), 3.10-2.96 (m. 4H)1 1.72-1.53 (m, 4H)1 1.53-1.40 (m, 2H).
Example 80: (1 RM -Phenyt-2-((6-[4-( Dyrrolidin-1 -ylsulfonyltohenyl]Pyrimidin-4- yllaminotethanol.
Figure imgf000080_0001
<n>
MS (ESI): mass calcd. for C22H24N4O3S1 424.2; m/z found, 425.2 [M +H]+. 1H NMR (CD3OD): 8.57-8.45 (m, 1 H)1 8.19-8.07 (m, 2H)1 7.98-7.91 (m, 2H)1 7.49- 7.39 (m, 2H)1 7.39-7.32 (m, 2H), 7.30-7.24 (m, 1H), 7.04-6.90 (m, 1 H), 5.01-4.85 (m, 1H), 3.87-3.69 (m, 1H), 3.67-3.59 (m, 1H)1 3.28-3.19 (m. 4H)1 1.91-1.61 (m. 4H).
Example 81: 4-(6-ff(2RV2-Hvdroxy-2-phenylethynamino)pyrimk.in-4- yl)benzenesulfonamide.
Figure imgf000080_0002
MS (ESI): mass calcd. for C18Hi8N4O3S1 370.1 ; m/z found, 373.2 [M-I-H]+. 1H NMR (CD3OD): 8.33 (s, 1 H), 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, 1 H)1 3.49-3.40 (m, 1H).
Example 82: HRV2-l{6-(4-Fluorophenyl)pyrimidin-4-yl]aminoM-ohenylethanol trifluoroacetic acid salt.
MS (ESI): mass calcd. for C18Hi6FN3O1 309.1; m/z found. 310.2 [M+H]+. 1H NMR ((CDs)2CO): 8.89 (br hump, 4 H)1 8.06 (br s. 2H)1 7.49 (d, J - 7.0 Hz. 2H). 7.37-7.34 (m, 4H)1 7.30-7.26 (m, 2H)1 5.05 (br s, 1 H)1 3.98 (br s, 1 H)1 3.75 (br s, 1H).
Example 83: M RV2-{r6-(3-Chloro-4-fluoroDhenyl)DVrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000081_0001
MS (ESI): mass calcd. for Ci8Hi5CIFN3O, 343.1 ; m/z found, 344.1 [M+H]*. 1H NMR ((CDa)2CO): 10.06 (br hump, 2H), 9.20-8.6 (br m, 2H), 8.13-7.98 (m, 2H), 7.51-7.47 (m, 2H)1 7.36-7.33 (m, 2H), 7.28-7.25 (m, 1H), 5.04 (br s, 1 H), 3.96 (br s, 1H)1 3.73 (br s, 1 H).
Example 84: MRV2-α6-r3-(MethylsulfanylbhenyJlDyrimiclin-4-v1)aminoV1- phenylethanol trifluoroacetic acid salt.
Figure imgf000081_0002
MS (ESI): mass calcd. for Ci9H19N3OS, 337.1 ; m/z found, 338.1 [M+H]*.
1H NMR ((CDa)2CO): 11.25 (br hump, 2H), 8.88 (s, 1H), 7.71 (s, 1H), 7.59 (br s, 1 H), 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)1 4.00-3.68 (br m, 2H), 2.55 (s, 3H).
Example 85: M RV2-f{6-M H-lndol-5-vQpyrimidin-4-yl]amino}-1 -phenylethanol trifluoroacetic acid salt.
Figure imgf000081_0003
MS (ESI): mass calcd. for C20Hi8N4O, 330.2; m/z found, 331.2 [M+H]*. 1H NMR ((CDa)2CO): 10.85 (s, 1H), 9.02 (br s. 1H)1 8.68 (s. 1 H)1 8.10 (s, 1H)1 7.55- 7.50 (m, 5H), 7.35 (t, J = 7.0 Hz, 2H), 7.26 (t, J - 7.0 Hz, 1 H)1 6.56 (s, 1 H), 5.10- 5.01 (br m, 1H), 3.95-3.92 (m, 1H), 3.70-3.65 (m. 1 H). Example 86: M RV1 -Phenyl-2-r(6-ouirM)lin-3-ylPyrimidin-4-yltamino1ethanol trifluoroacetic acid salt.
Figure imgf000082_0001
Figure imgf000082_0002
MS (ESI): mass calcd. for C2IHi8N4O1 342.2; m/z found, 343.2 [M+H]+. 1H NMR ((CDs)2CO): 12.63 (br s, 3H), 9.59-8.81 (m, 3H)1 8.26-8.14 (m, 2H)1 8.00 (br s, 1H), 7.81 (br s, 1H), 7.57-7.48 (m, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.29-7.26 (br t, J = 7.0 Hz1 1H), 5.12-5.07 (br m, 1H)1 4.04-3.81 (br m, 2H).
Example 87: M R)-2-f{6-(1 -Benzothk>Dhen-3-v1byrimidin-4-v1laminol-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000082_0003
Figure imgf000082_0004
MS (ESI): mass calcd. for C20H17N3OS, 347.1; m/z found, 348.1 [M+H]*. 1H NMR ((CDa)2CO): 10.13 (br hump, 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)1 7.36-7.32 (m, 3H), 7.27 (t, J = 7.0 Hz, 1 H), 5.06 (br s, 1 H), 3.98 (br s, 1 H), 3.71 (br s, 1 H).
Example 88: 2-Fluoro-4-(6-f{(2RV2-hydroxy-2-phenylethyl]amino)pyrimidin-4- yl)benzonitrile trifluoroacetic acid salt.
Figure imgf000082_0005
MS (ESI): mass calcd. for C19Hi5FN4O, 334.1 ; m/z found, 335.2 [M+H]*. 1H NMR ((CDa)2CO): 8.34 (br s, 1H), 8.03-8.00 (m, 2H)1 7.73 (br hump, 3H), 7.47 (br s, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.27 (t, J = 7.8 Hz, 1 H), 5.02 (br hump, 1 H), 3.95-3.68 (br m, 2H).
Example 89: 2-Fluoro-5-(6-f{(2RV2-hydroxy-2-phenylethyflamino)pyrimidin-4- yl)benzonitrile trifluoroacetic acid salt.
Figure imgf000083_0001
MS (ESI): mass calcd. for C19Hi5FN4O1 334.1 ; m/z found, 335.2 [M+H]+. 1H NMR ((CDa)2CO): 8.83 (br hump, 1H), 8.55-8.35 (br m, 3H)1 7.76 (br hump, 2H)1 7.62 (t, J = 9.0 Hz, 1 H), 7.47 (br s, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.26 (t, J * 7.2 Hz, 1 H), 5.02 (br hump, 1H), 3.95-3.68 (br m, 2H).
Example 90: M RV2-fl6-M -Methyl-1 H-indol-5-vQpyrimidin-4-yl]amino}-1 - Dhenylethanol trifluoroacetic acid salt.
Figure imgf000083_0002
MS (ESI): mass calcd. for C2IH20N4O, 344.2; m/z found, 345.2 [M+H]+. 1H
NMR ((CD3)2CO): 9.11 (s, 1H), 8.66 (s, 1H)1 8.04 (s. 1 H), 7.54-7.44 (m, 4H), 7.36- 7.33 (m, 4H), 7.27 (t, J = 7.2 Hz1 1H), 7.14 (s. 1H)1 6.52 (s, 1H)1 5.10-4.99 (m. 1H), 3.92-3.61 (br m, 2H), 3.81 (s, 3H).
Example 91 : M RV2-K6-l4-r(1 -Methy1ethy1^sulfanyliDhenyl)Dyrimidin-4-yl)aminol-1 ■ phenylethanoJ trifluoroacetic acid salt.
Figure imgf000083_0003
MS (ESI): mass calcd. for C2IH23N3OS, 365.2; m/z found, 366.2 [M+H]*. 1H NMR ((CDs)2CO): 9.31 (br s. 1H), 8.83 (s. 1H)1 7.80 (brd, J = 8.4 Hz1 2H)1 7.47-7.41 (m, 4H), 7.33 (t, J = 7.8 Hz, 2H)1 7.26 (br s, 2H), 5.09-5.02 (br m, 1H)1 3.97-3.62 (br m, 3H), 1.32 (d, J = 6.6 Hz1 6H).
Example 92: r4-(6-ffl2RV2-HvdiOxy-2-phenylethyflamino)pyrimidin-4- ynohenyliacetonitrile trifluoroacetic acid salt.
Figure imgf000084_0001
OH
MS (ESI): mass calcd. for C20Hi8N4O1 330.2; m/z found, 331.2 [M+H]*. 1H NMR ((CD3J2CO): 9.30 (s, 1 H), 8.88 (s, 1 H), 7.92 (d, J = 8.6 Hz, 2H), 7.79 (br hump, 1H), 7.58 (d, J = 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)1 3.98-3.69 (m, 2H).
Example 93: MRV2-^6-r3-Chloro-4-(trifluoromethyl)Dhenyt1-2- (trifluoromethy»Dyrimidin-4-yl)aminoV1-Dhenylethanol trifluoroacetic acid salt.
Figure imgf000084_0002
MS (ESI): mass calcd. for C20HuCIFeN3O1 461.1 ; m/z found, 462.1 [M+Hf..
1H NMR ((CDa)2CO): 8.38-8.19 (br m, 2H), 7.99 (d, J = 8.4 Hz1 1H), 7.49-7.45 (m, 3H), 7.35 (t, J = 7.8 Hz. 2H), 7.26 (t, J = 7.2 Hz, 1H)1 5.00 (br s, 1H), 3.97-3.54 (br m, 2H).
Example 94: HRV2-f{6-(3.4-DichloroDhenyiy2-methylDyrimidin-4-yl)amino)-1- phenylethanol.
Figure imgf000084_0003
MS (ESI): mass calcd. for Ci9Hi7Cl2N3O, 373.1 ; m/z found, 374.1 [M+H]+. 1H NMR (CD3OD): 8.06 (d, J = 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)1 3.59 (dd, J = 7.4, 13.8 Hz, 1H)1 2.49 (s, 3H).
Example 95: M RV2-l{6-(3.4-Dichlorophenyl Vpyrimidin-4-yl)amino)-1 - phenvlethanol.
Figure imgf000085_0001
MS (ESI): mass calcd. for CIeH15Cl2N3O, 359.1 ; m/z found. 360.1 [M+H]+. 1H NMR (CD3OD): 8.46 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H)1 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: (1 RV2-K6-[4-(EthylsulfanyltohenyliPyrimidin-4-yl)amino)-1 - phenylethanol.
Figure imgf000085_0002
MS (ESI): mass calcd. for C20H2IN3OS, 351.1 m/z found, 352.2 [M+H]*. 1H NMR (CD3OD): 8.44 (s, 1 H), 7.82 (d, J = 8.8 Hz, 2H), 7.44-7.42 (m, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.35-7.32 (m, 2H), 7.27-7.24 (m, 1 H), 6.86 (s, 1 H), 4.89 (dd, J - 7.7, 4.4 Hz, 1H), 3.75-3.69 (m, 1H), 3.58 (dd, J = 13.7, 7.7 Hz, 1H), 3.02 (q, J = 7.1 Hz, 2H). 1.33 (t, J = 7.1 Hz, 3H).
Example 97: M RV2-f{6-(3-Ethoxy])henyltoyrimidin-4-vflaminoM -phenylethanol.
^o
Figure imgf000085_0003
MS (ESI): mass calcd. for C20H2IN3O2, 335.2; m/z found, 336.2 [M+H]*. 1H NMR (CD3OD): 8.44 (s, 1 H)1 7.44-7.41 (m.4H). 7.38-7.32 (m, 3H)1 7.28-7.24 (m, 1H)1 7.01 (ddd, J = 8.1 , 2.5, 1.3 Hz1 1H), 6.87 (s, 1H), 4.91-4.89 (m, 1 H), 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: HRV1-Phenyl-2-f{6-(3-propoxyphenyl)pyrimidin-4-vflamino)ethanol.
Figure imgf000085_0004
MS (ESI): mass calcd. for C2IH23N3O2, 349.2; m/z found, 350.2 [M+H]+. 1H 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)14.00 (t, J = 6.6 Hz, 2H), 3.76-3.68 (m, 1H)1 3.61-3.55 (m, 1H)1 1.87-1.78 (m, 2H)1 1.07 (t, J = 7.3 Hz, 3H).
Example 99; M RV2-fl6-(3-Butoxvphenvlk)vrimidin-4-vllamino)-1 -phenvlethanol.
Figure imgf000086_0001
MS (ESI): mass calcd. for C22H25N3O2, 363.2; m/z found, 364.1 [M-I-H]+. 1H 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, 1 H), 4.91-4.89 (m, 1H), 4.05 (t, J - 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, J = 7.6 Hz1 3H).
Example 100: M RV2-l{6-M -Benzothiophen-5-yl)pyrimidin-4-yl]amino)-1 - phenylethanol trifluoroacetic acid salt.
Figure imgf000086_0002
MS (ESI): mass calcd. for C20Hi7N3OS, 347.1 ; m/z found, 348.1 [M-I-Hf. 1H NMR (CD3OD): 8.67 (s, 1H), 8.31 (d, J = 1.6 Hz, 1 H), 8.17 (d, J - 8.2 Hz, 1 H)1 7.79 (d, J = 5.5 Hz, 1 H), 7.72 (dd, J - 8.2, 1.7 Hz, 1 H), 7.55 (d, J - 5.5 Hz, 1 H)1 7.46-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.30-7.28 (m, 1 H), 7.07 (s, 1H), 4.97-4.94 (m, 1H), 3.97-3.91 (m, 1 H), 3.82 (dd, J = 13.7, 7.7 Hz, 1H).
Example 101 : M RV2-α6-r3-Chloro-4-(trifluoromethyl)phenyn-2- fdimethylamino)pyrimidin-4-yl)aminoV1 -phenylethanol trifluoroacetic acid salt.
Figure imgf000086_0003
MS (ESI): mass calcd. for C2IH20CIF3N4O1 436.1; m/z found, 437.1 [M+H]*. 1H NMR (CD3OD): 8.01 (s, 1H), 7.95 (d, J - 8.2 Hz1 1H)1 7.80 (d, J = 7.7 Hz1 1H)1 7.43-7.41 (m, 2H)1 7.36-7.33 (m, 2H), 7.29-7.26 (m, 1 H), 6.32 (s, 1H), 4.94-4.93 (m, 1H), 3.85-3.81 (m, 1 H), 3.71 (dd, J - 13.7. 7.7 Hz1 1H)1 3.28 (s, 6H).
Example 102: MRl2-α6-r3-Fluoro-4-t(rifluoromethynphenyl]-2- (methylsulfany^Dyrimidin-4-vJ)aminoV1-phenylethanol trifluoroacetic acid salt.
Figure imgf000087_0001
MS (ESI): mass calcd. for C20Hi7F4N3OS1 423.1; m/z found, 424.1 [M+H]*. 1H NMR (CD3OD): 7.86-7.83 (m, 3H)1 7.43-7.42 (m, 2H), 7.36-7.33 (m, 2H)1 7.28- 7.25 (m. 1H)1 6.68 (s, 1H), 4.95-4.92 (m, 1 H)1 3.87-3.78 (m, 1H)1 3.73-3.69 (m, 1H), 2.62 (s, 3H).
The compounds in Examples 103-104 were prepared using methods analogous to those in Example 20, substituting the appropriate triazine in Step A, and the appropriate boronic acid in Step B.
Example 103: M RV1 -Phenyl-2-α4-r4-(trifluoromethyθDhenyn-1.3.5-triazin-2- yllaminotethanol trifluoroacetic acid salt.
Figure imgf000087_0002
MS (ESI): mass calcd. for Ci8H15F3N4O, 360.3; m/z found, 361.2 [M+H]+. 1H NMR (CD3OD1 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)1 3.88-3.60 (m, 2H).
Example 104: M RV2-((4-r3-Chloro-4-t(rifluoromethyl)phenyfl-1 ,3.5-triazin-2- vflaminoVI-phenylethanol trifluoroacetic acid salt.
Figure imgf000087_0003
MS (ESI): mass calcd. for C18Hi4CIF3N4O, 394.8; m/z found, 395.1 [M+H]+. 1H NMR (CD3OD, 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, J = 9.0 Hz, 2H), 7.36-7.20 (m, 3H), 4.96-4.94 (m, 1H), 3.87-3.62 (m, 2H).
Example 105: HRM-Phenyl-2-((6-r3-t(rifluoromethyl)phenyl]Pyrimidin-4- vftaminotethanol.
Figure imgf000088_0001
The title compound was prepared in a manner similar to Example 1 , with modifications to Step B as follows:
To a round bottomed flask were added 2-[(6-chloropyrimidin-4-yl)amino]-1- phenylethanol (62.4 mg, 0.25 mmol), 3-trifluoromethylphenyl boronic ackJ (71.2 mg, 0.38 mmol), K3PO4 (106.1 mg, 0.5 mmol), 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-dk>xane (2.5 mL). The reaction mixture was heated at reflux for 2.5 h, before cooling to rt, diluting with EtOAc (15 mL), washing with water (2x10 mL), drying, and concentrating to dryness. The crude residue was purified (FCC) to yield the title compound (35.7 mg, 40%). MS (ESI): mass calcd. for C19H16F3N3O, 359.1 ; m/z found, 360.2 [M+H]*. 1H NMR (CD3OD): 8.50 (s, 1H), 8.23 (s, 1H)1 8.15 (d, J - 7.8 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H)1 7.44 (d, J = 7.3 Hz, 2H)1 7.37- 7.33 (m, 2H)1 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: MRV1-Phenyl-2-[(6-l4-r(trifluoromethylk3XylDheny1)Dyrimidin-4- ylteminoiethanol.
Figure imgf000088_0002
Step A. 4-Chloro-6-(4-trifluoromethoxy-Dhenyl)-Dyrimidine. To a suspension of 4,6-dichloropyrimidine (2.18 g, 14.7 mmol) and 4- trifluoromethoxyphenyl boronic acid (3.32 g, 16.1 mmol) in DME (72 mL) and water (18 mL) were added K3PO4 (6.24 g, 29.4 mmol) and Pd(PPh3)4 (0.51 g, 0.44 mmol). The reaction mixture was heated at 85 °C under N2 for 16 h. The reaction mixture was cooled to rt and the organic layer separated, dried (MgSO4), and concentrated. The residue was purified (FCC) to give the title compound as a yellow solid (2.20 g, 54%).
Step B. To a solution consisting of 4-chloro-6-(4- trifluoromethoxy)phenylpyrimidine (0.137 g, 0.5 mmol) and (R)-2-amino-1- phenylethanol (75 mg, 0.55 mmol) and dioxane (2 mL) was added NaHCO3 (252 mg, 3.0 mmol) at rt. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to rt and the precipitate was isolated via filtration. The precipitate was purified (FCC) to give a white solid (63 mg, 34%). MS (ESI): mass calcd. for Ci9Hi6F3N3O2, 375.1; m/z found, 376.1 [M+H]*. 1H NMR (CDCI3): 8.67 (s, 1H), 8.01-7.97 (m, 2H), 7.46-7.21 (m, 7H), 6.70 (s, 1H), 5.38-5.18 (m, 1 H)1 5.05-4.95 (m, 1 H)1 4.00-3.77 (m, 1 H), 3.68-3.54 (m, 1 H).
The compounds in Examples 107-130 were synthesized in a similar manner to those described in Example 106, substituting the appropriate boronic acids and esters in Step A and amino alcohols (prepared analogously to Intermediate B or C) in Step B.
Example 107: 1 -(4-Nitrophenyl V2-R644-[(trifluoiOmethyJ toxy1phenyl)Pyrimidin-4- yltøminoiethanol.
Figure imgf000089_0001
MS (ESI): mass calcd. for C19H15F3N4O4, 420.1; m/z found, 421.1 [M+H]+. 1H NMR (CDCI3): 8.71 (s, 1 H)1 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, 1 H), 3.74-3.56 (m, 1H).
Example 108: 2-K6-l4-rfTrifluoiOmethyltoxy1ohenyl)pyrimidin-4-yltaminol-1-[4- ftrifluoromethyl)phenyl]ethanol.
Figure imgf000090_0001
MS (ESI): mass calcd. for C20H15F6N3O2, 443.1 ; m/z found, 444.1 [M+H]+. 1H NMR (CDCI3): 8.69 (s, 1 H), 8.04-7.96 (m, 2H), 7.64 (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, 1 H), 5.20 (m, 1 H)1 5.13-5.04 (m, 1 H), 4.03-3.79 (m, 1 H), 3.74-3.56 (m, 1 H).
Example 109: 1 -(4-Chlorophenyl)-2-[(6-{4-r(trifluoromethvπoxylphenyl)pyrimidin- 4-yl)aminolethanol.
Figure imgf000090_0002
MS (ESI): mass calcd. for Ci9Hi5CIF3N3O2, 409.1 ; m/z found, 410.1
[M+H]+. 1H NMR (CDCI3): 8.67 (s, 1 H), 8.04-7.96 (m, 2H), 7.35 (s, 4H), 7.31 (d, J = 8.0 Hz, 2H), 6.71 (d, J - 1.1 Hz, 1 H), 5.25-5.16 (m, 1 H), 5.05-4.93 (m, 1 H), 4.05-3.78 (m, 1 H)1 3.68-3.50 (m, 1 H).
Example 110: 4-f1-Hvdroxy-2-f(6-{4-f(trifluoromethvπoxylphenyl)pyrimidin-4- vOaminolethvDphenol.
Figure imgf000090_0003
MS (ESI): mass calcd. for Ci9Hi6F3N3O3, 391.1 ; m/z found, 392.2 [M+H]+. 1H NMR (CDCI3): 8.66 (s, 1 H), 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, 1 H), 5.37-5.19 (m, 1 H), 5.08-4.85 (m, 2H)1 3.90-3.74 (m, 1 H), 3.66-3.51 (m, 1 H).
Example 111 : 1 -r4-(Methyloxy)phenyll-2-r(6-(4-r(trifluoromethyltoxy1phenylV pyrimidin-4-yl)aminolethanol.
Figure imgf000091_0001
MS (ESI): mass calcd. for C20Hi8F3N3O3, 405.1 ; m/z found, 406.2 [M+H]*. 1H NMR (CDCI3): 8.66 (s, 1H), 8.03-7.96 (m, 2H), 7.32 (m, 4H), 6.97-6.83 (m, 2H)1 6.69 (d, J - 1.0 Hz, 1 H), 5.43-5.12 (m, 1H)1 5.00-4.83 (m, 1H), 3.93-3.73 (m, 4H)1 3.66-3.53 (m, 1H).
Example 112: 441-Hvdroxy-2-r(6-l4-r(trifluoromethyl)oxyipheny1)Dyrimidin-4- yl)amino1ethyft-2-(methyioxytohenol.
Figure imgf000091_0002
MS (ESI): mass calcd. for C20Hi8F3N3O4. 421.1 ; m/z found. 422.2 [M+H]*.
1H NMR (CDCI3): 8.66 (s. 1H), 8.10-7.85 (m, 2H), 7.31 (d, J - 8.2 Hz, 2H), 7.00- 6.84 (m, 3H), 6.70 (s, 1H)1 5.63 (s. 1H)1 5.39-5.17 (m. 1H)1 4.99-4.83 (m. 1 H)1 3.90 (s, 3H), 3.87-3.75 (m, 1H), 3.68-3.54 (m, 1H).
Example 113: 1-(4-FluoroDhenyJV2-r(6-/4-r(trifluoromethylk)xylpheny1)pyrimklin- 4-ylteminolethanol.
Figure imgf000091_0003
MS (ESI): mass calcd. for C19H15F4N3O2, 393.1; m/z found, 394.1 [M+H]*. 1H NMR (CDCI3): 8.67 (s, 1 H), 8.08-7.92 (m, 2H)1 7.45-7.35 (m, 2H)1 7.33-7.29 (m, 2H)1 7.12-7.01 (m. 2H), 6.78-6.64 (m, 1H), 5.36-5.16 (m, 1H)1 5.08-4.91 (m, 1H)1 3.95-3.76 (m. 1 H)1 3.67-3.52 (m, 1H).
Example 114: 1-(3.4-Dichloropheny1V2-^644-r(trifluoronnethy1k)xylDhenyll- pyrimidin-4-yltaminolethanol.
Figure imgf000092_0001
MS (ESI): mass calcd. for C19Hi4Cl2F3N3O2. 443.0; m/z found, 444.1 [M+H]+. 1H NMR (CDCI3): 8.68 (s, 1 H)1 8.09-7.85 (m, 2H), 7.53 (d, J = 2.0 Hz, 1 H), 7.44 (d, J - 8.3 Hz, 1 H)1 7.31 (d, J = 8.0 Hz1 2H), 7.24 (d, J = 2.0 Hz, 1 H)1 6.73 (d. J = 1.1 Hz, 1 H)1 5.22-5.16 (m, 1H)1 5.02-4.93 (m. 1H), 3.96-3.83 (m, 1H), 3.66-3.51 (m. 1 H).
Example 115: 1-(2-Chlorophenyl)-2-r(6-(4-rftrifluoromethylk)xyiphenyftDyrimidin- 4-yl)aminoiethanol.
Figure imgf000092_0002
MS (ESI): mass calcd. for Ci9Hi5CIF3N3O2, 409.1; m/z found, 410.1 [M+H]+. 1H NMR (CDCI3): 8.68 (s, 1H)1 8.09-7.88 (m. 2H)1 7.65 (dd, J = 7.6, 1.7 Hz1 1H)1 7.39-7.20 (m. 5H)1 6.75 (s, 1H), 5.40-5.34 (m, 1H)1 5.33-5.22 (m, 1 H)1 3.98-3.84 (m. 1H)1 3.77-3.62 (m, 1H).
Example 116: 1-(3-ChloroDhenyl)-2-^644-r(trifluoroπnethy1V3xylDheny1)Dyrimidin- 4-yltaminolethanol.
Figure imgf000092_0003
MS (ESI): mass calcd. for CI9HI5CIF3N3O2, 409.1; m/z found, 410.1 [M+H]*. 1H NMR (CDCI3): 8.68 (s, 1H). 8.03-7.97 (m. 2H)1 7.46-7.40 (m, 1H), 7.34-7.28 (m. 5H)1 6.72 (d, J = 1.1 Hz, 1 H)1 5.29-5.18 (m, 1H), 5.03-4.92 (m, 1H), 4.02-3.82 (m, 1H)1 3.70-3.53 (m. 1H). Example 117: 1-r3-(Methyloxy)Dhenyn-2-[f6-[4-rftrifluoromethylk)xyiDhenylV- pyrimidin-4-yltaminolethanol.
Figure imgf000093_0001
MS (ESI): mass calcd. for C20Hi8F3N3O3, 405.1 ; m/z found, 406.2 [M+H]+. 1H NMR (CDCI3): 8.67 (s, 1 H), 8.07-7.91 (m, 2H), 7.34-7.27 (m, 3H), 7.06-6.94 (m, 2H), 6.90-6.80 (m, 1H), 6.70 (d, J = 1.0 Hz, 1H), 5.36-5.17 (m, 1H)1 5.04-4.92 (m, 1 H), 3.96-3.76 (m, 4H), 3.70-3.56 (m, 1H).
Example 118: 1-[2-(Methyloxy)Dhenyn-2-r(6-/4-r(trifluoromethylk?xylDhenyl)- pyrimidin-4-yltøminolethanol.
Figure imgf000093_0002
MS (ESI): mass calcd. for C20HiBF3N3O3, 405.13; m/z found, 406.2 [M-I-H]+. 1H NMR (CDCI3): 8.67 (s, 1 H), 8.09-7.89 (m, 2H), 7.47 (dd, J = 7.5, 1.4 Hz, 1H), 7.35-7.29 (m, 3H), 7.01-6.98 (m, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 6.74 (s, 1 H), 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: M R.2SV1 -PhenyJ-2-r(6-/4-[(trifluoromethylk)xylDhenyl)DyrimkJin-4- yltaminolpropan-1 -ol.
Figure imgf000093_0003
MS (ESI): mass calcd. for C20Hi8F3N3O2, 389.1; m/z found, 390.2 [M+H]*. 1H NMR (CDCI3): 8.60 (s, 1 H), 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)1 4.93 (d, J = 2.8 Hz, 1H), 4.67 (br s, 1 H), 4.43 (br s, 1 H), 1.13 (d, J= 7.1 Hz, 3H).
Example 120: MR.2RV2-rMethyl(6-{4-r(trifluoromethyltoxyiDhenyl)pyrimidin-4- yltamino1-1-phenyipropan-1-ol. F3C0A^J '
Figure imgf000094_0001
MS (ESI): mass calcd. for C2IH20F3N3O2, 403.2; m/z found, 404.2 [M+H]+. 1H NMR (CDCI3): 8.70 (s, 1H)1 8.05-7.99 (m, 2H). 7.45-7.29 (m, 7H), 6.77 (s, 1H)1 4.97-4.81 (m. 1H), 4.78-4.70 (m, 2H), 2.98 (s, 3H), 1.18 (d, J = 7.2 Hz, 3H).
Example 121 : MR.2SV2-rMethyU6-{4-Ktrifluoromethyltoxylphenyl)pyrimidin-4^ yl)amino1-1-DhenylproDan-1-ol.
Figure imgf000094_0002
MS (ESI): mass calcd. for C21H20F3N3O2, 403.2; m/z found, 404.2 [M+H]+. 1H NMR (CDCI3): 8.67 (d, J = 1.0 Hz, 1 H), 8.10-7.88 (m, 2H), 7.41-7.27 (m, 7H), 6.70 (d, J = 1.1 Hz, 1H), 4.99-4.84 (m, 3H)1 2.74 (s, 3H)1 1.33 (d, J = 7.1 Hz1 3H).
Example 122: 1-(2.2-Difluoro-1.3-benzodioxol-5-v1i-2-K6-{4- rftrifluoromethylk)xylphenyl)pyrimidin-4-yltemino1ethanol.
Figure imgf000094_0003
MS (ESI): mass calcd. for C20Hi4F5N3O4. 455.1 ; m/z found, 456.1 [M+H]+. 1H NMR (CDCI3): 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, 1 H), 3.93-3.79 (m, 1H), 3.68-3.48 (m, 1H).
Example 123: 1-Pyridin-2-yl-2-r(6-{4-rftrifluoromethyltoxyiphenyl)pyrimidin-4- vitaminoiethanol.
Figure imgf000094_0004
MS (ESI): mass calcd. for C18Hi5F3N4O2. 376.1; m/z found, 377.2 [M +H]+. 1H NMR (CDCI3): 8.64 (s, 1H), 8.59-8.54 (m, 1H)1 8.01-7.96 (m, 2H), 7.75-7.71 (m, 1H)1 7.51-7.44 (m, 1 H)1 7.34-7.20 (m, 3H)1 6.70 (6, J = 1.1 Hz1 1 H)1 5.48-5.37 (m, 1H), 5.04-5.00 (m, 1H), 4.15-3.95 (m, 1 H), 3.80-3.60 (m, 1H).
Example 124: 1-Pyridin-3-yl-2-r(6-l4-r(trifluoromethyl)oxyiDhenyt}pyrimidin-4- yl)aminoiethanol.
LJ I
Figure imgf000095_0001
MS (ESI): mass calcd. for C18H15F3N4O2, 376.1; m/z found, 377.1 [M+H]*. 1H NMR (CDCI3): 8.71-8.50 (m, 3H)1 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, 1 H), 3.99-3.85 (m, 1H), 3.73-3.56 (m, 1 H).
Example 125: 1-Pyridin-4-yl-2-rf6-{4-r(trifluoromethyltoxyiphenyl)pyrimidin-4- yl)aminolethanol.
Figure imgf000095_0002
MS (ESI): mass calcd. for Ci8Hi5F3N4O2, 376.1; m/z found, 377.1 [M+H]*.
1H NMR (CDCI3): 8.68 (s, 1H), 8.60-8.53 (m, 2H), 8.05-7.89 (m, 2H), 7.38-7.28 (m, 4H), 6.73 (s, 1H), 5.46-5.35 (m, 1H), 5.08-4.92 (m, 1 H), 4.02-3.90 (m, 1H), 3.70-3.53 (m, 1H).
Example 126: 1-(3.5-DichloroDheny1V2-r(644-r(tπfluoiOmethylk)xylDhenylV pyrimk.in-4-yltøminolethanol.
Cl
Figure imgf000095_0003
MS (ESI): mass calcd. for C19Hi4Cl2F3N3O2, 443.0; m/z found, 444.1 [M+H]*. 1H NMR (CDCI3): 8.69 (s, 1H), 8.04-7.97 (m, 2H), 7.35-7.28 (m, 5H), 6.74 (d. J = 1.1 Hz, 1H), 5.25-5.18 (m, 1H), 5.00-4.92 (m, 1 H)1 3.96-3.82 (m, 1H), 3.66-3.53 (m, 1H). Example 127: 1 -IΛ .3-Benzodk)xol-5-yl V2-K6-{4-rftrifluoromethyl toxylphenylV- Pyrimidin-4-ylteminolethanol.
Figure imgf000096_0001
MS (ESI): mass calcd. for C2OHi6F3N3O4, 419.1; m/z found, 420.1 [M+H]+. 1H NMR (CDCI3): 8.66 (s, 1H), 8.08-7.89 (m, 2H), 7.33-7.29 (m, 2H)1 6.93 (d, J = 1.6 Hz, 1 H)1 6.86 (dd, J = 8.0, 1.3 Hz, 1 H), 6.80 (d, J = 7.9 Hz, 1 H), 6.71 (d, J = 1.1 Hz, 1H)1 5.96 (s, 2H)1 5.28-5.21 (m. 1H), 4.98-4.86 (m, 1 H)1 3.87-3.75 (m, 1 H)1 3.65-3.52 (m, 1H).
Example 128: MSV-2-(f6-r3-Chloro-4-(trifluoromethylk)henynpyrimidin-4- vftaminoVI -phenyiethanol.
Figure imgf000096_0002
MS (ESI): mass calcd. for Ci9Hi5CIF3N3O1 393.1; m/z found, 394.1 [M+H]+. 1H NMR (CD3OD): 8.50 (s, 1H), 8.16 (s, 1H), 8.01-7.98 (m, 1 H). 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)1 6.97(s, 1H), 4.93-4.90 (m, 1H), 3.79-3.71 (m, 1H)1 3.60 (dd, J - 13.6, 7.6 Hz, 1H).
Example 129: MRV-2-(f6-[3-Fluoro-4-(1-hydroxyethylbhenynpyrimidin-4- v1)aminoV1-Dheny1ethanol trifluoroacetic acid salt.
Figure imgf000096_0003
To a solution consisting of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2- phenylethyl]amino}pyrimidin-4-y1)phenyl]ethanone (46.5 mg, 0.10 mmol) in ethanol (1 mL) at 0 °C was added NaBH4 (5.7 mg, 0.15 mmol). The reaction mixture was allowed to warm to rt and stirred for 10 min. Additional NaBH4 (5.7 mg, 0.15 mmol) was added and the reaction mixture was allowed to stir at rt for 15 min. An additional amount of NaBH4 (5.7 mg, 0.15 mmol) was added and stirring was continued at rt for an additional hour. The reaction mixture was then diluted with water (2 mL) and extracted with CH2Cb (10 mL). The organic extract was dried (Na2SO4) and concentrated. The crude material was purified by reverse phase chromatography to yield the title compound (32.2 mg, 69%). MS (ESI): mass calcd. for C20H2OFN3O2, 353.2; m/z found, 354.2 [M+H]*. 1H NMR (CD3OD): 8.66 (s, 1 H), 7.80 (t, J - 7.8 Hz1 1 H)1 7.64 (dd, J = 8.1 , 1.8 Hz, 1 H), 7.55 (m, 1H), 7.43 (d, J = 7.1 Hz1 2H), 7.38-7.34 (m, 2H), 7.30-7.27 (m, 1 H), 5.18 (q, J = 6.6 Hz, 1H), 4.95-4.92 (m, 1H), 3.92 (dd, J = 13.6. 4.3 Hz, 1 H), 3.80 (dd, J = 13.6, 7.6 Hz, 1H), 1.48 (d, J - 6.6 Hz, 3H).
Example 130: 2-α6-r3-Chloro-4-(trifluoromethyl)DhenyilDyrimidin-4-yl)aminoV1-r3- (trifluoromethoxytohenyliethanol trifluoroacetic acid salt.
c T3 nU A^ H OH Step A: 2-Amino-1-(3.4-difluoro-phenyl)-ethanol. To a solution consisting of 3,4-difluorobenzaldehyde (3.85 g, 27.1 mmol), zinc iodide (104.9 mg, 0.329 mmol) and THF (5 mL) at 0 °C under nitrogen was added TMSCN (4.60 mL, 33.9 mmol). The resultant mixture was stirred for 3.5 h at 0 °C and then cannulated into a 0 °C suspension of LiAIH4 (1.41 g, 67.7 mmol) in THF (80 mL). The resultant mixture was allowed to gradually warm to rt with stirring for 21 h. The reaction mixture was then re-cooled to 0°C and carefully treated with water (2.57 mL) followed by 15% aq. NaOH (2.57 mL) and lastly with water (7.7 mL). The resultant mixture was stirred for 1 h, the solids removed by vacuum filtration and the filtrate concentrated. The resulting crude product was purified by FCC (CH2Cl2ZMeOHZNH3) to give the desired product.
Step B. A vial containing a solution of 4-chloro-6-(3-chloro-4- trifluoromethyl-phenyl)-pyrimidine (59.9 mg, 0.204 mmol), 2-amino-1-(3- trifluoromethoxy-phenyl)-ethanol (72.4 mg, 0.327 mmol), π-BuOH (2 mL ) and DIPEA (0.15 mL, 0.86 mmol) was flushed with N2, capped and heated at 100 °C for 20 h. The reaction mixture was purified directly by reverse-phase HPLC. MS (ESI): mass calcd. for C20Hi4CIFeN3O2, 477.8; mZz found, 334.1 [M+H]*. 1H NMR ((CDa)2CO): 10.06 (br hump, 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, J = 6.6 Hz1 1 H), 5.20-5.01 (br m, 1 H), 4.29- 3.82 (br m, 2H).
The compounds in Examples 131-135 were prepared using methods analogous to those described in Example 130, using the appropriate aldehydes in Step A.
Example 131 : 2-((6-r3-Chloro-4-(trifluoiOmethyltohenyflDyrimidin-4-yl>aminoV1- (3-fluoroDhenyltethanol trifluoroacetic acid salt.
Figure imgf000098_0001
MS (ESI): mass calcd. for C19H14CIF4N3O, 411.8; m/z found, 412.1 [M+H]*. 1H NMR ((CDa)2CO): 10.52 (br hump, 2H), 8.95-8.81 (m, 1H), 8.34-8.21 (m, 1 H)1 8.07-8.03 (m, 1H)1 7.44-7.25 (m, 3H), 7.05-7.02 (m, 1H)1 5.15-4.98 (br m, 1H)1 4.05-3.53 (br m, 2H).
Example 132: 2-r6-(3-Chloro-4-trifluoromethy1-Dhenyl)-Dyrimidin-4-ylamino1-1- (3.4-difluoro-phenyl)-ethanol trifluoroacetic acid salt.
c fsX^r H OH
MS (ESI): mass calcd. for C19Hi3CIF5N3O, 429.8; m/z found, 430.1 [M+H]+. 1H NMR ((CDs)2CO): 9.65 (br hump, 2H)1 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-Chloro-3-fluoro-Dhenyl)-2-r6-(3-chloro-4-trifluoromethyl- Dhenyl)-pyrimidin-4-ylaminol-ethanol trifluoroacetic acid salt.
Figure imgf000098_0002
MS (ESI): mass calcd. for Ci9H13Cl2F4N3O, 446.2; m/z found, 446.1 [M+H]*. 1H NMR ((CDs)2CO): 10.06 (br hump, 2H)1 8.91-8.62 (m, 1H), 8.34-8.02 (m, 2H), 7.66-7.34 (m, 3H)1 5.15-5.10 (br m, 1 H), 4.01-3.80 (br m, 2H).
Example 134: 1-(3-Chloro-4-fluoroDhenyl)-2-((6-r3-chloro-4- ftrifluoromethy»phenyflDyrimiclin-4-yl)aminotethanol trifluoroacetic acid salt.
Figure imgf000099_0001
MS (ESI): mass calcd. for C19Hi3Cl2F4N3O, 446.2; m/z found, 446.1 [M+H]*. 1H NMR ((CDs)2CO): 10.14 (br hump, 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-r3-Chloro-4-ftrifluoromethyltohenynpyrimidin-4-yl)aminoV143- ftrifluoromethynphenyl]ethanol trifluoroacetic acid salt.
Figure imgf000099_0002
MS (ESI): mass calcd. for C20Hi4CIFeN3O, 461.8; m/z found, 462.1 [M+H]*. 1H NMR ((CDs)2CO): 10.35 (br hump, 2H), 8.92-8.81 (m, 1H), 8.34-8.21 (m, 1H), 8.09-8.02 (m, 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 136: M RV2-ff2-Cvclopropyl-6-(3.4-dichlorophenyltoyrimidin-4-yl]amino\- 1-Dhenylethanol.
Figure imgf000099_0003
Step A: 2-Cvclopropyl-6-(3.4-dichloro-phenyl)-pyrimidin-4-ol. To a solution consisting of 3-(3,4-dichlorophenyl)-3-oxo-propionic acid ethyl ester (252 mg, 0.967 mmol) and MeOH were added cyclopropylcarbamidine hydrochloride (140 mg, 1.16 mmol) and potassium tert-butoxide (266 mg, 2.37 mmol). The reaction mixture was stirred at rt overnight, 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 (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (133 mg, 49%).
Step B. 4-Chloro-2-cycloproDyl-6-(3.4-dichloro-Dhenyl)-Dyrimidine. To a suspension of 2-cyclopropyl-6-(3,4-dichloro-phenyl)-pyrimidin-4-ol (131 mg, 0.467 mmol) in acetonitrile was added POCI3 (0.13 mL, 1.42 mmol). The reaction mixture was heated at 80 °C for 105 min, cooled to rt, quenched with satd. aq. NaHCOa, and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (113 mg, 81%). Step C. A mixture of 4-chloro-2-cyck>propyl-6-(3,4-dichloro-phenyl)- pyrimidine (108 mg, 0.364 mmol), (R)-(-)-2-amino-1-phenylethanol (67.2 mg, 0.490 mmol), and NaHCO3 (190.1 mg, 2.26 mmol) and 1 ,4-dioxane was refluxed for 48 h. The mixture was poured into water and extracted with CH2Cb. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (119.4 mg, 82%). MS (ESI): mass calcd. for C2iH19Cl2N3O, 399.09; m/z found, 400.1 [M+H]+. 1H NMR (CD3OD): 8.13-8.05 (m, 1H), 7.85-7.79 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.31 (m, 4H), 7.30-7.23 (m, 1H)1 6.68-6.59 (m, 1H), 4.93-4.85 (m, 1H), 3.81-3.65 (m, 1H), 3.56-3.48 (m, 1H), 2.16-2.01 (m, 1H), 1.16-1.09 (m, 2H)1 1.02-0.94 (m, 2H).
Example 137: MRl2-ff6-(3.4-Dichlorophenyl)-2-M-methylethyltoyrimidin-4- yl]aminoV 1 -ohenylethanol.
Figure imgf000100_0001
The title compound was prepared in a similar manner to that in Example 136, substituting isobutyramidine in Step A. MS (ESI): mass calcd. for C2IH2ICl2N3O1 401.11; m/z found, 402.1 [M+H]*. 1H NMR (CD3OD): 8.14-8.08 (m, 1H), 7.87-7.80 (m, 1 H), 7.63-7.57 (m, 1H)1 7.44-7.38 (m, 2H), 7.36-7.29 (m, 2H), 7.27-7.22 (m, 1 H), 6.71-6.64 (m, 1H)1 4.96-4.90 (m. 1H)1 3.84-3.70 (m, 1 H)1 3.61-3.53 (m. 1 H), 3.06-2.95 (m, 1H)1 1.36-1.27 (m, 6H).
Example 138: M RV2-((6-r3-ChlorD-4-t(rifluoromethy^phenyt1-2- (methy1sutfonynDyrimkiin-4-yl)aminoV1-Dhenyiethanol.
Figure imgf000101_0001
To a solution consisting of (1R)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2- (methylsulfanyl)pyrimidin-4-yl}amino)-1-phenylethanol (55.4 mg, 0.10 mmol) and CH2Cl2 (2 mL) was slowly added 3-chloroperoxybenzoic acid (45 mg, 0.20 mmol) . The reaction mixture was stirred at rt for 3 h and then washed with aq. Na2SO3 (4 mL x 2) followed by a satd. aq. NaHCO3 (5 mL x 2). The layers were separated and extracted with CH2Cl2 (15 mL), dried (Na2SO*) and concentrated. The crude material was purified by reverse phase chromatography to yield the final product (20 mg, 43%). MS (ESI): mass calcd. for C20Hi7CIF3N3O3S, 471.1 ; m/z found. 472.1 [M+H]*. 1H NMR (CD3OD): 8.30 (s, 1 H)1 8.14 (d. J = 8.2 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.45-7.44 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.21 (m, 1H)1 7.15 (s, 1H)1 4.95-4.91 (m, 1H), 3.87-3.80 (m, 1H), 3.70-3.65 (m, 1H), 3.34 (s, 3H).
Example 139: f1RV2-((6-r3-Chloro-4-t(rifluoromethyltohenyn-2- (methylsulfinyhPyrimidin-4-yl)aminoV1-phenylethanol.
Figure imgf000101_0002
The title compound was prepared analogously to Example 138 using 1 molar equivalent of 3-chloroperoxybenzoic acid. MS (ESI): mass calcd. for C20Hi7CIF3N3O2S1 455.1 ; m/z found, 456.1 [M+H]*. 1H NMR (CD3OD): 8.35 (s, 1H), 8.13 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.2 Hz1 1H)1 7.44-7.43 (m, 2H)1 7.35- 7.32 (m, 2H)1 7.26-7.23 (m, 1H)1 7.05 (s, 1H)1 4.92-4.90 (m, 1H)1 3.87-3.79 (m. 1H)1 3.74-3.67 (m, 1H)1 2.94 (s, 0.34H)1 2.93 (s. 0.66H).
Example 140: M RV2-ir6-(3-Methyl-1H-indazol-6-vibyrimidin-4-vt1amino)-1- phenylethanol trifluoroacetic acid salt.
Figure imgf000102_0001
A solution consisting of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2- phenylethyl]amino}pyrimidin-4-yl)phenyl]ethanone (68 mg, 0.15 mmol) and hydrazine monohydrate (1.5 ml.) was heated to reflux in a sealed tube for 10 h. The reaction mixture was poured over ice and the precipitate was filtered and washed with hexanes (15 mL). Reverse phase chromatography yielded the title compound (19 mg. 29%). MS (ESI): mass calcd. for C20H19N5O. 345.2; m/z found, 346.2 [M+H]*. 1H NMR (CD3OD): 8.65 (s, 1H)1 7.96-7.93 (m, 2H)1 7.48- 7.44 (m, 3H)1 7.38-7.35 (m, 2H)1 7.30-7.26 (m, 1 H)1 7.06 (s, 1 H)1 4.96-4.94 (m, 1 H)1 3.96-3.91 (m. 1 H)1 3.83-3.79 (m. 1 H)1 2.61 (s. 3H).
Example 141: M R)-2M 6-r3-Chloro-4-t(rifluoromethy»phenyn-2- (methyJamino)Dyrimidin-4-v1)amino)-1-pheny1ethanol trifluoroacetic acid salt.
Figure imgf000102_0002
To a solution consisting of (1 R)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-
(methylsulfonyl)pyrimidin-4-yl}amino)-1-phenylethanol (47.2 mg, 0.10 mmol) and f-amyl alcohol (1 mL) in a sealed tube was added methylamine (0.2 M in THF; 0.15 mL). The reaction mixture was heated at 130 °C for 18 h. The crude material was filtered through a syringe tip filter eluting with f-amyl alcohol (0.5 mL) and directly purified by reverse phase chromatography to yield the final product (36 mg, 67%)). MS (ESI): mass calcd. for C2OHi8CIF3N4O1 422.1; m/z found, 423.1 [M+H]*. 1H NMR (CD3OD): 7.99-7.97 (m, 2H), 7.80 (d, J - 7.7 Hz, 1 H), 7.44-7.43 (m, 2H), 7.37-7.34 (m, 2H), 7.29-7.26 (m, 1H), 6.39 (s, 1 H)1 4.96-4.94 (m, 1 H), 3.89-3.85 (m, 1 H), 3.75-3.70 (m, 1 H)1 3.05 (s, 3H).
Example 142: M RV2-f{6-(4-lodophenyltoyrimidin-4-yriamino}-1-phenylethanol.
Figure imgf000103_0001
Step A: f4-(6-Chloro-Dyrimidin-4-vJ>-Dhenyn-carbamic acid tert-butyl ester. The title compound was prepared analogously to that described in Example 20, Step B.
Step B: 4-(6-Chloro-pyrimidin-4-yl)-phenylamine. A mixture of [4-(6- chloro-pyrimkJin-4-y1)-phenyl]-carbamic acid tert-butyl ester (918 mg, 3.00 mmol). CH2Cl2 (30 mL) and HCI (4 N in dioxane; 3.80 mL) was stirred overnight at rt and the solid isolated by filtration. The resultant solid was taken up in water, treated with satd. aq. NaHCO3 and extracted with CH2Cl2. The extract was dried, filtered, and concentrated. The material was used directly in Step C. Step C: 4-Chloro-6-(4-iodo-phenyl)-pyrimidine. A solution consisting of 4-
(6-chloro-pyrimidin-4-yl)-phenylamine (399 mg, 1.94 mmol) and CH3CN (40 mL) was cooled to 0 °C under N2 and treated with tert-butyl nitrite (0.39 mL, 3.24 mmol) to give a dark brown mixture. After 30 min, CuI (1.50 g, 7.88 mmol) was added. After 30 min at 0 °C. the mixture was heated to 75 °C for 30 min. The mixture was cooled to rt, diluted with EtOAc1 and washed with water followed by satd. aq. NaHCOa. The organic layer was dried (MgSO4), filtered and concentrated. Purification of the residue by FCC (CH2Cl2/hexanes) gave 218.1 mg (36%) of the pure product. MS (ESI): mass calcd. for C10H6CI I N2, 315.93; m/z found, 317.0 [M+H]*. 1H NMR ((CDa)2CO): 9.04 (br s, 1H)1 8.18 (d, J - 1.2 Hz1 1 H), 8.08-8.06 (m, 2H), 7.98-7.97 (m, 2H).
Step D. The title compound was prepared analogously to that described in Example 1, Step A. MS (ESI): mass calcd. for C18H16IN3O, 417.3; m/z found, 418 [M+H]*. 1H NMR ((CDa)2CO): 8.53 (s, 1 H)1 7.84 (s, 4H), 7.46 (d, J = 7.8 Hz, 2H)1 7.35-7.33 (m, 2H), 7.27-7.24 (m, 1 H)1 6.81 (br s, 1 H), 5.05 (br s, 1 H), 4.97 (br t, J = 3.6 Hz, 1 H)1 3.84 (br s, 1 H), 3.56-3.52 (m, 1 H).. The compounds in Examples 143-146 were prepared using methods analogous to those described for the preceding examples. Example 143: MSV2-r6-(3-Chloro-4-trifluoromethyl-phenyl)-Dyrim8din-4-ylamino1- 1 -(3.4-difluoro-Dhenvl Methanol.
Figure imgf000104_0001
Analytical data obtained for this compound compared favorably with that obtained for Example 132.
Example 144: M RV2-[6-(3-Chloro-4-trifluoromethyl-phenyl)-Dyrimidin-4-ylaminol- 1-(3.4-difluoro-phenyl)-ethanol.
_ -X^ H OH
Analytical data obtained for this compound compared favorably with that obtained for Example 132.
Example 145: MSV1-(4-Chloro-3-fluoro-phenyl)-2-r6-(3-chloro-4-trifluoromethyl- phenyl)-pyrimidin-4-ylamiriol-ethanol.
Figure imgf000104_0002
Analytical data obtained for this compound compared favorably with that obtained for Example 133.
Example 146: M R)-1-(4-Chloro-3-fluoro-Phenyl)-2-r6-(3-chloro-4-trifluoromethyl- phenyl)-pyrimidin-4-ylaminol-ethanol.
Figure imgf000104_0003
Analytical data obtained for this compound compared favorably with that obtained for Example 133.
The compounds in Examples 147-154 were prepared using methods analogous to those described for the preceding examples. Example 147: 2-((644-(Methyloxytohenyl]Dyrimidin-4-yl}aminoi-1 -phenylethanol.
Figure imgf000105_0001
MS (ESI): mass calcd. for Ci9Hi9N3O2, 321.2; m/z found, 322.2 [M+H]+. 1H NMR (CD3OD): 8.41 (s, 1H), 7.85 (d, J - 9.3 Hz, 2H)1 7.43 (d, J = 7.7 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.28-7.25 (m, 1 H), 7.02 (d, J = 8.8 Hz1 2H), 6.82 (s, 1 H), 4.91^.88 (m, 1H)1 3.85 (s, 3H)1 3.76-3.67 (m. 1H), 3.57 (do, J = 13.7, 7.7 Hz1 1 H).
Example 148: 2-l{6-(3-Methylphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol.
Figure imgf000105_0002
MS (ESI): mass calcd. for Ci9Hi9N3O1 305.2; m/z found, 306.2 [M+H]*. 1H
NMR (CD3OD): 8.45 (s. 1H)1 7.70 (s. 1H)1 7.65 (d, J = 7.6 Hz1 1H)1 7.44-7.43 (m, 2H)1 7.37-7.33 (m, 3H)1 7.30-7.24 (m. 2H)1 6.86 (s, 1H)1 4.92-4.90 (m. 1H)1 3.77- 3.66 (m. 1H)1 3.58 (dd. J = 13.9. 7.8 Hz1 1H)1 2.42 (s. 3H).
Example 149: 1-Phenyl-2-K6-(3-rftrifluoromethyltoxyiphenyl)pyrimidin-4- yltaminolethanol.
F3CO
Figure imgf000105_0003
MS (ESI): mass calcd. for Ci9Hi6F3N3O2, 375.1 ; m/z found, 376.2 [M+H]*. 1H NMR (CD3OD): 8.48 (s, 1H)1 7.91-7.89 (m, 1H)1 7.84 (S1 1 H)1 7.59 (t, J = 8.1 Hz1 1H)1 7.44 (d. J = 7.1 Hz1 2H)1 7.40-7.38 (m, 1H)1 7.36-7.33 (m, 2H)1 7.28-7.24 (m, 1 H)1 6.93 (s. 1 H)1 4.93-4.90 (m. 1 H)1 3.79-3.68 (m, 1 H)1 3.59 (dd. J = 13.6, 7.6 Hz1 I H). Example 150: M S.2RV1 -Phenyl-2-K6-l4-rftrifluoromethylk)xyiPheny1)pyrimidin-4- ylteminoioropan-1 -ol.
Figure imgf000106_0001
MS (ESI): mass calcd. for C20Hi8F3N3O2, 389.1 ; m/z found, 390.2 [M+H]*. 1H NMR (CDCI3): 8.58 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.35-7.34 (m, 4H), 7.32- 7.26 (m, 3H)1 6.63 (d, J = 1.0 Hz, 1 H)1 5.20 (br s, 1 H)1 4.92 (d, J - 2.5 Hz, 1 H)1 4.86 (br s, 1H)1 4.41 (br s, 1H)1 1.12 (d, J = 7.1 Hz1 3H).
Example 151: MSV1-Phenyl-2-K6-{4-r(trifIuoromethyltoxyiphenyftpyrimidin-4- ylteminolethanol.
Figure imgf000106_0002
MS (ESI): mass calcd. for C19H16F3N3O2, 375.1 ; m/z found, 376.2 [M+H]*. 1H NMR (CDCI3): 8.62 (s, 1 H)1 7.97 (d, J = 8.8 Hz1 2H), 7.43-7.36 (m, 4H)1 7.33- 7.28 (m, 3H), 6.67 (d, J = 1.0 Hz1 1H)1 5.41 (br s. 1H)1 4.99-4.96 (m, 1 H), 4.25 (br s, 1H), 3.89-3.83 (m, 1 H), 3.62-3.55 (m, 1H).
Example 152: M RV2-((6-r2.4-Bis(trifluoromethyl)phenyl]Pyrimidin-4-yl)aminoV1 ■ phenylethanol trifluoroacetic acid salt.
Figure imgf000106_0003
MS (ESI): mass calcd. for C20H15F6N3O1 427.1 ; m/z found, 428.1 [M+H]*. 1H NMR (CD3OD): 8.67 (s, 1H)1 8.22 (s, 1H)1 8.18 (d, J = 7.7 Hz1 1H)1 7.87-7.85 (m. 1H)1 7.44-7.43 (m, 2H)1 7.37-7.34 (m, 2H)1 7.30-7.27 (m, 1H)1 6.80 (s. 1H)1 4.95-4.94 (m, 1H)1 3.94-3.90 (m, 1 H)1 3.83-3.79 (m, 1H).
Example 153: MRV2-((6-r2-Methoxy-4-ftrifluoromethoxy)phenyl]Pyrimidin-4- vnaminoVI -phenylethanol trifluoroacetic acid salt.
Figure imgf000107_0001
MS (ESI): mass calcd. for C20Hi8F3N3O3, 405.1 ; m/z found, 406.2 [M+H]*. 1H NMR (CD3OD): 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, 1H), 7.11-7.09 (m, 1 H), 6.94 (s, 1 H), 4.95- 4.92 (m, 1H), 3.96 (s, 3H), 3.95-3.91 (m, 1H), 3.80 (dd, J = 13.7, 7.7 Hz1 1H).
Example 154: MRV2-f{6-(4-Ethoxy-2-methylphenyltoyrimidin-4-yriamino}-1- DhenyJethanol trifluoroacetic acid salt.
Figure imgf000107_0002
MS (ESI): mass calcd. for C2IH23N3O2, 349.2; m/z found, 350.2 [M+H]*. 1H NMR (CD3OD): 8.61 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.38-7.31 (m, 3H), 7.30- 7.27 (m, 1H), 6.95 (s, 1H), 6.92 (dd, J = 8.8, 2.2 Hz1 1H), 6.71 (s, 1 H), 4.94 (dd, J = 7.7, 4.4 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.95-3.91 (m, 1 H), 3.81 (dd, J = 13.7, 7.7 Hz, 1H), 2.36 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).
The compounds in Examples 155-156 were prepared using methods analogous to those described in Example 136.
Example 155: M RV2-ff6-(3.4-Dichlorophenyl V2-methylPyrimidin-4-vπamino)-1 - phenyiethanol.
Figure imgf000107_0003
MS (ESI): mass calcd. for Ci9Hi7Cl2N3O, 373.07; m/z found, 374.1 [M+H]*. 1H NMR (CD3OD): 8.06 (d, J = 2.1 Hz, 1 H), 7.79 (dd, J = 2.1, 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.45-7.39 (m, 2H)1 7.37-7.30 (m, 2H), 7.28-7.22 (m, 1 H), 6.67 (s, 1H), 4.91-4.88 (m, 1H), 3.80-3.67 (m, 1 H), 3.59 (dd, J = 7.4, 13.8 Hz, 1H), 2.49 (s, 3H). Example 156: (1 R)-2-(f6-(3.4-Dichlorophenvπ-pyrimidin-4-yllamino)-1 - phenylethanol.
Figure imgf000108_0001
MS (ESI): mass calcd. for Ci8Hi5CI2N3O, 359.06; m/z found, 360.1 [M+H]+. 1H NMR (CD3OD): 8.46 (s, 1 H), 8.10 (d, J = 2.1 Hz, 1 H), 7.83 (dd, J = 2.1 , 8.4 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.28-7.23 (m, 1 H), 6.90 (s, 1 H), 4.92-4.88 (m, 1 H), 3.80-3.67 (m, 1 H), 3.59 (dd, J = 7.7, 13.7 Hz, 1 H).
The compounds prepared in Example 157-162 were prepared using methods analogous to those described in Example 141.
Example 157: (1 R)-2-((2-r(2-Aminoethvnaminol-6-r3-chloro-4- (trifluoromethyl)phenvnpyrimidin-4-yl)amino)-1 -phenylethanol trifluoroacetic acid salt.
Figure imgf000108_0002
MS (ESI): mass calcd. for C2iH2iCIF3N5O, 451.14; m/z found, 452.2 [M+H]+. 1H NMR (CD3OD): 8.02 (s, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 9.3 Hz, 1 H), 7.45-7.43 (m, 2H), 7.38-7.35 (m, 2H), 7.30-7.27 (m, 1 H), 6.46 (s, 1 H), 4.93-4.90 (m, 1 H), 3.81-3.76 (m, 4H), 3.26-3.23 (m, 2H).
Example 158: (1 R)-2-f(6-r3-Chloro-4-(trifluoromethyl)phenyl1-2-(r2- (dimethylamino)ethyllamino)pyrimidin-4-yl)amino1-1 -phenylethanol trifluoroacetic acid salt.
Figure imgf000109_0001
MS (ESI): mass calcd. for C23H25CIF3N5O, 479.17; m/z found, 480.2 [M+H]*. 1H NMR (CD3OD): 8.02 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H)1 7.85 (d, J = 8.8 Hz1 1H), 7.44 (d, J = 7.8 Hz, 2H), 7.39-7.35 (m, 2H), 7.31-7.27 (m, 1H), 6.47 (s, 1 H)1 4.93- 4.90 (m, 1H), 3.92-3.87 (m, 2H), 3.82-3.77 (m, 2H), 3.49-3.44 (m, 2H)1 2.97 (s, 6H).
Example 159: MRV2-a6-r3-Chloro-4-(trifluoromethy1)Dhenyfl-2- (ethylaminotoyrimidin-4-yl)aminoV1-phenylethanol trifluoroacetic acid salt.
Figure imgf000109_0002
MS (ESI): mass calcd. for C2IH20CIF3N4O1 436.13; m/z found, 437.2 [M-I-H]+. 1H NMR (CD3OD): 7.99-7.97 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.44-7.42 (m, 2H), 7.37-7.34 (m, 2H)1 7.30-7.26 (m, 1H), 6.39 (s, 1H), 4.96-4.92 (m, 1 H), 3.88-3.82 (m, 1 H), 3.71 (dd, J = 13.4, 7.6 Hz, 1 H), 3.53 (q. J = 7.1 Hz, 2H), 1.28 (t, J = 7.3 Hz, 3H).
Example 160: MRV-2-((6-r3-Chloro-4-(trifluoromethyltohenyl]-2-r(2- hydroxyethyl)aminolpyrimidin-4-yl)aminoV1-phenyiethanol trifluoroacetic acid salt.
Figure imgf000109_0003
MS (ESI): mass calcd. for C2IH20CIF3N4O2, 452.12; m/z found, 453.1 [M+H]+. 1H NMR (CD3OD): 8.00-7.98 (m, 2H), 7.81 (d. J = 8.8 Hz, 1 H)1 7.43 (d, J = 7.6 Hz1 2H)1 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.42 (s, 1 H)1 4.95-4.92 (m, 1H)1 3.86- 3.81 (m, 1H), 3.78-3.69 (m, 3H), 3.64-3.62 (m, 2H). Example 161 : M Ri-2-α2-Azetidin-1-yl-6-r3-chloro-4- ftrifluoromethyl)DhenyπDyrimidin-4-yl)aminoV1-Dhenylethanol trifluoroacetic acid salt.
Figure imgf000110_0001
MS (ESI): mass calcd. for C22H20CIF3N4O, 448.13; m/z found, 449.2 [M-I-H]+. 1H NMR (CD3OD): 7.98 (s, 1 H), 7.96 (d, J - 8.3 Hz, 1H)1 7.78-7.76 (m, 1 H), 7.43- 7.41 (m, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.29 (s, 1 H), 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, J = 13.6, 7.8 Hz, 1H), 2.50 (pentet, J = 7.8 Hz, 2H).
Example 162: (1RV2-((6-r3-Chloro-4-(trifluoiOmethyltohenyn-2- fcvclopropylaminotoyrimidin-4-yl)aminoH-phenylethanol trifluoroacetic acid salt.
Figure imgf000110_0002
MS (ESI): mass calcd. for C22H20CIF3N4O, 448.13; m/z found, 449.1 [M+H]*. 1H NMR (CD3OD): 7.99-7.98 (m, 2H), 7.80 (d, J = 8.1 Hz, 1H)1 7.44 (d, J = 7.3 Hz1 2H), 7.37-7.33 (m, 2H), 7.30-7.26 (m, 1H)1 6.41 (s, 1H), 4.98-4.92 (br hump, 1 H)1 3.91-3.84 (m, 1H), 3.72-3.67 (m, 1H), 2.88-2.80 (br hump, 1H), 0.92 (d, J = 5.8 Hz, 2H), 0.74-0.68 (br hump, 2H).
Example 163: f1RV2-rf6-r3-Chloro-4-t(rifluoromethyl)phenyn-2-ir2- (methylaminotethyl)amino)pyrimidin-4-yltaminoM-phenylethanol hydrochloride salt.
Figure imgf000111_0001
Step A: M RW2-[4-(3-Chloro-4-trifluoromethyl-Dhenyl>-6-^2-hydroxy-2-Dhenyl- ethylaminoVpyrimidin-2-ylaminol-ethyl)-methyl-cart)amic acid tert-buM ester. The title compound was prepared using methods analogous to those described in Example 141.
Step B: To a solution consisting of (1 R)-{2-[4-(3-chloro-4-trifluoromethyl-phenyl)- 6-(2-hydroxy-2-phenyl-ethylamino)-pyrimidin-2-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester (40 mg, 0.06 mmol) and CH2Cb (1.5 mL) was added HCI (2 M in Et2O, 0.15 mL). The reaction mixture was allowed to stir at rt for 18 h giving a white solid. The solid was isolated via vacuum filtration and then washed with Et2O to yield the title compound (18 mg, 63%). MS (ESI): mass calcd. for C22H23CIF3N5O, 465.15; m/z found, 466.2 [M+Hf. 1H NMR (D2O): 8.04 (d, J = 8.3 Hz1 1H), 8.01 (br s, 1H)1 7.85-7.80 (m, 1 H)1 7.53-7.44 (m, 5H), 6.46 (br s, 1H)1 5.11-5.08 (m, 1H), 4.05-3.92 (m, 2H), 3.90-3.87 (m, 2H), 3.39 (t, J = 5.8 Hz1 2H)1 2.83 (S1 3H).
Example 164: MRV2-((6-r3-Chloro-4-(trifluoromethyl)Dhenyn-2-methoxy])yrimidin- 4-vDaminoH-phenylethanol trifluoroacetic acid salt.
Figure imgf000111_0002
A solution consisting of (1 R)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]-2-
(methylsulfonyl)pyrimidin-4-yl}amino)-1-phenylethanol (50.0 mg, 0.11 mmol) and NaOMe (25%, 0.75 mL) was heated in a sealed tube at 60 °C for 2 h. The reaction mixture was cooled to rt, filtered and washed with MeOH (0.75 mL). The filtrate was concentrated and purified via reverse phase chromatography to yield the title compound (38 mg, 66%). MS (ESI): mass calcd. for C2OHIrCIF3N3O2, 423.09; m/z found, 424.1 [M+H]*. 1H NMR (CD3OD): 8.06 (s, 1 H), 7.95 (d. J = 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)1 4.96-4.93 (m, 1H), 4.11 (s, 3H), 3.90-3.82 (m, 1H), 3.78-3.73 (m, 1H).
Example 165: MRV2-f{6-(3-Methyl-1.2-benzisQxazol-6-yl)pyrimidin-4-v1laminol-1- phenylethanol.
Figure imgf000112_0001
N-O
A mixture of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenyl-ethy1]amino}-pyrinnk.in-4- yl)-phenyl]ethanone (88 mg, 0.25 mmol), hydroxyl amine hydrochloride (41 mg, 0.60 mmol), KOH (85% aq.,0.158 mL), isopropanol (0.5 mL) and water (0.5 mL) was heated in a sealed tube at 90 °C for 10 h. An additional amount of KOH (85% aq., 2.38 mmol) was added and the temperature increased to 120 °C for an additional 21 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined extracts were dried (Na2SO4), concentrated, and the crude product purified (FCC) to yield the title compound (24 mg, 28%). MS (ESI): mass calcd. for C20Hi8N4O2. 346.14; m/z found, 347.2 [M+Hf. 1H NMR (CDCI3): 8.70 (d, J = 0.8 Hz1 1H), 8.13 (dd, J = 1.3, 0.8 Hz1 1H)1 7.93 (dd. J = 8.3, . 1.3 Hz1 1H)1 7.70 (dd, J - 8.3, 0.8 Hz, 1H)1 7.45-7.37 (m. 4H)1 7.34-7.30 (m, 1H)1 6.80 (d. J = 1.0 Hz1 1H), 5.35-5.30 (m, 1 H), 5.03-4.99 (m, 1H)1 3.94-3.87 (m. 1H)1 3.67-3.60 (m, 1 H)1 2.62 (S1 3H).
Example 166: 1-(f6-r3-Chloro^-(trifluoromethyltohenyflpyrimidin-4-yl)aminoi-2- phenylpropan-2-ol.
Figure imgf000112_0002
Title compound was prepared using analogous methods to those described in Example 106. MS (ESI): mass calcd. for C20H17CIF3N3O1 407.10; m/z found, 408.1 [M+H]*. 1H NMR (CD3OD): 8.45 (br s. 1 H)1 8.14 (s. 1H)1 7.96 (d. J = 8.2 Hz1 1 H)1 7.85 (d. J = 8.2 Hz1 1 H)1 7.53 (d, J = 7.7 Hz, 2H)1 7.31 (d. J = 7.7 Hz1 2H)1 - 7.20 (t, J = 6.6 Hz, 1 H), 6.96 (br s, 1H), 3.88-3.80 (m, 1 H)1 3.73-3.70 (m, 1 H), 1.58 (s, 3H) .
Example 167: 2-(f6-r3-Chloro-4-(trifluoromethyl)DhenynDyrimidin-4-yl)amino>-1 -F4- (methylsulfanyl)phenynethanol.
Figure imgf000113_0001
Step A: 2-Azido-1-(4-methylsulfanyl-phenyl)-ethanone. A solution consisting of 2- bromo-1-(4-methylsulfanyl-phenyl)-ethanone (2.00 g, 8.16 mmol) and DMF (7 mL) was cooled to 15 °C and treated portion-wise with sodium azide (583 mg, 8.98 mmol). Once addition was complete, the reaction mixture was stirred for 3 h with gradual warming to rt. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (25 mL x 2), NaHCOa (satd. ,25 mL x 2), and brine. The combined organic phases were dried (Na2SO4) and concentrated to dryness to yield the title compound (1.69 g, 100%). Step B: 2-Azido-1-(4-methylsulfanyl-phenyl)-ethanol. A solution consisting of 2- azido-1-(4-methylsulfanyl-phenyl)-ethanone (1.69 g, 8.15 mmol) and THF (8.15 mL) was cooled to 0 °C before slowly adding BH3-THF (1.0 M solution, 8.15 ml) over 10 min. The resulting solution was stirred at 0 °C for 2 h. The reaction was quenched by slow addition of MeOH (10 mL) at 0 °C1 and then concentrating to dryness to yield the title compound (1.74 g, 100%).
Step C: 2-Amino-1-(4-methylsulfanyl-phenyl)-ethanol. To a stirred rt suspension consisting of 2-azido-1-(4-methylsulfanyl-phenyl)-ethanol (104.6 mg, 0.50 mmol), 10% Pd/C (100 mg, 0.10 mmol) and MeOH (25 mL) was added ammonium formate (316 mg, 5.0 mmol) under a N2 atmosphere. The resulting mixture was heated at 64 °C for 2 h. After cooling to rt, the catalyst was removed by filtration through a pad of celite and the celite pad washed with MeOH. The filtrate was concentrated and purified (FCC) to yield the title compound (66 mg, 72%).
Step D: Title compound was prepared using methods analogous to those in Example 106, Step B. MS (ESI): mass calcd. for C20H17CIF3N3OS, 439.07; m/z found, 440.1 [M+H]+. 1H NMR (CD3OD): 8.49 (s, 1H), 8.16 (s, 1H), 7.99 (d, J = 7.7 Hz1 1H)1 7.88 (d, J =8.2 Hz1 1H)1 7.38-7.30 (m. 2H)1 7.25-7.23 (m, 2H)1 6.96 (br s, 1H)1 3.75-3.67 (m, 1H)1 3.60 (dd. J = 13.7, 7.7 Hz1 1H). 2.43 (s. 3H).
The compounds in Example 168-169 were prepared using methods analogous to those described in Example 167.
Example 168: 2-a6-r3-Chloro-4-rtrifluoromethy1)DhenyflDyrimidin-4-yl)aminoV1- thiophen-3-ylethanoJ.
Figure imgf000114_0001
MS (ESI): mass calcd. for Ci7Hi3CIF3N3OS1 399.04; m/z found. 400.1 [M-I-H]+. 1H
NMR (CD3OD): 8.50 (s, 1 H)1 8.17 (s. 1H), 8.01 (d, J = 8.8 Hz1 1H)1 7.88 (d. J = 8.3
Hz1 1H). 7.38 (dd. J = 5.1. 3.0 Hz, 1H), 7.35-7.34 (m. 1 H)1 7.18 (dd. J = 4.8. 1.3
Hz, 1H)1 6.98 (S, 1H), 4.99 (dd. J - 7.6, 4.8 Hz. 1H)1 3.84-3.76 (m, 1H)1 3.65 (dd. J
= 13.9. 7.6 Hz1 1H).
Example 169: 2-K6-r3-Chloro-4-t(rifluoromethyltohenyl]pyrimidin-4-yl)aminoV1-
M .3-thiazol-2-yltethanol.
Figure imgf000114_0002
MS (ESI): mass calcd. for Ci6H12CIF3N4OS, 400.04; m/z found. 401.1 [M+H]*. 1H NMR (CDCI3): 8.68 (d. J = 1.0 Hz. 1H), 8.12 (d. J = 0.8 Hz. 1 H), 7.92 (dq, J = 8.1, 0.8 Hz1 1 H), 7.78 (d. J = 3.3 Hz, 1 H)1 7.77 (d. J = 8.3 Hz. 1 H). 7.32 (d, J = 3.3 Hz1 1H)1 6.78 (d. J = 1.3 Hz1 1 H)1 5.49-5.44 (m. 1H)1 5.27-5.24 (m. 1 H)1 4.20-4.14 (m. 1H)1 4.01-3.95 (m, 1H).
Examples 170-172 were synthesized using methods analogous to those described in Example 20.
Example 170: M RV1-Phenyl-2-rf6-ouinolin-6-ylPyrimidin-4-yl)aminolethanol.
Figure imgf000115_0001
MS (ESI): mass calcd. for C2IH18N4O, 342.15; m/z found, 343.2 [M+H if*. 1 Ηι NMR (CD3OD): 8.90 (dd, J = 4.4, 1.6 Hz, 1H), 8.53 (d, J = 2.2 Hz, 2H), 8.49 (d, J = 8.2 Hz, 1H)1 8.29 (dd, J = 8.8, 2.2 Hz, 1H), 8.13 (d, J = 8.8Hz, 1H), 7.62-7.59 (m, 1H)1 7.44 (d, J - 7.7 Hz1 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.26 (t, J = 7.1 Hz1 1H), 7.06 (s, 1H), 4.94-4.91 (m, 1H), 3.79-3.71 (m, 1H), 3.63 (dd, J = 13.7, 7.7 Hz, 1H).
Example 171 : N-tert-Butvt-4-(6-irf2RV2-hydroxy-2-Dhenytethyt1amino>Pyrimidin-4- yl)benzenesulfonamide.
Figure imgf000115_0002
MS (ESI): mass calcd. for C22H28N4O3S, 426.17; m/z found, 427.2 [M+H]*. 1H NMR (CD3OD): 8.22 (s, 1 H), 7.82-7.73 (m, 2H), 7.73-7.68 (m, 2H)1 7.21-7.13 (m, 2H), 7.11-7.04 (m. 2H)1 7.03-6.94 (m, 1H), 6.73-6.62 (m. 1H)1 4.67-4.61 (m. 1H)1 3.56-3.42 (m, 1H), 3.34 (dd, J = 13.7, 7.6 Hz, 1H), 0.94 (s, 9H).
Example 172: M RV1-Phenyl-2-((6-[4-(thiomorpholin-4-ylsulfonyltohenynpyrimidin- 4-vftaminotethanol.
Figure imgf000115_0003
MS (ESI): mass calcd. for C22H24N4O3S2, 456.13; m/z found, 457.4 [M+H]+. 1H NMR (CD3OD): 8.69-8.36 (m, 1 H)1 8.18-8.09 (m, 2H)1 7.92-7.86 (m, 2H), 7.45 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.30-7.25 (m, 1H)1 7.04-6.94 (m. 1H), 4.76-4.51 (m, 2H)1 3.88-3.70 (m, 1 H)1 3.62 (dd, J = 13.7, 7.8 Hz, 1H), 3.41-3.33 (m. 4H)1 2.76-2.68 (m, 4H). The compounds prepared in Example 173-182 were prepared using methods analogous to those described in Example 20.
Example 173: MRH-(4-Fluorophenyl>-2-K6-r3-fluon>4- (trifluoromethyl)DhenyflPyrimidin-4-vi)amino)ethanol.
c n^L^ H OH
MS (ESI): mass calcd. for C19H14F5N3O, 395.10; m/z found, 396.1 [M+H]*. 1H NMR (CDCI3): 8.68 (d, J = 0.8 Hz, 1 H), 7.85-7.81 (m, 2H), 7.71-7.67 (m, 1H)1 7.40 (d, J - 8.3 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.07 (d, J - 8.6 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1 H), 6.74 (d, J = 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: (1R)-1-(4-Fluorophenyl)-2-K6-r3-fluoro-4- ftrifluorometrroxytohenyl]pyrimidin-4-vttaminotethanol trifluoroacetic acid salt.
Figure imgf000116_0001
MS (ESI): mass calcd. for C19H14F5N3O2, 411.10; m/z found, 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 (m, 3H)1 4.95-4.92 (m, 1H), 3.91-3.86 (m, 1 H), 3.79-3.74 (m, 1H).
Example 175: M RV2-(f6-r3-Chloro-4-t(rifluoromethoxy)phenynpyrimidin-4- vJ)aminoV1-(4-fluoroDheny1>ethanol trifluoroacetic acid salt.
Figure imgf000116_0002
MS (ESI): mass calcd. for C19H14CIF4N3O2, 427.07; m/z found, 428.1 [M+H]*. 1H NMR (CD3OD): 8.67 (s, 1H)1 8.09 (s, 1H), 7.86 (d. J = 8.6 Hz, 1 H), 7.69 (d, J = 8.6 Hz1 1H)1 7.48-7.44 (m, 2H)1 7.10-7.06 (m, 2H)1 7.01 (s, 1H), 4.95-4.93 (m, 1H)1 3.93-3.87 (m, 1H)1 3.81-3.75 (m, 1 H).
Example 176: M R V1 -(4-fluoroDhenyi V2-α6-r3-rDentafluoroethyJV1.2- benzisoxazol-6-yl]pyrimidin-4-vi)aminotethanol trifluoroacetic acid salt.
Figure imgf000117_0001
F3C
Title compound was prepared using similar methods to those in Example 20. MS (ESI): mass calcd. for C2IHi4F6N4O2, 468.10; m/z found, 469.1 [M+H]+. 1H NMR (CD3OD): 8.75 (s. 1 H)1 8.36 (s, 1 H)1 8.15 (d. J = 8.4 Hz1 1H)1 7.95 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 5.5, 8.3 Hz, 2H)1 7.15 (s. 1H)1 7.09 (t. J = 8.7Hz1 2H)1 4.97-4.95 (m. 1 H), 3.95-3.91 (m, 1H), 3.85-3.80 (m, 1 H).
Example 177: M RV1-(4-FluoroDhenyl)-2-α6-r3-(trifluoromethy1V1 ,2-benzisoxazol- 6-yl]DyrimkJin-4-vftaminotethanol trifluoroacetic acid salt.
Figure imgf000117_0002
MS (ESI): mass calcd. for C20H14F4N4O2, 418.10; m/z found. 419.2 [M+H]*. 1H NMR (CD3OD): 8.69 (br s, 1H), 8.36 (s, 1H), 8.13 (d, J = 8.3 Hz1 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.49-7.45 (m, 2H)1 7.13-7.07 (m, 3H), 4.97-4.94 (m, 1H), 3.92-3.86 (br hump, 1H), 3.80-3.75 (m, 1H).
Example 178: HRV2-W6-r3-Fluoro-4-(2.2.2-trifluoroethoxytohenyl]pyrimidin-4- yllaminoVI-phenylethanol trifluoroacetic acid salt.
Figure imgf000117_0003
MS (ESI): mass calcd. for C20Hi7F4N3O2, 407.13; m/z found, 408.2 [M+H]*. 1H NMR (CD3OD): 8.63 (s, 1 H), 7.71 (dd, J = 11.9, 1.8 Hz, 1H)1 7.66-7.63 (m, 1H)1 7.45-7.41 (m, 3H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 6.96 (s, 1H)1 4.94 (dd, J = 7.1, 5.1Hz1 1H)1 4.75 (q, J = 8.3 Hz, 2H), 3.95-3.90 (m, 1H), 3.79 (dd, J = 13.6, 7.6 Hz1 1H).
Example 179: H R.2SV-2-K6-r3-chloro-4-(trifluoromethyltohenyl]Pyrimidin-4- vflaminoV 1 -phenylpropan-1 -ol.
Figure imgf000118_0001
MS (ESI): mass calcd. for C20Hi7CIF3N3O, 407.10; m/z found. 408.1 [M+H]+. 1H NMR (CDCI3): 8.69 (s, 1H), 8.12 (s, 1H), 7.93 (d, J - 8.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.37-7.36 (m. 4H), 7.33-7.28 (m, 1H)1 6.72 (s, 1 H)1 5.02-4.97 (m. 2H), 4.56-4.47 (br hump, 1 H), 1.17 (d, J = 6.8 Hz, 3H).
Example 180: M RV1-Phenyl-2-r(644-r(trifluoromethynsulfany1lDheny1)pyrimidin-4- yltøminolethanol.
F3C.eXj
Figure imgf000118_0002
OH
MS (ESI): mass calcd. for Ci9Hi6F3N3OS, 391.10; m/z found, 392.4 [M+H]\ 1H NMR (CDCI3): 8.66 (s. 1H)1 8.00 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.43-7.42 (m, 2H), 7.40-7.37 (m, 2H)1 7.34-7.31 (m, 1H), 6.77 (s, 1 H)1 5.03-5.01 (m, 1H), 3.91-3.80 (br hump, 1H), 3.65-3.59 (m, 1 H).
Example 181 : H RV2-(f6-r3-ChloiO-4-t(rifluoromethoxytohenyliPyrimidin-4- vDamino V1 -phenylethanol.
Figure imgf000118_0003
MS (ESI): mass calcd. for C19HiSCIF3N3O2. 409.08; m/z found, 410.4 [M+H]+. 1H NMR (CDCI3): 8.66 (s, 1H)1 8.11 (d. J = 1.9 Hz1 1H), 7.88 (dd, J = 8.5, 2.2 Hz, 1 H)1 7.43-7.37 (m, 5H), 7.34-7.31 (m, 1H), 6.68 (s, 1H), 5.36-5.30 (br hump, 1H), 5.01-4.99 (m, 1H), 3.92-3.85 (br hump, 1H), 3.64-3.59 (m, 1H).
Example 182: (1 RM-Phenyl-2-(f6-r3-(trifluoromethyl)-1.2-benzisoxazol-6- \riiDyrimidin-4-ylteminotethanol.
XJ H
Figure imgf000119_0001
N-O
MS (ESI): mass calcd. for C20H15F3N4O2, 400.11 ; m/z found, 401.4 [M+H]*. 1H NMR (CDCI3): 8.69 (s. 1H), 8.31 (s, 1H), 8.03 (dd, 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)1 6.81 (s. 1 H), 5.53-5.43 (br hump, 1 H), 5.01 (dd, J = 7.4, 3.3 Hz, 1 H), 3.95-3.87 (br hump, 1H)1 3.65-3.60 (m, 1H).
Example 183: (1RV2-ir6-(2.2-Difluoro-1.3-penzodioxol-5-yl)pyrimidin-4-vflaminol- 1-phenylethanol.
Figure imgf000119_0002
H OH
Title compound was synthesized using methods analogous to those described in Example 20, with modifications to Step B as follows: Step B. (1R)-2-[(6-Chloropyrimkiin-4-y1)amino]-1-phenylethanol (75 mg, 0.30 mmol), 2,2-difluoro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- benzo[1 ,3]dioxole (85 mg, 0.30 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol, 2 mol%),. 2-dicyclohexy1phosphino-2',6'-dimethoxy-1 ,r-biphenyl (S-Phos) (4.9 mg, 0.012 mmol, 4 md%) and K3PO4 (191mg, 0.900 mmol) were dissolved in dioxane (1.0 mL), which had been degassed by bubbling N2 into the solvent and water (0.1 mL) in a sealed tube. The tube was flushed with N2 and heated at 100 °C for 16 h before cooling to rt and filtering through a pad of celite. The celite was washed with CH2Cl2 (5 mL) and the filtrate concentrated to dryness. The crude material was purified by (FCC) to yield the title compound (92 mg, 83%). MS (ESI): mass calcd. for C19H15F2N3O3, 371.11; m/z found, 372.1 [M+H]*. 1H NMR (CDCI3): 8.64 (s, 1H), 7.73-7.71 (m, 2H)1 7.43-7.37 (m, 4H)1 7.34-7.30 (m, 1 H)1 7.14-7.12 (m. 1H), 6.65 (d. J = 1.1 Hz, 1 H)1 5.31-5.25 (br hump, 1 H)1 5.01-4.99 (m, 1H), 3.91- 3.85 (br hump, 1 H), 3.64-3.59 (m, 1H).
Examples 184-187 were prepared using methods analogous to those described in Example 183.
Example 184: MRV1-Phenyl-2-((6-r5-t(rifluoromethyl)-1-benzothiophen-2- vf]pyrimidin-4-yl)aminotethal)ol trifluoroacetic acid salt.
Figure imgf000120_0001
FsC
MS (ESI): mass calcd. for C2IHi6F3N3OS, 415.10; m/z found, 416.4 [M+H]*. 1H NMR (CD3OD): 8.61 (s, 1 H), 8.31 (s, 1H), 8.22, (s, 1H), 8.20 (d, J - 8.5 Hz1 1H), 7.75 (d, J = 8.5 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 2H)1 7.38-7.35 (m, 2H), 7.30-7.27 (m, 1H), 7.08 (s, 1H)1 4.96-4.93 (m, 1 H)1 3.92-3.86 (m, 1 H), 3.78-3.74 (m, 1H).
Example 185: M RV1-Phenyl-2-((6-r5-(trifluoromethoxyV1-benzothiophen-2- vflpyrimidin-4-yl)aminotethanol trifluoroacetic acid salt.
Figure imgf000120_0002
F3C-O
MS (ESI): mass calcd. for C2i Hi8F3N3O2S, 431.10; m/z found, 432.4 [M+H]*. 1H NMR (CD3OD): 8.57 (s, 1 H), 8.13 (s, 1H)1 8.08 (d. J = 8.8 Hz1 1H)1 7.89 (s. 1H)1 7.46-7.41 (m, 3H), 7.38-7.34 (m, 2H), 7.29-7.26 (m, 1H)1 7.05 (S1 1H)1 4.95-4.92 (m, 1H), 3.90-3.83 (m, 1 H), 3.78-3.72 (m, 1H).
Example 186: HRV1-Phenyl-2-((6-r6-t(rifluoromethyll1-benzothiophen-2- yl)pyrimidin-4-yl]aminotethanol trifluoroacetic acid salt.
Figure imgf000121_0001
MS (ESI): mass calcd. for C2IH16F3N3OS, 415.10; m/z found, 416.4 [M+H i]+*. 11ιH NMR (CD3OD): 8.56 (s, 1H), 8.37 (d, J = 0.8 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.71 (dd, J = 8.3, 1.5 Hz1 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.38-7.34 (m, 2H), 7.29-7.25 (m, 1 H), 7.08 (s, 1H), 4.95-4.92 (m, 1H), 3.90-3.80 (m, 1H), 3.73 (dd, J = 13.6, 7.6 Hz, 1H).
Example 187: MRV2-f(6-[5-Fluoro-1-benzothioDhen-2-yltoyrimidin-4-yl]aminoV1- phenylethanol.
Figure imgf000121_0002
MS (ESI): mass calcd. for C20HIeFN3OS, 365.10; m/z found, 366.4 [M+H]*. 1H NMR (CDCI3): 8.62 (s, 1H), 7.85 (s, 1H), 7.79 (dd, J = 8.8, 4.7 Hz, 1 H), 7.47 (dd, J = 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, 1 H), 5.36-5.31 (br hump, 1H), 5.02-4.99 (m, 1 H), 3.91- 3.86 (m, 1 H), 3.64-3.59 (m, 1H).
Example 188: MRV2-K6-r3-(pentafluomethyl)-1 ■Σ-benzisoxazol-β-yl)DyrimidirM- vftaminoVI-phenylethanol trifluoroacetlc acid salt.
Figure imgf000121_0003
MS (ESI): mass calcd. for C2IHi5F5N4O2, 450.11 ; m/z found, 451.2 [M+H]*. 1H NMR (CD3OD): 8.74 (s, 1 H), 8.36 (s, 1H), 8.15 (d, J = 8.4 Hz, 1 H), 7.94 (dd, J = 0.8, 8.4 Hz, 1 H)1 7.45 (d, J = 7.4 Hz1 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.1 Hz, 1H), 7.14 (S1 1 H), 4.97-4.95 (m, 1H), 3.96-3.93 (m, 1 H), 3.84-3.80 (m, 1H). Example 189: 2-^6-r3-Chloro-4-(trifluoromethyl)DhenyflDyrimidin-4-yl)aminoV1 -F2- (difluoromethoxy)phenyl]ethanol.
Figure imgf000122_0001
Title compound was prepared using methods analogous to those described in Example 130. MS (ESI): mass calcd. for C2OHi5CIF5N3O2, 459.08; m/z found, 460.1 [M+Hf. 1H NMR ((CDa)2CO): 8.53-8.48 (m, 1H), 8.28-8.18 (m, 1H), 8.11- 8.03 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H)1 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, J - 3.5 Hz, 1H)1 5.14-5.08 (m, 1 H), 3.76- 3.56 (m, 1H), 3.57-3.45 (m, 1 H).
Example 190: 2-^6-r3-Chloro-4-(trifluorOmethyl)phenynpyrimidin-4-yl)aminoV1-(4- fluorophen yl Methanol .
Figure imgf000122_0002
OH
F3C
Title compound was prepared using methods analogous to those described in Example 130 with modifications to Step A as follows:
Step A: 2-amino-1-(4-fluoro-phenyl)-ethanol. To a solution consisting of 2-amino- 1-(4-fluoro-phenyl)-ethanone (150 mg, 0.9 mmol) and MeOH (5 mL) was added NaBH4 (97 mg, 2.6 mmol). The mixture was stirred at rt for 45 min and then concentrated to dryness. The residue was diluted with EtOAc and washed with a satd. NH4CI solution before drying (Na2SO4), and concentrating to give 2-amino-1- (4-fluoro-phenyl)-ethanol (139 mg, 100%) which was used without further purification.
Step B. MS (ESI): mass calcd. for C19H14CIF4N3O, 411.08; m/z found, 412.4 [M+H]+. 1H NMR (CDCI3): 8.70 (s, 1H), 8.17-8.10 (m, 1H), 7.95 (d, J = 8.2 Hz1 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.44-7.37 (m, 2H)1 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)1 3.61 (ddd, J = 14.0, 7.5, 5.2 Hz1 1H). Example 191 : 4-F2-(f6-r3-Chloro-4-ftrifluoromethyi)DhenytiDyrimidin-4-yl)aminoV1- hydroxyethynbenzonitrile.
c r A^ H OH
Title compound was prepared using methods analogous to those described in Example 130 with modifications to Step A as follows:
Step A. 4-(2-Amino-1-hydroxy-ethyl)-benzonitrile. To a solution consisting of 4-(2- bromo-acetyl)-benzonitrile (1 g, 4.5 mmol) and THF (17 mL) was added BtVTHF (1 M in THF1 5.4 mL) at 0°C. The solution was warmed to rt over 1 h. MeOH (4 mL) was added slowly to the reaction vessel and the reaction mixture stirred for an additional 30 min. The reaction mixture was then concentrated dryness and re-dissolved in MeOH (10 mL) before treating with NH4OH (10mL). The mixture was stirred at rt for 12 h and then concentrated. The residue was dissolved in water and extracted with EtOAC. The organic layer was dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (246 mg, 34%).
Step B. MS (ESI): mass calcd. for C20H14CIF3N4O, 418.08; m/z found, 419.1 [M+H]*. 1H NMR ((CDa)2CO): 8.69-8.39 (m, 2H), 8.29-8.19 (m, 1H), 8.14-8.05 (m, 1H), 8.00 (d, J = 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).
Example 192: 2-a6-r3-Chloro-4-(trifluoromethyl^Dheny1lPyrimk.in-4-v1)aminoV1- naDhthalen-2-vlethanol.
Cl
Figure imgf000123_0001
Title compound was synthesized using procedures analogous to those described in Example 191. MS (ESI): mass calcd. for C23Hi7CIF3N3O, 443.10; m/z found, 444.1 [M+H]*. 1H NMR (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)1 3.95-3.79 (m, 1H)1 3.74 (dd, J = 13.8, 7.4 Hz, 1H). Example 193: 2-(f6-r3-Chloro-4-t(rifluoromethy»DhenynDyrimidin-4-vt)aminoV1-(4- Dyridin-2-ylDhenyi Methanol.
Figure imgf000124_0002
Figure imgf000124_0001
Step A: 2-Nitro-1-(4-Dyridin-2-yl-DhenyJV-ethanol. To a cooled (0 °C) solution consisting of 4-pyridin-2-yl-benzaldehyde (346 mg, 1.9 mmol) in THF (5 ml.) and NO2CH3 (0.3 mL) and MeOH (2.5 mL) was added KOH (2.5 M, 1.13 mL). The reaction mixture was stirred at 0 °C for 30 min. and then quenched with a saturated NH4CI solution. The aqueous mixture was extracted with EtOAC. The organic layer was dried (Na2SO.*) and concentrated. The crude residue was purified (FCC) to give the title compound (257 mg, 60%). Step B: 2-Amino-1-(4-Dyridin-2-vJ-Dheny1V-ethanol. To a solution of consisting of 2-nitro-1-(4-pyridin-2-yl-phenyl)-ethanol (275 mg, 1.1 mmol) and acetone (5 mL) were added NH4CI (900 mg, 16.9 mmol), Zn dust (1.10 g, 16.9 mmol), and water (1 mL). The reaction mixture was stirred for 2 h at rt and then filtered. The filtrate was washed with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (45 mg, 19%). Step C: Title compound was prepared using methods analogous to those described in Example 130. MS (ESI): mass calcd. for C24HiBCIF3N4O, 470.11 ; m/z found, 471.5 [M+H]*. 1H NMR (CDCI3): 8.70-8.69 (m, 1H)1 8.12 (s, 1 H), 8.01 (d, J =8.3 Hz, 2 H)1 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)1 4.02-3.93 (m, 1H), 3.70-3.64 (m, 1 H).
Example 194: 2-((6-[3-Chlorc>-4-(trifluoronnethylk)heny1lDyrimidin-4-yl)aminoV-1 -(4- thiophen-2-vlphenvltethanol.
Figure imgf000125_0001
Title compound was synthesized using methods analogous to those described in Example 193. MS (ESI): mass calcd. for 023Hi7CIFaNaOS, 475.07; m/z found, 476.4 [M+H]*. 1H NMR (CDCI3): 8.71 (s, 1H), 8.15-8.10 (m, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 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, J = 5.1 , 3.6 Hz, 1 H)1 6.75 (s, 1 H), 5.14- 4.96 (m, 1H), 3.73-3.58 (m, 1H)1 3.53-3.49 (m, 1H).
Example 195: 1 -Biphenyl-4-vt-2-K6-r3-chloro^-(trifluoromethyl tohenyl]Pyrimidin-4- vDaminotethanol.
Figure imgf000125_0002
Title compound was prepared using methods analogous to those described in Example 130 with modifications to Step A as follows:
Step A: 2-Amino-1-bipheny1-4-yl-ethanol. To a solution consisting of 1-biphenyl-4- yl-2-bromo-ethanone (412 mg. 1.5 mmol) and EtOH (6 ml.) was added NaN3 (107 mg, 1.6 mmol) at rt. 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 stirred for 45 min. A mixture (black slurry) of CuSO4 «5H2O (37 mg)/NaBH4 (28 mg) in MeOH 2 mL) was prepared by adding the NaBH4 to CuSO4-5H2O in MeOH at 0 °C. This slurry was poured into the reaction mixture. The reaction vessel was allowed to gradually warm to rt. An additional amount of NaBH4 (28 mg) was added 30 min after the addition of the slurry. 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, 80%).
Step B. MS (ESI): mass calcd. for C25Hi9CIF3N3O, 469.12; m/z found. 470.2 [M+H]*. 1H NMR (CDCI3): 8.69 (s, 1 H), 8.15-8.08 (m, 1H), 7.92 (d, J = 8.1 Hz, 1 H), 7.77 (d, J = 8.2 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 2H), 7.58 (d, J - 7.9 Hz, 2H), 7.49 (d, J = 8.4 Hz1 2H)1 7.45 (t, J = 7.7 Hz, 2H), 7.39-7.33 (m, 1 H), 6.74 (s, 1 H), 5.52-5.29 (m, 1H)1 5.11-4.96 (m, 1H)1 4.03-3.82 (m, 1H)1 3.70-3.63 (m. 1H).
Examples 196-218 were prepared using methods analogous to those described in Example 195.
Example 196: 1-(1-Benzothiophen-2-yl)-2-K6-r3-chloro-4- l-vftaminotethanol.
Figure imgf000126_0001
MS (ESI): mass calcd. for C2IH15CIF3N3OS1449.06; m/z found, 450.1 [M+H]+. 1H NMR (CDCI3): 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. J = 8.3 Hz, 1H), 7.75-7.72 (m, 1H), 7.40-7.27 (m, 3H)1 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-((6-r3-Chloro-4-t(rifluoromethy^Dhenynpyrimidin-4-yl>aminoV1 -[3- fluoro-4-t(rifluoromethyl)phenyl]ethanol.
Ii T T c nΛ^ H OH
MS (ESI): mass calcd. for C20Hi3CIF7N3O, 479.06; m/z found, 480.1 [M+H]*. 1H NMR (CDCI3): 8.72 (s, 1H), 8.13 (d, J = 0.7 Hz1 1H), 7.94 (dd, J = 8.3, 0.8 Hz1 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.61 (t, J = 7.6 Hz1 1 H), 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, J = 14.6, 6.8, 5.8 Hz, 1H).
Example 198: 2-(l6-r3-chloro-4-(trifluoromethyl^phenynpyrimidin-4-vt)aminoV1 -13- rftrifluoromethvOsulfanvflphenvltethanol.
Figure imgf000126_0002
MS (ESI): mass calcd. for C2OHuCIFeN3OS, 493.04; m/z found, 494.1 [M+H]*. 1H NMR (CDCI3): 8.69 (d, J = 0.7 Hz1 1H)1 8.11 (s, 1H), 7.92 (dd, J = 8.2, 0.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.72-7.69 (m, 1 H), 7.63-7.57 (m, 1H), 7.56-7.52 (m, 1H), 7.44 (t, J = 7.7 Hz, 1 H), 6.74 (d, J = 1.1 Hz, 1H)1 5.42-5.19 (m, 1H), 5.04 (dd, J = 7.2, 2.9 Hz, 1H), 4.02-3.81 (m, 1H), 3.62 (ddd, J = 14.3. 7.2, 5.4 Hz, 1H).
Example 199: 2-α6-r3-Chloro-4-(tπfluoromethy1)Dhenyl]Dyrimidin-4-v1)aminoV1- (2.3-dihydro-1.4-benzodioxin-6-v1 Methanol.
Figure imgf000127_0001
MS (ESI): mass calcd. for C2i Hi7CIF3N3O3, 451.09; m/z found, 452.1 [M+H]*. 1H NMR (CDCI3): 8.67 (s, 1H), 8.12 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 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, 1 H), 4.90-4.87 (m, 1 H), 4.35-4.18 (m, 4H), 3.92-3.76 (m, 1H), 3.62-3.54 (m, 1 H).
Example 200: 2-((6-r3-Chloro-4-(trifluoromethy1)Dhenyl]DyrimkJin-4-yl)annino V1 -F4- M H-imkJazoH -vQphenyflethanol.
Figure imgf000127_0002
MS (ESI): mass calcd. for C22Hi7CIF3N5O, 459.11 ; m/z found, 460.1 [M+H]*. 1H NMR (CDCI3): 8.71 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J = 8.3 Hz, 1 H)1 7.55 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.29- 7.27 (m, 1H), 7.23-7.20 (m, 1 H), 6.78-6.77 (m, 1H), 5.47-5.31 (m, 1 H), 5.10-5.07 (m, 1H)1 4.12-3.81 (m, 1H), 3.74-3.55 (m, 1H).
Example 201 : 1-M-benzothiophen-3-yl)-2-((6-r3-chloro-4- ftrifluoromethvθphenvliPvrimidin-4-vlteminotethanol.
Figure imgf000128_0001
MS (ESI): mass calcd. for C2IH15CIF3N3OS, 449.06; m/z found, 450.1 [M+H]*. 1H NMR (CDCI3): 8.70 (s, 1H), 8.08 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.90-7.82 (m, 2H)1 7.76 (d, J = 8.2 Hz, 1H), 7.52-7.47 (m, 1H)1 7.46-7.35 (m, 2H), 6.68 (s, 1H)1 5.47-5.34 (m, 2H), 4.21-4.01 (m, 1H), 3.77 (ddd, J = 14.3, 7.0, 5.4 Hz, 1H).
Example 202: 2-(f6-r3-Chloro-4-(trifluoromethyi)DhenyliDyrimidin-4-yl)aminoV1- (3.4-dimethoxy])henyl Methanol.
Figure imgf000128_0002
MS (ESI): mass calcd. for C2i Hi9CIF3N3O3, 453.11 ; m/z found, 454.2 [M+H]*. 1H NMR (CDCI3): 8.82-8.54 (m, 1 H), 8.17-8.08 (m. 1H)1 7.93 (d, J = 8.4 Hz, 1 H), 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).
Example 203: 1-(3-Chloro-4-methoχyphenyl)-2-((6-r3-chloro-4- ftrifluoromethyQphenyl]pyrimidin-4-yl)aminotethanol.
Figure imgf000128_0003
MS (ESI): mass calcd. for C20HIeCl2F3N3O2, 457.06; m/z found, 458.1 [M+H]*. 1H NMR (CDCI3): 8.68 (d, J = 0.8 Hz, 1H)1 8.12 (d, J = 0.8 Hz, 1H), 7.93 (ddd, J = 8.1 , 1.5, 0.7 Hz, 1 H), 7.78 (d, J = 8.3 Hz1 1 H)1 7.44 (d. J = 2.0 Hz, 1 H), 7.28 (dd, J = 2.2, 0.4 Hz1 1H)1 6.93 (d, J - 8.5 Hz, 1H)1 6.74 (d, J = 1.1 Hz1 1H)1 5.45-5.17 (m, 1H), 4.97-4.87 (m, 1H)1 3.90 (s. 3H), 3.87-3.82 (m, 1H), 3.59 (ddd, J = 14.1 , 7.4, 5.3 Hz, 1H). Example 204: 2-(f6-r3-Chloro-4-t(rifluoromethy»Dhenyl]Dyrimidin-4-yl)aminoV1- (3.4-dihydro-2H-1.5-benzodioxepin-7-yl)ethanol.
Figure imgf000129_0001
MS (ESI): mass calcd. for C22Hi9CIF3N3O3, 465.11 ; m/z found, 455.4 [M+H]*. 1H NMR (CDCI3): 8.67 (d, J = 0.5 Hz, 1H), 8.12 (s, 1H), 7.92 (dd, J = 8.3, 0.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.06-7.01 (m, 1H)1 6.98-6.95 (m, 2H), 6.72-6.70 (m, 1H), 5.50-5.11 (m, 1H)1 4.92-4.87 (m, 1H), 4.28-4.10 (m, 4H), 3.91-3.78 (m, 1 H), 3.58 (ddd, J - 13.9, 7.5, 5.3 Hz, 1H), 2.23-2.16 (m, 2H).
Example 205: 2-(f6-r3-Chloro-4-(trifluoromethyl)DhenynDyrimidin-4-vftaminoV1-r2- fluoro-5-(trifluoromethyl)phenyflethanol.
Figure imgf000129_0002
MS (ESI): mass calcd. for C20H13CIF7N3O, 479.06; m/z found, 480.1 [M+H]+. 1H NMR (CDCI3): 8.71 (s, 1H), 8.15-8.10 (m, 1H)1 7.96-7.90 (m, 2H), 7.79 (d, J = 8.2 Hz, 1H)1 7.60-7.53 (m. 1H)1 7.17 (t. J = 9.3 Hz1 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-r2-(f6-r3-Chloro-4-t(rifluoromethyl)phenyl]pyrimidin-4-yl)aminoV1- hydroxyethyflbenzonitrile.
Figure imgf000129_0003
MS (ESI): mass calcd. for C20H14CIF3N4O, 418.08; m/z found, 419.1 [M+H]+. 1H NMR (CDCI3): 8.76-8.66 (m, 1 H), 8.15-8.10 (m, 1H), 7.94 (d, J = 8.2 Hz1 1H)1 7.79 (d, J = 8.2 Hz, 1H), 7.76-7.74 (m, 1H), 7.67 (d, J = 7.8 Hz1 1H), 7.62-7.59 (m, 1H), 7.52-7.47 (m, 1H), 6.78 (d, J = 1.0 Hz, 1H), 5.40-5.17 (m, 1H)1 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-r3-Chloro-4-(trifluoromethylbhenytiDyrimidin-4-vftamino)-1 -(3- phenylisoxazol-5-yl Methanol.
Figure imgf000130_0001
MS (ESI): mass calcd. for C22Hi6CIF3N4O2, 460.09; m/z found, 461.1 [M+H]*. 1H NMR (CDCI3): 8.70 (d, J = 0.8 Hz, 1 H)1 8.12 (d, J = 0.8 Hz, 1 H)1 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, 1 H), 6.63 (d, J - 0.9 Hz, 1H)1 5.44-5.30 (m, 1H)1 5.23-5.13 (m, 2H), 4.19-4.11 (m, 1 H), 3.98- 3.89 (m, 1H).
Example 208: 2-α6-r3-Chloro-4-αrifluoromethy1)DhenyflDyrimidin-4-v1\aminoV1-(4- pyrτolidin-1 -ylphenyl)ethanol.
Figure imgf000130_0002
MS (ESI): mass calcd. for C23H22CIF3N4O, 462.14; m/z found, 463.2 [M+H]*. 1H NMR (CDCI3): 8.69-8.62 (m, 1H), 8.11 (s, 1 H), 7.91 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1 H), 7.25-7.24 (m, 2H), 6.75-6.62 (m, 1 H)1 6.56 (d, J = 8.6 Hz, 2H), 5.45-5.37 (m, 1 H)1 4.93-4.78 (m, 1H), 3.89-3.70 (m, 1H)1 3.65-3.57 (m, 1H), 3.31- 3.22 (m, 4H), 2.07-1.85 (m, 4H).
Example 209: 2-((6-r3-Chloro-4-ftrifluoromethy1bhenyflDyrimidin-4-v1)aminoV1 -(5- pyridin-2-ylthiophen-2-vi Methanol.
Figure imgf000130_0003
MS (ESI): mass calcd. for C22Hi6CIF3N4OS1 476.07; m/z found, 477.1 [M+H]*. 1H NMR (CDCI3): 8.68 (d, J = 0.7 Hz1 1H), 8.55 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.14- 8.10 (m, 1H), 7.92 (dd, J = 8.2, 0.8 Hz1 1H), 7.75 (d, J = 8.2 Hz1 1H)1 7.71-7.66 (m, 1H)1 7.63-7.60 (m, 1H)1 7.45 (d. J = 3.7 Hz1 1H)1 7.15 (ddd, J = 7.3, 4.9. 1.2 Hz1 1H), 7.05 (dd, J = 3.7, 0.8 Hz1 1H), 6.76 (d, J = 1.1 Hz1 1H)1 5.50-5.34 (m, 1H)1 5.29-5.21 (m, 1H)1 4.15-3.93 (m, 1H), 3.77 (ddd, J = 14.2, 6.4, 5.8 Hz, 1 H).
Example 210: 5-r2-((6-r3-Chloro-4-arifluoromethy1)Dhenyl]Dyrimidin-4-yl)aminoV1- hydroxyethyl]-2-fluorobenzonitrile.
Figure imgf000131_0001
MS (ESI): mass calcd. for C20H13CIF4N4O, 436.07; m/z found, 437.4 [M+H]*. 1H NMR (CD3OD): 8.52 (s, 1 H)1 8.22-8.16 (m, 1H)1 8.02 (d, J = 8.3 Hz, 1H), 7.9 (d, J = 8.3 Hz, 1H), 7.86-7.76 (m, 2H), 7.35 (t, J = 8.9 Hz1 1H), 7.00 (d, J = 1.1 Hz1 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-((6-r3-Chloro-4-t(rifluoromethy»DhenyfiDyrimidin-4-yl)aminoV1- f2.6-difluorophenyl Methanol.
Figure imgf000131_0003
MS (ESI): mass calcd. for CIgH13CIF5N3O, 429.07; m/z found, 430.1 [M-I-Hf. 1H NMR (CDCI3): 8.68 (s, 1H), 8.15-8.10 (m, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.2 Hz1 1 H), 7.30-7.26 (m, 1H), 6.92 (t, J = 8.2 Hz, 2H), 6.80-6.78 (m, 1 H), 5.50- 5.40 (m, 1H), 5.33 (dt, J = 7.7, 3.6 Hz1 1H)1 4.08-3.93 (m, 1H)1 3.90-3.81 (m, 1 H).
Example 212: 2-α6-r3-Chloro-4-t(rifluoromethy»phenynpyrimidin-4-vftaminoV1 -12- fluorophenyl Methanol.
Figure imgf000131_0002
MS (ESI): mass calcd. for Ci9Hi4CIF4N3O, 411.08; m/z found, 412.1 [M+H]*. 1H NMR (CDCI3): 8.13 (s, 1H), 7.93 (d, J = 8.3 Hz1 1H)1 7.78 (d. J = 8.3 Hz, 1 H), 7.57 (dt, J = 7.3, 1.4 Hz, 1H), 7.34-7.28 (m, 2H), 7.21-7.14 (m, 1 H), 7.10-7.02 (m, 1H). 6.82-6.71 (m, 1H)1 5.44-5.33 (m, 1H), 5.33-5.27 (m, 1H)1 4.05-3.82 (m, 1H)1 3.77- 3.66 (m, 1H).
Example 213: 2-r6-(3-Chloro-4-trifluoromethyl-phenylWpyrimidin-4-ylamino'l-1 -I3- (3.4-dichloro-Dhenyl)-isoxa2θl-5-vfl-ethanol.
Figure imgf000132_0001
MS (ESI): mass calcd. for C22HuCI3F3N4O2, 528.01 ; m/z found, 531 [M+H]*. 1H NMR (CDCI3): 8.71 (s, 1 H), 8.12 (s, 1H), 7.92 (dd, J = 8.3, 0.7 Hz, 1 H), 7.89 (d, J = 2.0 Hz1 1H)1 7.78 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.52 (d. J = 8.4 Hz1 1H), 6.81 (d, J = 1.1 Hz1 1H)1 6.62 (d, J = 0.9 Hz, 1H), 5.43-5.29 (m, 1 H), 5.23-5.15 (m, 1 H)1 4.15 (ddd, J = 14.8, 5.6, 2.3 Hz1 1H)1 3.94 (td. J = 14.8, 6.0 Hz1 1H).
Example 214: 1-r3-(4-Chloro-Phenyl)-isoxazol-5-yl]-2-r6-(3-chloro-4- trifluoromethyl-phenyl)-pyrimidin-4-ylaminoi-ethanol.
Figure imgf000132_0002
MS (ESI): mass calcd. for C22Hi5Cl2F3N4O2, 494.05; m/z found, 495.1 [M+Hf. 1H NMR (CDCI3): 8.71 (d, J = 0.6 Hz1 1H)1 8.16-8.06 (m. 1H)1 7.91 (dd. J = 8.2, 0.68 Hz1 1 H), 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, 1 H), 6.62 (d, J = 0.9 Hz, 1H), 5.44-5.31 (m, 1H), 5.21-5.15 (m. 1H)1 4.18-4.11 (m. 1H), 3.99-3.88 (m, 1H).
Example 215: 2-r6-(3-Chloro-4-trifluoromethyl-phenyl Vpyrimk.in-4-ylaminoi-i -F3- (2.4-dichloro-phenyl)-isoxazol-5-yl]-ethanol.
Figure imgf000132_0003
MS (ESI): mass calcd. for C22H14CI3F3N4O2, 528.01; m/z found, 531 [M+H]+. 1H NMR (CDCI3): 8.75-8.64 (m, 1 H)1 8.13 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.3 Hz1 1H), 7.66 (d, J = 8.4 Hz1 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1 H), 6.81 (d, J = 1.1 Hz, 1H), 6.76 (d, J = 0.8 Hz, 1H), 5.46-5.32 (m, 1 H), 5.24-5.18 (m, 1H), 4.20-4.07 (m, 1H), 4.02-3.92 (m, 1H).
Example 216: 1-Benzothiazol-2-yl-2-r6-(3-chloro-4-trifluoromethyl-phenyl)- pyrimidin-4-ylaminol-ethanol.
Figure imgf000133_0001
MS (ESI): mass calcd. for C20H14CIF3N4OS, 450.05; m/z found, 451.1 [M+H]*. 1H NMR (CDCI3): 8.71 (s, 1 H), 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)1 7.49 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.42-7.37 (m, 1H), 6.77 (d, J = 1.1 Hz, 1H), 5.54-5.40 (m, 1H), 5.35 (dt, J = 5.3, 2.6 Hz, 1 H), 4.37-4.19 (m, 1 H), 4.09 (td, J = 14.6, 5.8, Hz1 1H).
Example 217: 1-r3.5-Bisftrifluoromethy»Dhenyn-2-(f6-r3-chloro-4- (trifluoromethy1)Dheny1lPyrirτιidin-4-yl)amino^ethanol.
CF3
Figure imgf000133_0002
MS (ESI): mass calcd. for C2IH13CIF9N3O1 529.06; m/z found, 530.1 [M+H]+. 1H NMR (CDCI3): 8.73 (s, 1H), 8.13 (s, 1H), 7.96-7.88 (m, 3H), 7.83-7.77 (m, 2H)1 6.87-6.73 (m, 1H), 5.35-5.23 (m, 1H)1 5.19-5.13 (m. 1 H)1 4.05-3.85 (m, 1 H)1 3.77- 3.64 (m, 1 H).
Example 218: 1-(5-Bromo-1-benzothioprten-2-yl)-2-((6-r3-chloro-4- rtrifluoromethyl)pheny1iDyrimidin-4-v1)amino>ethanol.
Br
Figure imgf000133_0003
MS (ESI): mass calcd. for C2IH14BrCIF3N3OS, 526.97; m/z found, 530.0 [M-I-H]+. 1H NMR (CDCI3): 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 219-221 were prepared using methods analogous to those described in Example 20.
Example 219: MRVPhenyl-2-l6-[4-(1.2.2.2-tetrafluoro-1-trifluoromethyl-ethyl)- Dhenyl]-Dyrimidin-4-ylaminoV-ethanol
F3C> Js^ H
Figure imgf000134_0001
F CF3
MS (ESI+): calcd for C21H16F7N3O m/z 459.12, found 460.1 (M+H)+. 1H NMR (CD3. OD): 8.50 (s, 1H), 8.24 (s, 1H), 8.14-8.09 (m, 1H)1 7.77-7.69 (m, 2H)1 7.43 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 4.92- 4.90 (m, 1H)1 3.74 (br s, 1H), 3.62-3.58 (m, 1 H).
Example 220: MRVPhenyl-2-l6-r3-M .2.2.2-tetrafluoro-1-trifluoromethyl-ethyl)- phenyn-pyrimidin-4-ylaminoV-ethanol
Figure imgf000134_0002
MS (ESI+): calcd for C21H16F7N3O m/z 459.12, found 460.2 (M-I-H)+. 1H NMR (CD3. OD): 8.50 (s, 1H)1 8.24 (s, 1H), 8.13 (d, J = 7.5 Hz, 1H)1 7.76 (d. J = 8.0 Hz, 1H)1 7.71 (t, J = 7.5 Hz1 1H)1 7.43 (d, J = 7.5 Hz1 2H)1 7.34 (t, J = 7.5 Hz, 2H)1 7.25 (t, J = 7.5 Hz1 1H)1 4.92-4.89 (m. 1H), 3.74 (br s, 1 H), 3.62-3.58 (m, 1H).
Example 221 : HR)-Phenyl-2-r6-(3-trifluoromethyl-benzorblthiophen-6-yl)- pyrimidin-4-ethanol.
Figure imgf000135_0001
MS (ESI): mass calcd. for C2IHi6F3N3OS, 415.10; m/z found, 416.1 [M+H]*. 1H NMR (CD3OD): 8.70 (s, 1H)1 8.52-8.51 (m, 2H), 8.13 (d, J = 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)1 7.30-7.26 (m, 1H), 7.12 (s, 1H), 4.98-4.95 (m, 1H), 3.95 (dd, J = 4.2, 14 Hz, 1H)1 3.85-3.80 (m, 1H).
Example 222 can be prepared using methods analogous to those described in Example 141.
Example 222: 4-(3-Chloro-4-trifluoromethyl-phenyl)-^(2-hydroxy-2-phenyl-MRV- ethylaminoVDyrimidine-2-carbonitrile.
Figure imgf000135_0002
The compounds of the following Examples 223-245 were obtained by our employer from a third party as library compounds and therefore were known to us as compounds per so. We discovered that these compounds have FAAH- modulating activity, and that they therefore have utility in the therapeutic compositions and methods according to the invention, as reflected by the assay results for these compounds shown in Table 1.
Example 223: 2-l{6-(3.4-DimethylDhenyl)Dyrimidin-4-yl]amino)-1 -phem/lethanol.
Figure imgf000135_0003
Example 224: 2-((6-f4-(1.1-Dimethylethyl)phenvnpyrimidin-4-yl)amino)-1- phenylethanol.
Figure imgf000136_0001
Example 225: 2-r6-(4-Methylsulfanyl-phenyl)-pyrimidin-4-ylamino1-1 -phenyl ethanol.
Figure imgf000136_0002
Example 226: 4-(6-r(2-Hvdroxy-2-phenylethyl)aminoipyrimidin-4-yl)benzonitrile.
Figure imgf000136_0003
Example 227: 2-(6-Benzorblthiophen-2-yl-pyrimidin-4-ylamino)-1 -phenyl-ethanol.
Figure imgf000136_0004
Example 228: 1 -(4-(6-r(2-Hvdroxy-2-phenylethyl)amino1pyrimidin-4- vDphenvPethanone.
Figure imgf000136_0005
Example 229: 2-r6-(3,4-Dimethoxy-phenyl)-pyrimidin-4-ylaminol-1 -phenyl- ethanol.
Figure imgf000137_0001
Example 230: 2-/r6-(4-MethyJDhenylkιyrimidin-4-yl]amino)-1-Dheny1ethanol.
Figure imgf000137_0002
Example 231: 1-Phenyl-2-rf6-l4-rftrifluoromethylk)xyiphenyl>Dyrimidin-4- yitøminolethanol trifluoroacetic acid salt.
Figure imgf000137_0003
Example 232: 2-(β-BenzoH .3ldioxol-5-yl-pyrimidin^-ylamino)-1-phenyl-ethanol.
Figure imgf000137_0004
Example 233: 2-[6-(3-Methoxy-Dhenyl)-pyrimidin-4-ylamino1-1-phenyl-ethanol.
Figure imgf000137_0005
Example 234: 2-r6-(3-Nitro-pheny1>-pyriπnk-in-4-v1aminol-1-Dheny1-ethanol.
Figure imgf000137_0006
Example 235: 2-r(6-Naphthalen-2-vlpvrimidin-4-v0amino1-1 -phenviethanol.
Figure imgf000138_0001
Example 236: 1 -Iδ-rβ-^-Hvdroxy^-Dhenyt-ethylamino^-Dyrimidin^-vti-thioDhen- 2-ylV-ethanone.
Figure imgf000138_0002
Example 237: 246-(2.6-Difluoro-phenylVpyrimk.in^-ylaminol1-phenyl-ethanol.
Figure imgf000138_0003
Example 238: 4-r6-(2-Hvdroxy-2-Dhenyl-ethyJaminoVDyrimidin-4-v11-Dhenol.
Figure imgf000138_0004
Example 239: 2-r6-(3.5-Bis-trifluoromethy1-Dhenyl)-Dyrimidin-4-ylaminol-1 -Dhenyl- ethanol.
Figure imgf000138_0005
Example 240: 2-r6-(3-Amino-phenyl)-DyrimkJin-4-ylamino1-1-Dhenyl-ethanol.
Figure imgf000138_0006
Example 241: 2-r6-^4-Hvdroxymethyl-Dhenyl)-Dyrimidin-4-ylamino1-1-Dhenyl- ethanol.
Figure imgf000139_0001
Example 242: N43-r6-/2-Hvdroxy-2-Dhenyl-ethylaminoVDyrimk)in-4-yl)-DhenylV- acetamide.
Figure imgf000139_0002
Example 243: 1-Phenyl-2-(6-phenyl-Pyrimidin-4-ylaminoVethanol.
Figure imgf000139_0003
Example 244: 1-Pheny1-2-(6-thiophen-2-v1-Dyrimidin-4-v1aminoVethanol.
Figure imgf000139_0004
Example 245: 1-Phenyl-2-(6-thto phen-3-yl-Pyrimidin-4-ylamino)-ethanol.
Figure imgf000139_0005
Comparative Examples
The compounds of the following Comparative Examples 1-8 were also obtained by our employer from a third party as library compounds and therefore were known to us as compounds per se. The comparative assay results for these compounds are shown in Table 2. Comparative Example 1 : 246-(2.6-Bis-trifluoromethyl-phenyl)-pyrimidin-4- ylaminoi-1 -Dheny]-ethanol.
Figure imgf000140_0002
Figure imgf000140_0001
Comparative Example 2: N-/3-r6-(2-Hvdroxy-2-phenyl-ethylaminoVpyrimidin-4-vn- phenyD-acetamide.
Figure imgf000140_0003
Comparative Example 3: 1-Phenyl-2-(6-phenyl-pyrimidin-4-ylaminoVethanol.
Figure imgf000140_0004
Comparative Example 4: 2-r6-(2.6-Difluoro-phenyl)-pyrimidin-4-ylamino1-1- phenyl-ethanol.
Figure imgf000140_0005
Comparative Example 5: 1-Phenyl-2-(6-thioDhen-2-yl-pyrimidin-4-ylaminoV ethanol.
Figure imgf000140_0006
Figure imgf000140_0007
Comparative Example 6: 4-[6-(2-Hvdroxy-2-Dhenyl-ethy1aminoVDyrimidin-4-vfl- phenol.
Figure imgf000141_0001
Comparative Example 7: 1-Phenyl-2-(6-thiophen-3-yl-pyrim8din-4-ylaminoV ethanol.
Figure imgf000141_0002
Comparative Example 8: 2-r6-(3-Amino-phenyl)-pyrimidin-4-ylaminol-1-phenyl- ethanol.
Figure imgf000141_0003
Biological Testing: Assay Method 1 A. Transfection of Cells with Human FAAH
A 10-cm tissue culture dish with a confluent monolayer of SK-N-MC cells was split 2 days (d) prior to transfection. Using sterile technique, the media was removed and the cells were detached from the dish by the addition of trypsin. One fifth of the cells were then placed onto a new 10-cm dish. Cells were grown in a 37 °C incubator with 5% CO2 in Minimal Essential Media Eagle with 10% Fetal Bovine Serum. After 2 d, cells were approximately 80% confluent. These cells were removed from the dish with trypsin and pelleted in a clinical centrifuge. The pellet was re-suspended in 400 μl_ complete media and transferred to an electroporation cuvette with a 0.4 cm gap between the electrodes. Supercoiled human FAAH cDNA (1 μg) was added to the cells and mixed. The voltage for the electroporation was set at 0.25 kV, and the capacitance was set at 960 μF. After electroporation , the cells were diluted into complete media (10 mL) and plated onto four 10-cm dishes. Because of the variability in the efficiency of electroporation, four different concentrations of cells were plated. The ratios used were 1 :20, 1 :10, and 1 :5, with the remainder of the cells being added to the fourth dish. The cells were allowed to recover for 24 h before adding the selection media (complete media with 600 μg/mL G418). After 10 d, dishes were analyzed for surviving colonies of cells. Dishes with well-isolated colonies were used. Cells from individual colonies were isolated and tested. The clones that showed the most FAAH activity, as measured by anandamide hydrolysis, were used for further study. B. FAAH Assay
T84 frozen cell pellets or transfected SK-N-MC cells (contents of 1 x 15 cm culture dishes) were homogenized in 50 mL of FAAH assay buffer (125 mM Tris, 1mM EDTA, 0.2% Glycerol, 0.02% Triton X-100, 0.4 mM Hepes, pH 9). The assay mixture consisted of 50 μL of the cell homogenate, 10 μL of the test compound, and 40 μL of anandamide [1-3H-ethanolamine] (3H-AEA, Perkin- Elmer, 10.3 C|/mmol), which was added last, for a final tracer concentration of 80 nM. The reaction mixture was incubated at rt for 1 h. During the incubation, 96- well Multiscreen filter plates (catalog number MAFCNOB50; Millipore, Bedford, MA, USA) were loaded with 25 μL of activated charcoal (Multiscreen column loader, catalog number MACL09625, Millipore) and washed once with 100 μL of MeOH. Also during the incubation, 96-well DYNEX MicrpLite plates (catalog number NL510410) were loaded with 100 μL of M icroScint40 (catalog number 6013641, Packard Bioscience, Meriden, CT, USA). After the 1 h incubation, 60 μL of the reaction mixture were transferred to the charcoal plates, which were then assembled on top of the DYNEX plates using Centrifuge Alignment Frames (catalog number MACF09604, Millipore). The unbound labeled ethanolamine was centrifuged through to the bottom plate (5 min at 2000 rpm), which was preloaded with the scintillant, as described above. The plates were sealed and left at rt for 1 h before counting on a Hewlett Packard TopCount. Assay Method 2 A. Transfection of Cells with Rat FAAH- 1 A 10-cm tissue culture dish with a confluent monolayer of SK-N-MC cells was split 2 days (d) prior to transfection. Using sterile technique, the media was removed and the cells were detached from the dish by the addition of trypsin. One fifth of the cells were then placed onto a new 10-cm dish. Cells were grown in a 37 °C incubator with 5% CO2 in Minimal Essential Media Eagle with 10% Fetal Bovine Serum. After 2 d, cells were approximately 80% confluent. These cells were removed from the dish with trypsin and pelleted in a clinical centrifuge. The pellet was re-suspended in 400 μl_ complete media and transferred to an electroporation cuvette with a 0.4 cm gap between the electrodes. Supercoiled rat FAAH cONA (1 μg) was added to the cells and mixed. The voltage for the electroporation was set at 0.25 kV, and the capacitance was set at 960 μF. After electroporation, the cells were diluted into complete media (10 mL) and plated onto four 10-cm dishes. Because of the variability in the efficiency of electroporation, four different concentrations of cells were plated. The ratios used were 1 :20, 1:10, and 1 :5, with the remainder of the cells being added to the fourth dish. The cells were allowed to recover for 24 h before adding the selection media (complete media with 600 μg/mL G418). After 10 d, dishes were analyzed for surviving colonies of cells. Dishes with well-isolated colonies were used. Cells from individual colonies were isolated and tested. The clones that showed the most FAAH activity, as measured by anandamide hydrolysis, were used for further study. B. Rat FAAH-1 Assay
T84 frozen cell pellets or transfected SK-N-MC cells (contents of 1 x 15 cm culture dishes) were homogenized in 50 ml. of FAAH assay buffer (125 mM Tris, 1 mM EDTA, 0.2% Glycerol. 0.02% Triton X-100, 0.4 mM Hepes, pH 9). The assay mixture consisted of 50 μl_ of the cell homogenate, 10 μL of the test compound, and 40 μL of anandamide [1-3H^ethanolamine] (3H-AEA, Perkin- Elmer, 10.3 C1/mmol), which was added last, for a final tracer concentration of 80 nM. The reaction mixture was incubated at rt for 1 h. During the incubation, 96- well Multiscreen filter plates (catalog number MAFCNOB50; Millipore, Bedford, MA, USA) were loaded with 25 μL of activated charcoal (Multiscreen column loader, catalog number MACL09625, Millipore) and washed once with 100 μL of MeOH. Also during the incubation, 96-well DYNEX MicroLite plates (catalog number NL510410) were loaded with 100 μL of MicroScint40 (catalog number 6013641 , Packard Bioscience, Me rid en, CT, USA). After the 1 h incubation, 60 μL of the reaction mixture were transferred to the charcoal plates, which were then assembled on top of the DYNEX plates using Centrifuge Alignment Frames (catalog number MACF09604, Millipore). The unbound labeled ethanolamine was centrifuged through to the bottom plate (5 min at 2000 rpm), which was preloaded with the scintillant, as described above. The plates were sealed and left at rt for 1 h before counting on a Hewlett Packard TopCount.
Results for Example compounds tested in these assays are presented in Table 1. Results for Comparative Example compounds tested in these assays are presented in Table 2. Where activity is shown as greater than (>) a particular value, the value is the solubility limit of the compound in the assay medium or the highest concentration tested in the assay. Reference to the term "NT" in the tables means the compound was not tested.
Table 1
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Table 2
Figure imgf000148_0001
While the invention has been illustrated by reference to exemplary and preferred embodiments, it will be understood that the invention is intended not to be limited to the foregoing detailed description, but to be defined by the appended claims as properly construed under principles of patent law.

Claims

What is claimed is:
1. A compound of Formula (I-A):
R1 N^N R2
A^v-s R3- OH 1 <'-A> wherein: R1 is -H1 -C^alkyl, -OC^alkyl, -S(O)o.2C1-4alkyl, -CN1 -CF3, -N(Ra)Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H, -Chalkyl optionally substituted with -OH, N(Rm)Rn, where Rm and Rn are -H1 C^alkyl; or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with; (i) one, two, or three Rc moieties, where each Rc moiety is independently -Chalkyl, -C1^alkyl-OH, -C-Malkyl-CN, -CF3, -OH, -OCi-4alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2Ci-*alkyl, -SCF3, -SO2CF3, -CHO, -COC1-ialkyl. -CO2Ci^alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN1 phenyl, pyridyl, or halo, where Rd and R* are each independently -H or -Chalkyl, or taken together Rd and Rβ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring; or (ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)i.3O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -C^alkyl, -C1- 4alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2Ci^alkyl, -SCF3, -SO2CF3, -CHO1 -COC^alkyl, -CO2C1. 4alkyl, -CO2H1 -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, or halo, where Rd and R* are each independently -H or -C1^alkyl;
X is N or C(Rf), where Rf is -H or methyl; Ar2 Js:
(i) a phenyl group substituted with: (a) one, two, or three R° moieties each at a meta or para position, and optionally with one or two additional R° moieties at an ortho position; where each Rg moiety is independently -Ci^alkyl, -C^alkyl-OH, -C1-4alkyl- CN, perhaloalkyl, perhaloalkoxy , -OC1-*alkyl, -OCi^alkyl-(monocyclic cycloalkyl), -S(O)o.2Ci^alkyl, -SCF3, -SO2CF3, -CHO, -COC1-4alky1, -CO2C1-4alkyl, -CO2H, -N(Rh)R', -SO2NRiRk, -NR11SO2R1, -C(O)NRjRk, -NO2, -CN, or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -Chalkyl, -OC^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo; where Rh is -H or -C^alkyl; R1 is -Ci^alkyl or monoyclic cycloalkyl group; or Rh and R1 taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R1 is -H or -Ci^alkyl; and Rk is -H, -C1^alkyl or monoyclic cycloalkyl group; or R1 and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or
(b) two adjacent R° moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups;
(ii) a monocyclic heteroaryl group substituted with one, two, or three R° moieties, where each R0 moiety is independently or two adjacent R° moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups; or
(iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties; where each R1 moiety is independently -Ci^alkyl, -OCi^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo;
R2 is -H or methyl; and R3 is -H or methyl; provided, however, that Ar2 is not -CHO or para substituted -OCF3 when Ar1 is unsubstituted phenyl; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.
2. A compound as defined in claim 1 , wherein R1 is -H1 methyl, isopropyl, trifluoromethyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl.
3. A compound as defined in claim 1 , wherein R1 is -H.
4. A compound as defined in claim 1 , wherein Ar1 is a phenyl group, unsubstituted or substituted with one, two, or three Rc moieties.
5. A compound as defined in claim 1 , wherein X is C(Rf).
6. A compound as defined in claim 5, wherein Rf is -H.
7. A compound as defined in claim 1 , wherein Ar2 is a phenyl substituted with one, two or three R° moieties each at a meta or para position.
8. A compound as defined in claim 1 , wherein Ar2 is a thiophenyl, pyridinyl, pyrimidinyl, or pyrazolyl group, each substituted with one, two, or three R° moieties.
9. A compound as defined in claim 1 , wherein Ar2 is a naphthyl, benzoxadiazolyl, indolyl, benzothiophenyl, quinolinyl, or indazolyl, each unsubstituted or substituted with one, two, or three R1 moieties.
10. A compound as defined in claim 1 , wherein R2 is -H.
11. A compound as defined in claim 1 , wherein R3 is -H.
12. A compound selected from the group consisting of:
(1R)-2-({6-[4-(Ethyloxy)-3-(trifluoro1τrøthyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol;
(1 R)-1 -Phenyl-2^{6-l4-(trifluororτiethyl)phenyl]pyrimidin-4-yl}amino)ethanol;
(1 R)-2-({6-[3-Chloro^trifluorc^nethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-[3-Chk>ro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol hydrochloride salt;
(1 R}-2-({6-[4-(1-Methylethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol;
(1 R)-2-l(6-{3-Chloro-4-[(1 -methylethyl)oxy]phenyl}pyrimidin-4-yl)amino]-1 -phenylethanol;
(1 R)-2-{[6-(3-Fluoro-4-methylphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-[4-{Hydroxymethyl)phenyl]pyrimldin-4-yl}amino)-1 -phenylethanol;
4-(6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzaldehyde;
3-(6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzaldehyde;
(1R)-1-Phenyl-2-[(6-{4-[(2,2,2-t1ifluoroethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
(1 R)- 1 -Phenyl-2-[(β-{3-[(2l2l2-trfπuoroethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
(1 R)-2-{[6-(4-Chloro-3-methylphenyl)pyr1midin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(4-Chloro-3-fluorophenyl)pyrimidin-4-y1]amino}-1 -phenylethanol;
(1 R)-2-({6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrimldin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{[6-<4-Ethoxy-3-fluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
( 1 R)-2-{[6-(4-Ethoxy-3-methylphenyl)pyrimidin-4-yl]amlno}-1 -phenylethanol;
(1 R)-2-({6-[4-<Cyclopropylmethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{[6-(4-Butoxy-3-fluorophenyl)pyrimldin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(4-Butoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[β-(3-Fluoro-4-propoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({β-{3-Fluoro-4-(1 -methylethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-{4-(2-Methylpropoxy)phenyl]pyrimidin-4-yl}amlno)-1 -phenylethanol;
(1 R)-2-{[6-(4-Methoxy-3-methylphenyl)pyrimkJin-4-yl]am!no}-1 -phenylethanol;
(1 R)-2-{I6-(3-Chloro-4-methylphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1R)-2-{[6-(3l5-Dimethylphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-{3-Fluoro-4-(trifluoromethyl)phenyrjpyrirnidln-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-{3-Fluoro-5-(trrfluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{[6-(3-Chloro-5-fluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-1 -Phenyl-2-{[e-(4-propoxyphenyl)pyrimidin-4-y0amino}ethanol;
(1 R)-2-fl6-(2,1 ,3-Benzoxadiazol-5-yl)pyrimidin-4-yl]amlno}-1 -phenylethanol;
(1 R)-2-({6-{3-Methyl-4-(1 -methylethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol; (1 R)-2^{6^3^hlo^o^(trifluoromethyl)phenyl]-5-methylpyrimidin-4-y^}amino^1 - phenylethanol;
(1 R)-2-({6-[3-Fluoro^trifluoromethyl)phenyl]-5-methylpyrimidin-4-yl)amino)-1 - phenylethanol;
(1 R)-2-({6-[4^Dlfluoromethoxy)-3,5-difluorophenyI]pyrimidin-4-y1}amino)-1 -phenylethanol;
2-[4-(6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrimidin-4-y1)phenyl]-2- methylpropanenitrile;
1-[2-Fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-y1)phenyl]ethanone;
(1 R)-2-({6-[3,5-Dimethyl-4-(1 -methylethoxy)phenyl]pyrimidin-4-yi}amino)-1 - phenylethanol;
(1 R)-2-{[6-(1 H-lndol-6-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)- 1 -Phenyl-2-{[6-(3,4,5-trifluorophenyl)pyrimidin-4-y1]amino}ethanol;
(1 R)-2-{[6-(1-Methyl-1 H-lndol-2-y1)pyrimldin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-dβ-(5-Methyl-1 -benzothiophen-2-yl)pyrimidin-4-yt]amino}-1 -phenylethanol;
[4-(6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrinnldin-4-yl)phenyl](phenyl)methanone;
(1R)-2-{[6-(3l5-Difluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(3,4-Difluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoroiriethyl)phenyl]-2-(methylsulfanyl)pyrimidin-4-yl}amino)-1 - phenylethanol;
(1 R)-2-<{2-Amino-6-I3-chloro^(trifluofomethyl)phenyl]pyrimidin-4-yl}amino)-1 - phenylethanol;
(1 R)-2-{{6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -(4- fluorophenyl)ethanol;
(1 R)-2-{[6-(6-Methoxypyridin-3-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(6-Ethoxypyridin-3-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-{4-(Dimethylamino)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({β-[4-(Methylsulfonyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
N-Cyclopropyl-4-<6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimldin-4- yl)benzenesulfonamide;
(1 R)-2-{[6-(3-Chloro-4-ethoxyphenyl)pyrimidin-4-yl]amlno)-1 -phenylethanol;
(1 R)-2-[(Z-Mθrpholin-4-yμ4,5<-bipyrimidirv6-yl)amino]-1 -phenylethanol;
(1 R)-2-{[β-(6-Morpholin-4-ylpyridin-3-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-d6-(3-Fluoro-4-methoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(2,3-Dihydro-1 ,4-benzodioxin-6-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-methylpyrimidin-4-yl}amino)-1 - phenylethanol; (1R)-2-{[6-(1-E3enzyl-1H-pyrazol-4-y1)pyrimidin-4-yt]amino}-1-phenytethanol;
(1 R)-2-{[6-(6-Fluofo-5-methylpyrklin-3-yl)pyrimidin-4-yt]amino}-1 -phenylethanol;
4-(6-{[(2R)-2-Hydroxy-2-phenylethyQamino}pyrimidin-4-yl)-N , N- dimethylbenzenesulfonamide;
5-<6^(2R)-2-Hydroxy-2-phenylethyqamirκ)}pyrimidin-^yt)pyridine-2-carbonitrile;
(1 R)-2-({6-[6-(Dimethylamino)pyridin-3-yl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-1 -Phenyl-2-({β-[4-(piperldin-1 -ylsulfonyl)phenyl]pyrimidin-4-yl}amino)ethanol;
(1 R)-1 -Phenyl-2-({6-[4-(pyrrolidin-1 -ylsulfonyl)phenyl]pyrimidinτ4-yl}amino)ethanol;
4-<6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzenesulfonamide;
(1 R)-2-{[6-(4-Fluorophenyl)pyrimidin-4-y1]amino}-1 -phenylethanol;
(1 R)-2-{I6-(3-Chloro-4-fluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-[3-(Methylsulfanyl)phenyl]pyrlmidin-4-yl}annino)-1 -phenylethanol;
(1R)-2-{[6-(1 H-I ndol-5-yl)pyrimiclin-4-yl]amino}-1 -phenylethanol;
(1R)-1-Phenyl-2-[(6-quinolin-3-ylpyrimidin-4-yl)amino]ethanol;
(1 R)-2-{[6-(1 -Benzothk>phen-3-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
2-Fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimkJin-4-yl)benzonitrile;
2-Fluoro-5-(β-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzonitrile;
(1 R)-2-{[6-(1 -Methyl- 1 H-lndol-5-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-[(6-{4-[(1 -Methylethyl)sulfanyl]phenyl}pyrimidin-4-yl)amino]-1 -phenylethanol;
[4-(6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl]acetonitrile;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(trifluofomethyl)pyrimidin-4-yl}amino)-1 - phenylethanol;
(1 RJ-Σ-flβ-φ^-DichlorOphenylJ-Σ-methylpyrimldirv^yπamino}-i -phenylethanol;
(1 R)-2-fl6-(3,4-Dichtorophenyl)-pyrimidin-4-yηamino}-1 -phenylethanol;
(1 R)-2-({6-[4-(Ethylsulfanyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{[6-(3-Ethoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)- 1 -Phenyl-2-{[β-(3-propoxyphenyl)pyrimidin-4-yl]amino}ethanol;
(1 R)-2-{[6-<3-Butoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(1 -Benzothiophen-5-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-Σ-ttβ-ia-Chloro-A-(trifluoromethylΪphenylJ^dimethylamino)pyrimKlin-A-yOamino)-i - phenylethanol;
( 1 R)-2-({6-[3-Fluoro-4-(trifluoromethyl)phenyπ-2-(methylsulfanyl)pyrlmldin-4-yl}amino)-1 - phenylethanol;
(1 R)-1 -Phenyl-2-({4-[4-(trifluoromethyl)phenyl]-1 ,3,5-triazin-2-yl}amino)ethanol;
(1 R)-2-({4-[3-Chloro-4-(trifluoromethyl)phenyl]-1 ,3,5-triazin-2-yl}amino)-1 -phenylethanol;
(1 RH -Phenyl-2-({β-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol; (1 R,2S)-1 -Phenyl-2-[(6^4-[(trlfluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]propan-1 -oJ;
(1R,2R)-2-[Methyl(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-y1)amino]-1- phenylpropan-1-ol;
(1 R,2S}-2-[Methyl(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]-1 - phenylpropan-1-ol;
(1 R)-2-({6-[3-Fluoro-4-(1 -hydroxyethyl)phenyl]pyrimldin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{I2-Cydopropyl-6-(3,4-dichlorophenyl)pyrimidin-4-yl]amino}-1 -phenytethanol;
(1 R)-2-fl6-(3,4-Dichlorophenyl)-2-(1 -methytethyl)pyrimidin-4-y1]amino}-1 -phenytethanol;
(1 R^-ttβ-lS-Chloro-A-^rifluoromethyl)phenyO^methylsulfonyiΪpyrimkdin^yl}aminoJ-1- phenylethanol;
(1 R)-2-({6^3-ChloiO-4-(trifIuoromethyl)phenyt]-2-(methylsulfinyl)pyrimidin-4-yt}amino)-1 - phenylethanol;
(1 R)-2-fl6-(3-Methyl-1 H-indazol-6-yl)pyrimidin-4-yQamino}-1 -phenylethanol;
(1R)-2-({6-[3-Chk)ro-4-(trifluoromethyl)phenyl]-2-(methylamino)pyrimidin-4-yl}amino)-1- phenylethanol;
(1R)-2-{[6-(4-lodophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1R)-2-[6-(3-Chloro^trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-1-(3,4-difluoro-phenyl)- ethanol;
(1 R)-1 -(A-Chloro-3-fliioro-phenyl^-Iβ-CS-chloro^-trifluoromethyl-phenylJ-pyrlmidin^- ylaminoj-ethanol;
(1 R)-2-({6-[2,4-Bis(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-[2-Methoxy-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{I6-(4-Ethoxy-2-methylphenyl)pyrimldin-4-yl]amino}-1 -phenylethanol;
(1 R^-dβ-(S^-Dichlorophenyl^-methylpyrimidin^-yqamino^i -phenylethanol;
(1 R)-2-{[6-(3,4-Dichlorophenyl)-pyrimidin-4-yl]amino}-1 -phenylethanol;
(1R)-2-<{2-[(2-Aminoethyl)amino]-6-[3-chloiO-4-<trifluoromethyl)phenyt]pyrimidln-4- yl}amino)-1 -phenylethanol;
(1R)-2-[(6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-{[2-
(dimethylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(ethylamino)pyrimidin-4-yl}amino)-1 - phenylethanol;
(1R)-2-({6-[3-Chto ro-4-(trifluoromethyl)phenyl]-2-[(2-hydroxyethyl)amino]pyrimidin-4- yl}amino)-1 -phenylethanol;
(1 R)-2-({2-Azetidin-1 -yl-€-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 - phenylethanol;
(1R)-2-({6-[3-ChloiO-4-(triflLK)romethyl)phenyl]-2-(cyclopropylamino)pyrimidin-4- yl}amino)-1 -phenytethanol;
(1R)-2-[(6-[3-Chk>ro^-(trifluoromethyl)phenyl]-2^2-(methylamino)θthyl]amino}pyrimkJin-
4-yl)amino]-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro^(trifluoromethyl)phenyl]-2-methoxypyrimk.irv4-yl}amino)-1 - phenytethanol;
(1 R)-2-{[6-(3-Methyl-1 ,2-benzisoxazol-6-yl)pyrimidin-4-yl]amino}-1 -phenylethand;
(1 R)- 1 -Phenyl-2-[(6-quinolin-6-ylpyrimidin-4-yl)amino]ethanol;
N-tert-Butyl-4-(6-{I(2R)-2-hydroxy-2-phenylethyf]amino}pyrimidin-4- yl)benzenesulfonamide;
(1R)-1-Phenyl-2-({6-[4-(thiomorpholin-4-ylsulfonyl)phθnyηpyrimidin-4-yl}amino)ethanol;
(1 R)- 1 -(4-Fluorophenyl)-2-({6-I3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4- yt}amino)ethanol;
(1 R)-1 -(4-Fluorophenyl)-2-({6-[3-fluoro^(trifluoromethoxy)phenyl]pyrimidin-4- . . yt}amino)ethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimkJin-4-yl}amir>o)-1 -(4- fluorophenyl)ethanol;
(1 R)- 1 -(4-fluorophenyl)-2-({6-[3-(pentafluoroethyl)-1 ,2-benzisoxazol-6-yt]pyrimidin-4- y1}amino)ethanol;
(1 R)- 1 -(4-Fluorophenyl)-2-({6-[3-(trifluoromethyl)-1 ,2-benzisoxazol-6-yl]pyrimidin-4- y1}amino)ethanol;
(1 R)-2-({6-[3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyηpyrimidin-4-yl}amino)-1 - phenytethanol;
(1 R,2S)-2-({6-[3-chloixM^(trifluoromethyt)phenyt]pyrimidin-4-yl}amino)-1 -phenylpropan-1 -
Ot;
(1 R)-1 -Phenyt-2-[(6-{4-[(trifIuoromethyl)sulfanyt]phenyl}pyrimidin-4-yt)amino]ethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yt}amino)-1 -phenytethanol;
(1 RM -Phenyl-2-({6-[3-(trifluoromethyl)-1 ,2-benzisoxazol-β-yl]pyrimidin-4- yl}amino)ethanol;
(1 R)-2-{[6-(2l2-Difluoro-1 ,3-benzodioxol-5-yl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)- 1 -Phenyt-2-({6-[5-(trifluoromethyt)-1 -benzothlophen-2-yt]pyrimidin-4- yl}amino)ethanol;
(1 R)-1 -Phenyl-2-({β-[5-(trifluoromethoxy)-1 -benzothlophen-2-yl]pyrimldin-4- yl}amino)ethanol;
(1 R)-1 -Phenyl-2-{{6-l6-(trifluoromethyl)-1 -benzothiophen-2-yl]pyrimidin-4- yl}amino)etharκ)l;
(1 R)-2-d6-(5-Fluoro-1 -benzothlophen-2-yl)pyrimldin-4-yt]amino}-1 -phenytethanol; (1 R)-2-({6-[3-(pentafluoroethyl)-1 ,2-benzisoxazol-6-yl]pyrimidin-4-yl}amino)-1 - phenylethanol;
(IR^Phenyl^-lβ-^-CI ^^^-tetrafluoro-i-trifluoromethyl-ethyO-phenylJ-pyrimidin-A- ylamino}-ethanol; and
(I RJ-Phenyl^-te-tS-CI ^^^-tetrafluoro-i-trifluoromethyl-ethyO-phenylJ-pyrimidin^- ylamino}-ethanol;
(1 R)-Phenyl-2-[6-(3-trifluoromethyl-benzo[b]thiophen-6-yl)-pyrimidin-4-ethanol; and
4-(3-Chloro-4-trifluoromethyl-phenyl)-6-(2-hydroxy-2-phenyl-(1 R)-ethylamino)-pyrimidine-
2-carbonitrile; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.
13. A compound of Formula (I-B):
Figure imgf000157_0001
wherein:
R1 is -Ci-4alkyl, -OCi-4alkyl, -S(O)0-2Ci-4alkyl, -CN, -CF3, -N(Ra)Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H, -Ci-4alkyl optionally substituted with -OH, N(Rm)Rn, where Rm and Rn are -H, C1-4alkyl; or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring; Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with; (i) one, two, or three Rc moieties, where each Rc moiety is independently -C1-4alkyl, -Ci-4alkyl-OH, -Ci-4alkyl-CN,
-CF3, -OH, -OCi-4alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)0-2C1-4alkyl, -SCF3, -SO2CF3, -CHO, -COC1-4alkyl, -CO2C1-4alkyl, -CO2H, -N(Rd)Re,
-SO2NRdRe, -NRdSO2Re, -C(O)NRdRe, -NO2, -CN, phenyl, pyridyl, or halo, where Rd and Rβ are each independently -H or -d^alkyl, or taken together Rd and Rβ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring; or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)i^O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -Ci^alkyl, -C1- 4alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -SfOfeaCi^alkyl, -SCF3, -SO2CF3, -CHO1 -COC1-»alkyl, -CO2CL 4alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, or halo, where Rd and Rβ are each independently -H or -d^alkyl; X is N or C(Rf), where Rf is -H or methyl; Ar2 Is: (i) a phenyl group substituted with: (a) one, two, or three R° moieties each at a meta or para position, and optionally with one or two additional R° moieties at an ortho position; where each R0 moiety is independently -Ci^alkyl, -Ci^alkyl-OH, -Ci^alkyl-
CN, perhaloalkyl, perhaloalkoxy , -OC-Melkyl, -OCi^alkyl-(monocyclic cycloalkyl), -S(O)o.2Ci^alkyl. -SCF3, -SO2CF3, -CHO. -COC^alkyl, -CO2C1^alkyl, -CO2H, -N(Rh)R', -SO2NRJRk, -NR11SO2R1, -C(O)NRJRk, -NO2, -CN, or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -Chalkyl, -OC^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN1 or halo; where Rh is -H or -C^alkyi;
R1 is -Ci^alkyl or monoyclic cycloalkyl group; or Rh and R1 taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; RJ is -H or-C^alkyl; and Rk is -H, -Ci-4alkyl or monoyclic cycloalkyl group; or RJ and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or (b) two adjacent R° moieties together form -O(CH2)i-2O- unsubstituted or substituted with one or two fluoro groups; (ii) a monocyclic heteroaryl group substituted with one, two, or three R° moieties, where each R0 moiety is independent or two adjacent R° moieties together form -O(CH2)i-2O- unsubstituted or substituted with one or two fluoro groups; or
(iii) a naphthyl or tricyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties; where each R1 moiety is independently -C^alkyl, -OC^alkyl, perhaloalkyl, peitialoalkoxy , -NO2, -CN1 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 said compound.
14. A compound as defined in claim 13, wherein R1 is methyl, iso propyl, trifluoro methyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl.
15. A compound as defined in claim 13, wherein Ar1 is a phenyl group, each unsubstituted or substituted with one, two, or three Rc moieties.
16. A compound as defined in claim 13, wherein X is C(Rf).
17. A compound as defined in claim 16, wherein Rf is -H.
18. A compound as defined in claim 13, wherein Ar2 is a phenyl substituted with one, two or three R° moieties each at a meta or para position.
19. A compound as defined in claim 13, wherein Ar2 is a thiophenyl, pyridinyl, pyrimidinyl, or pyrazolyl group, each substituted with one, two, or three R9 moieties.
20. A compound as defined in claim 13, wherein Ar2 is a naphthyl, benzoxadiazolyl, indolyl, benzothiophenyl, quinolinyl, or indazolyl, each unsubstituted or substituted with one, two, or three R1 moieties.
21. A compound as defined in claim 13, wherein each R1 moiety is independently methyl.
22. A compound as defined in claim 13, wherein R2 is -H.
23. A compound as defined in claim 13, wherein R3 is -H.
24. A compound as defined in claim 13, wherein the secondary hydroxyl group adjacent to Ar1 is in the configuration as shown below:
Figure imgf000160_0001
25. A compound selected from the group consisting of: (1R)-2-({6-[3-Chloro^(trifluoromethyl)phenyπ-2-(methylsulfanyl)pyrimidin^yl}amino)-1- phenytethanol;
(1 R)-2-({2-Amino^l3^loro^trifluoromethyl)phenyf]pyrimidin-4-yI}amino)-1 - phenylethanol;
(1 R)-2-({6-[3^hloro^(trifluoronfiethyl)phenyl]-2-methylpyrimidin-4-yl}amino)-1 - phenylethanol;
(1 R)-2-({6-[3-Chloro^(trifluororτ>ethyl)phenyπ-2-(trffl^ phenylethanol;
(1 R)-2-{[6-(3,4-DichloiOphenyl)-2-methylpyrimidin-4-yl]amino}-1 -phenylethanol;
(1R)-2-({6-[3-Chloro-4-(trifluororτγethyl)phenyl]-2-(dimethylamino)pyrimidin-4-yl}amino)-1- phenylethanol;
(1R)-2-({6-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-(methylsulfanyl)pyrimidin-4-yl}amino)-1- phenylethanol;
(1 R)-2-{[2-Cyclopropyl-β-(3,4-dichlorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-fl6-(3,4-Dichlorophenyl)-2-(1 -methylethyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyq-2-(methylsulfonyl)pyrimidin-4-yl}amino)-1- phenylethanol; (1 R)-2-({6-[3-ChlorO^trifluoromethyl)phenyt]-2^methytsulfinyl)pyrimidin^yt}amino)-1 - phenylethanol;
(1 R)-2-({6-[3-Chloro^(trifluoromethyl)phenyl]-2^methylamino)pyrimidin^-yl}amino)-1 - phenylethanol;
(1 RK-flβ-φ.^Dichlorophenyl^-methylpyrimidiiv^yl]aminoM -phenylethanol;
(1R)-2-({2-[(2-Aminoethyl)amino]^3^k)ro^trifluoromethyl)phenyl]pyrimidin-4- yl}amino)-1 -phenylethanol;
(1R)-2-l(6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-{I2-
(dimethylamino)ethyl]amino}pyrimidin-4-yl)amino]-1-phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(tnϊluoromethyl)phenyl]-2-(ethylamino)pyrimldin-4-yl}amino)-1 - phenylethanol;
(1R)-2-({6-[3-Chk>ro-4-(trifluoromethyl)phenyQ-2-[(2-hydroxyethyl)amino]pyrimidin-4- yl}amino)-1 -phenylethanol;
(1 R)-2-({2-Azetidin-1 -yl-6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 - phenylethanol;
(1R)-2-({6-[3-Chk)iO-4-(trifluoromethyl)phenyl]-2-(cyclopropylamino)pyrimidin-4- yl}amino)-1 -phenylethanol;
(1R)-2-[(6-[3-Chloro^trifluoronrιethyl)phenyl]-2-{[2-(methylamino)ethyl]amino}pyrimidin-
4-yl)amino]-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-methoxypyrimldin-4-yl}amino)-1 - phenylethanol; and
4-(3-Chloro-4-trifluoronrtethyl-phenyl)-6-(2-hydroxy-2-phenyl-{1R)-ethylamino)-pyrimidine-
2-carbonitrile; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound..
26. A compound of Formula (I-C):
Figure imgf000161_0001
wherein:
R1 is -H, -C1.4alkyl, -OC^alkyl, -S(O)o.2Ci-»alky1, -CN, -CF3, -N(R')Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H, -d^alkyl optionally substituted with -OH, N(Rm)Rn, where Rm and Rn are -H, C^alkyl; or taken together with the nitrogen of attachment Ra and Rb form a 4-7 membered heterocycloalkyl ring; Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon a the point of attachment, or a 9 or 10 membered bicyclic heteroaryl group with carbon at the point of attachment, each unsubstituted or substituted with;
(i) one, two, or three Rc moieties, where each Rc moiety is independently -Ci^alkyl, -Ci^alkyl-OH, -Ci^alkyl-CN, -CF3, -OH, -OCi.4alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2Ci^alkyl. -SCF3, -SO2CF3, -CHO, -COC1^alkyl, -CO2C^alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, phenyl, pyridyl, or halo, where Rd and Rβ are each independently -H or -C1^alkyl, or taken together Rd and Rβ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl; or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)i^O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -C-Malkyl, -C1. 4alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2Ci-4alkyl, -SCF3, -SO2CF3, -CHO, -COCi^alkyl, -CO2C1. 4alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, or halo, where Rd and Rβ are each independently -H or -d^alkyl; X is N or C(Rf), where Rf is -H or methyl; R*1 Ry, and R2 are each independently a) - c): a) R* and Rz are each -H, and Ry is -NO2, -C^alkyl, -OC2-*alkyl, or phenoxy; b) Rx and R2 are each -H, Ry is -OCF3, and Ar1 is a substituted phenyl group or an unsubstituted or substituted pyridyl group; or c) one of Rx, Ry, and R2 is -Cl, -F, or -CF3, and the other two are: (i) independently -H or an R0 moiety, provided that when Ry is -H then Rx and Rz are not CF3; where each Rs moiety is -C^alkyl, -d^alkyl-OH, -C^alkyl-CN, perhaloalkyl, perhaloalkoxy , -Od^alkyl, -OC1-4alky1-(monocyclic cycloalkyl), -S(O)0. 2Ci-»alkyl, -SCF3, -SO2CF3, -CHO, -COC^alkyl, -CO2C1-«alkyl, -CO2H, -N(Rh)R', -SO2NRJRk, -NRhSO2R', -C(O)NRiRk, -NO2, -CN, or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -C-Melkyl, -OC1-4alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN1 or halo; where Rh is -H or -C1^alkyl; R1 is -C-Malkyl or monoyclic cycloalkyl group; or Rh and R* taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; RJ is -H or -C1^alkyl; and
Rk is -H, -Chalkyl or monoyclic cycloalkyl group; or Rj and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or
(ii) two adjacent R° moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups; or (iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties; where each R1 moiety is independently -C^alkyl, -OC^alkyl, perhaloalkyl, perhaloalkoxy, -NO2, -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 said compound.
27. A compound as defined in claim 26, wherein R1 is -H, methyl, isopropyl, trifluoromethyl, methylsulfanyl, methylsulfinyl, methanesulfonyl, amino, methylamino, dimethylamino, or cyclopropyl.
28. A compound as defined in claim 26, wherein R1 is -H.
29. A compound as defined in claim 26, wherein Ar1 is a phenyl group, each unsubstituted or substituted with one, two, or three Rc moieties.
30. A compound as defined in claim 26, wherein X is C(Rf).
31. A compound as defined in claim 30, wherein Rf is -H.
32. A compound as defined in claim 26, wherein R" is -Cl or -F1 R2 is -H, and Ry is -H or Rg.
33. A compound as defined in claim 26, wherein Rx is -Cl or -F, R2 is -H, and Ry is -C1-4alky1, -CF3, -OC1^alkyl, -OCF3, or halo.
34. A compound as defined in claim 26, wherein R2 is -H.
35. A compound as defined in claim 26, wherein R3 is -H.
36. A compound as defined in claim 26, wherein the secondary hydroxyl group adjacent to Ar1 is in the configuration as shown below:
/γAr1 OH
37. A compound selected from the group consisting of:
(1 R)-2-({6-[4-(Emyloxy)-3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenytethanol;
2-{[6-(4-Chlorophenyl)pyrimidin-4-yf]amino}-1-phenylethanol;
2-{[6-(4-Fluorophenyl)pyrimidin-4-yl]amino}-1-phenylethanol;
1-Phenyt-2-({β-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol;
2-{[6-(4-NitiOphβnyl)pyrimidin-4-ylJamino}-1-phenylethanol;
2-{[6-(4-Ethylphenyl)pyrimidin-4-yl]amino}-1-phenylethanol;
2-({6-[4-(1 -Methylethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
2-{[6-(3,4-Dichlorophenyl)pyrimidin-4-yl]amino}-1-phenylethanol;
2-{[6-{3-Chlorophenyl)pyrimk.in-4-yl]amino}-1-phenylethanol;
2-({6-[3-Chtoro^(trifluoromβthyl)phβnyl]pyrimidin-4-yl}amino)-1-phenylethanol; 2-({6-[4-(Ethytoxy)phenyi]pyrimidin-4-y1}amino)-1-phenylethanol;
2-[(6-{4-I(1 -Methylethyl)oxy]phenyl}pyrlmldin-4-yl)amino]-1 -phenylethanol;
1-Phenyl-2-({6-[4-(phenyloxy)phenyl]pyrimidin-4-yl}amino)ethanol;
2-({β-[3-Chloro-4-<ethyloxy)phenyqpyrimidin-4-yt}amino)-1-phenytethanol;
(1 R)-1 -Phenyt-2-({6-[4-(trifluoromethyl)phenyt]pyrimidin-4-yt}amino)ethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyI]pyrimldin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-<trifluoromethyl)phenyl]pyrimidin-4-yt}amino)-1 -phenytethanol hydrochloride salt;
(1 R)-2-({6-[4-(1 -Methylethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenytethanol;
(1 R)-2-[(6-{3-Chloro-4-[(1 -methylethyl)oxy]phenyl}pyrimldin-4-yl)amino]-1 -phenytethanol;
(1 R)-2-d6-(3-Fluoro-4-methylphenyl)pyrimidin-4-yl]amino}-1 -phenytethanol;
(1 R)-2-{[6-(4-Chloro-3-methylphenyl)pyrimk_in-4-yl]amino}-1 -phenylethanol;
(1R)-2-{[6-(4-Chloro-3-fluorophenyl)pyrimidin-4-yl]amino)-1 -phenytethanol;
(1 R)-2-({6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}amlno)-1 -phenylethanol;
(1 R)-2-{[6-(4-Ethoxy-3-fluorophenyl)pyrimkJin-4-yl]amino}-1 -phenytethanol;
(1 R)-2-{[6-(4-BiJtoxy-3-fluorophenyl)pyrimidin-4-yl]amino}-1 -phenytethanol;
(1 R)-2-{[β-(4-Butoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(3-Fluoro-4-propoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-({6-[3-Fluoro-4-(1 -methylethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenytethanol;
(1 R)-2-({6-[4-(2-Methylpropoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{[6-(3-Chloro-4-methylphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1R)-2-({6-l3-Fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-({6-[3-Fluoro-5-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
(1 R)-2-{[β-(3-Chloro-5-fluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 RH -Phenyl-2-{I6-<4-propoxyphenyl)pyrimidin-4-yl]amino}ethanol;
(1 R)-2-({6-[3-Chloro^-(trifluoiOmethyl)phenyl]-5-methylpyrimidin-4-yl}amino)-1 - phenytethanol;
(1 R)-2-({6-[3-Fluoro-^(trifluoromethyl)phenyl]-5-methylpyrimldin-4-yl}amino)-1 - phenylethanol;
(1R)-2-({6-[4-(Dlfluoromethoxy)-3,5-difluorophenyl]pyrimldin-4-yl}amino)-1 -phenylethanol;
1-[2-Fluoro-4-(6-{[(2R)-2-hydroxy-2-phenytethyl]amino}pyrimidin-4-yl)phenyl]ethanone;
(1R)-1-Phenyl-2-{[e-(3l4l5-trlfluorophenyl)pyrimidin-4-yl]amino}ethanol;
(1R)-2-{[6-(3,5-Difluorophenyl)pyrimidin-4-yl]amino}-1-phenylethanol;
(1 R)-2-{[6-(3,4-Difluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol; (1R)-2-({6-[3-Chloro^^trifluoromethyl)phenyq-2-(methylsulfanyl)pyrimkJin-4-yt}amino)-1- phenylethanol;
(1 R)-2-({2-Amino^3-chloro^-(trifluoromethy()phenyt]pyrimidin-4-yl}amino)-1 - phenylethanol;
(1 R)-2^{6^3-Chloro-4-(trifIuoromethyt)phenyl]pyrimldin-4-yl}amino)-1 -(4- fluorophenyl)ethanol;
(1 R)-2-{Iβ-(3-Chloro-4-ethoxyphenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2^[6-(3-Fluoro-4-methoxyphenyl)pyrimidin-4-yf]amino}-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-methylpyrimidin-4-yl}amino)-1 - phenylethanol;
(1 R)-2-{[6-(4-Fluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R)-2-{[6-(3-Chloro-4-fluorophenyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
2-Fluoro-4-(6-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzonitrile;
2-Fluoro-5-(β-{[(2R)-2-hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)benzonitrile;
(1 R)-2-({6-[3-Chloro-4-(trifluoiOmethyl)phenyq-2-(trifliioromethyl)pyrimidin-4-yl}aminp)-1 - phenylethanol;
(1 R)-2-{[6-(3,4-Dichlorophenyl)-2-methylpyrimidin-4-yl]amino}-1 -phenylethanol;
(1 R^-flβ-φ^-DichlorophenylJ-pyrimidirM-yl]aminoH -phenylethanol;
(1 R)-2-({6-[3-ChloiO-4-(trifluoromethyl)phenyl]-2-(dimethylamino)pyrimidin-4-yl}amino)-1 - phenylethanol;
(1R)-2-({6-[3-Fluoro-4-(trifluoromethyl)phenyη-2-(methylsulfanyl)pyrimkJin-4-yl}amino)-1- phenylethanol;
(1 R)-1-Phenyl-2-({4-[4-(trifluoromethyl)phenyl]-1 ,3,5-triazln-2-yl}amino)ethanol;
(1 R)-2-({4-[3-Chloro-4-(trifluoromethyl)phenyl]-1 ,3,5-triazin-2-yl}amino)-1 -phenylethanol;
(1 R)- 1 -Phenyl-2-({β-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)ethanol;
1-(4-Nitrophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
2-[(6-{4-[(Trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]-1-[4-
(trifluoromethyl)phenyl]ethanol;
1-(4-Chlorophenyl)-2-[(6-{4-{(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
4-{1-Hydroxy-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethyl}phenol;
1-[4-(Methyloxy)phenyl]-2-{(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidin-4- yl)amino]ethanol;
4-{1-Hydroxy-2-[(6-{4-[(triflικ)romethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethyl}-2-
(methyloxy)phenol;
1-(4-Fluorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
1-(3,4-Dichlorophenyl)-2-[(6-{4-[(triflιιoromethyl)oxy]phenyl}-pyrimidin-4-yl)amino]ethanol; 1-(2-Chlorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
1-(3-Chlorophenyl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
1-[3-(Methyloxy)phenyl]-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidin-4- yl)amino]ethanol;
1 -[2-(Methyloxy)phenyl]-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidin-4- yl)amino]ethanol;
1-(2,2-Difluoro-1 >3-benzodioxol-5-yl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4- yl)amino]ethanol;
1-Pyridin-2-yl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
1-Pyridin-3-yl-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol;
1-Pyridin-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-Benzodioxol-5-yl)-2-[(6-{4-[(trifluoromethyl)oxy]phenyl}-pyrimidin-4- yl)amino]ethanol;
(1 S)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol;
(1 R)-2-({6-[3-Fluoro-4-(1-hydroxyethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[3-
(trifluoromethoxy)phenyl]ethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(3-fluorophenyl)ethanol;
2-[6-(3-Chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-1-(3,4-difluoro-phenyl)- ethanol;
1-(4-Chloro-3-fluoro-phenyl)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4- yl}amino)ethanol;
^(S-Chloro^-fluorophenyl^-^θ-tS-chloro^-CtrifluoromethyOphenyllpyrimidin^- yl}amino)ethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[3-
(trifluoromethyl)phenyl]ethanol;
(1 R)-2-{[2-Cyclopropyl-6-(3,4-dichlorophenyl)pyrimidin-4-yl]amino}-1-phenylethanol;
(1 R)-2-{[6-(3,4-Dichlorophenyl)-2-(1 -methylethyl)pyrimidin-4-yl]amino}-1 -phenylethanol;
(^^-({e-tS-Chloro^-OrifluoromethyOphenyll^-CmethylsulfonyOpyrimidin^-ylJamino)-!- phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(methylsulfinyl)pyrimidin-4-yl}amino)-1- phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(methylannino)pyrimidin-4-yl}amino)-1- phenylethanol; (1S)-2-[6-(3-Chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-1-(3,4-difluoro-phenyl)- ethanol;
(1 R)-2-[6-(3-Chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-1-(3,4-difluoro-phenyl)- ethanol;
(1S)-1-(4-Chloro-3-fluoro-phenyl)-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidin-4- ylamino]-ethanol;
(1 R)-1-(4-Chloro-3-fluoro-phenyl)-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidin-4- ylamino]-ethanol;
(1 R)-2-{[6-(3,4-Dichloropheπyl)-2-methylpyrimidin-4-yl]amino}-1-phenylethanol;
(1 R)-2-{[6-(3,4-Dichlorophenyl)-pyrimidin-4-yl]amino}-1-phenylethanol;
(1 R)-2-({2-[(2-Aminoethyl)amino]-6-[3-chloro-4-(trifluorornethyl)phenyl]pyrimidin-4- yl}amino)-1 -phenylethanol;
(1 R)-2-[(6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-{[2-
(dimethylamino)ethyl]amino}pyrimidin-4-yl)amino]-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(ethylamino)pyrimidin-4-yl}amino)-1- phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(thfluoromethyl)phenyl]-2-[(2-hydroxyethyl)amino]pyrimidin-4- yl}amino)-1 -phenylethanol;
(1 R)-2-({2-Azetidin-1-yl-6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1- phenylethanol;
(I RJ^-^θ-fS-Chloro^-^rifluoromethyOphenylJ^-^yclopropylaminoJpyrimidin^- yl}amino)-1 -phenylethanol;
(1 R)-2-[(6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-{[2-(methylamino)ethyl]amino}pyrimidin-
4-yl)amino]-1 -phenylethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]-2-methoxypyrimidin-4-yl}amino)-1- phenylethanol; i-^θ-tS-Chloro^-CtrifluoromethyOphenyllpyrinnidin^-ylJamino^-phenylpropan^-ol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[4-
(methylsulfanyl)phenyl]ethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-thiophen-3-ylethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(1 ,3-thiazol-2-yl)ethanol;
(1 R)-1-(4-Fluorophenyl)-2-({6-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4- yl}amino)ethanol;
(1 R)-1-(4-Fluorophenyl)-2-({6-[3-fluoro-4-(thfluoromethoxy)phenyl]pyrimidin-4- yl}amino)ethanol;
(1 R)-2-({6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}amino)-1-(4- fluorophenyl)ethanol;
(1 R)-2-({β-[3-Fluor()-4-(2,2,2-trifluoiOethoxy)phenyl]pyrimldin-4-yf}amino)-1 - phenylethanol;
(1 R,2S)-2-({6^3-chloro^(trifluoiOmethyl)phenyl]pyrimidin-4-yl}amino)-1 -phenylpropan-1 - ol;
(1 R)-2-({6^3-Chloro^-(trif]uoromethoxy)phenyl]pyrimidin-4-yl}amino)-1 -phenylethanol;
2-({6-[3-Chk>ro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[2-
(difluoromethoxy)phenyl]ethanol;
2-({6-{3-Chloro-4-(trifluoromethyl)phenyqpyrimidin-4-yl}amino)-1-(4-fluorophenyl)etharK)l;
4-[2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1- hydroxyethyl]benzonitrile;
2-({β^3-Chkxo^-(trifluoromethyl)phenyl]pyιimkJirv4-yl}amino)-1-naphthalen-2-ylethaTOl;
2-({β-[3-Chloro-4-(trifluoromethyl)phenyl]pyrim}din-4-yl}amino)-1-(4-pyridin-2- ylphenyl)ethanol;
2-({6-[3-Chl(xo^-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-(4-thiophen-2- ylphenyl)ethanol;
1-Biphenyl-4-yl-2^{6^3-chtorc>^(trifluoromethyl)phenynpyrimidin-4-yl}amino)ethanol;
1 -(1 -Benzothiopherv2-yl)-2-({6-[3-chloro-4-(tιifluoromethyl)phenyl]pyrimkJin-4- yl}amino)ethanol;
2-({6-[3-Chk)iO-4-(tιifluoromethyl)phenyqpyrimidin-4-yl}amino)-1-[3-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-Chtoro-4-(trifluoromethyl)phenyl]pyrimkJin-4-yl}amino)-1 -(2,3-dihydro-1 ,4- benzodioxin-6-yl)ethanol;
2-({6-[3-Chlcκ-o-4-(trifluc)romethyl)ptienyl]pyrirrιidin-4-yl}amino)-1 -[4-(1 H-imidazol-1 - yl)phenyl]ethanol;
1 -(1 -benzothiopheiva-yl^-ttβ-IS-chloro^^trifluoromethyl)phenyπpyrimidin^ yl}amino)ethanol;
2-({6-{3-ChlorD-4-(trifluoiOmethyl)phenyl]pyrimidin-4-yl}amino)-1-(3l4- dimethoxyphenyl)ethanol;
1-(3-Chloro^methoxyphenyl)-2-({6-[3-chk)ro-4-(trifluoiOmethyl)phenyqpyrimidin-4- yl}amino)ethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1 -(3,4-dihydro-2H-1 ,5- benzodk>xepin-7-yl)ethanol;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-[2-fluoro-5- (trifluoromethyl)phenyl]ethanol;
3-[2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1- hydroxyethyljbenzonitrile;
2-({6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}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;
S-^-^θ-lS-Chloro^-CtπfluoromethyOphenyllpyrirnidin^-ylJamino^i-hydroxyethyl]^- 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]-1 -[3-(3,4-dichloro-phenyl)- isoxazol-5-yl]-ethanol;
1-[3-(4-Chloro-phenyl)-isoxazol-5-yl]-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidin-4- ylamino]-ethanol;
2-[6-(3-Chloro-4-trifluoromethyl-phenyl)-pyrinnidin-4-ylamino]-1 -[3-(2,4-dichloro-phenyl)- isoxazol-5-yl]-ethanol;
1-Benzothiazol-2-yl-2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrinriidin-4-ylamino]-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-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4- yl}amino)ethanol; and
4-(3-Chloro-4-trifluoromethyl-phenyl)-6-(2-hydroxy-2-phenyl-(1 R)-ethylamino)-pyrimidine-
2-carbonitrile; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound..
38. A pharmaceutical composition comprising:
(a) an effective amount of at least one FAAH-modulating agent selected from the group consisting of compounds of Formula (I): N^N R2
Ar2 Ay'X.,X^^ (')
R3 OH wherein:
R1 is -H1 -Chalkyl, -OC^alkyl, -SfO^C^alkyl, -CN1 -CF3, -N(Ra)Rb, or a monocyclic cycloalkyl group, where Ra and Rb are each independently -H1 -d^alkyl optionally substituted with -OH1 N(Rm)Rn, where Rm and Rn are -H, C^alkyl; or taken together with the nitrogen of attachment R" and Rb form a 4-7 membered heterocycloalkyl ring;
Ar1 is a phenyl, napthyl, a 5 or 6 membered monocyclic heteroaryl group with carbon at the point of attachment, or a 9 or 10 membered bicyclic heteraryl group with carbon at the point of attachment, each unsubstituted or substituted with; (i) one, two, or three Rc moieties, where each Rc moiety is independently -C^alkyl, -C^alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(0)o.2Ci-*alkyl, -SCF3, -SO2CF3, -CHO, -C0C1-4alkyl, -CO2C^alkyl, -CO2H, -N(Rd)Rβ, -S02NRdRβ, -NRdS02Rβ, -C(0)NRdRβ, -NO2, -CN, phenyl, pyridyl, or halo, where Rd and Rβ are each independently -H or -Ci^alkyl, or taken together Rd and Rβ with the nitrogen of attachment form a 4-7 membered heterocycloalkyl ring; or
(ii) two or three Rc moieties where two Rc moieties are adjacent to each other and together form -O(CH2)^O- unsubstituted or substituted with one or two fluoro groups, and the third Rc moiety, when present, is -C^alkyl, -C1- 4alkyl-OH, -C^alkyl-CN, -CF3, -OH, -OC^alkyl, -OCF3, -OCHF2, -OCH2CF3, -S(O)o.2C1-4alkyl, -SCF3, -SO2CF3, -CHO, -COCi^alkyl, -CO2CL
4alkyl, -CO2H, -N(Rd)Rβ, -SO2NRdRβ, -NRdSO2Rβ, -C(O)NRdRβ, -NO2, -CN, or halo, where Rd and R* are each independently -H or -C1-4alky1; X is N or C(Rf), where Rf is -H or methyl;
Ar2 Is: (i) a phenyl group substituted with: (a) one, two, or three R° moieties each at a meta or para position, and optionally with one or two additional R° moieties at an ortho position; where each R° moiety is independently -Chalkyl, -Ci-«alkyl-OH, -Ci^alkyl- CN, perhaloalkyl, perhaloalkoxy , -OC^alkyl, -OCi^alkyl-(monocyclic cycloalkyl), -S(O)o-2Ci.4alkyl, -SCF3, -SO2CF3, -CHO, -COC^alkyl, -CO2Ci-»alkyl, -CO2H, -N(Rh)R', -SO2NRJRk, -NRhSO2R', -C(O)NRJRk, -NO2, -CN, or halo; or a phenoxy, benzyl, phenethyl, or benzoyl group unsubstituted or substituted with -C^alkyl, -OCi^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo; where Rh is -H or -C1^alkyl; R1 is -Ci^alkyl or monoyclic cycloalkyl group; or Rh and R1 taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; R1 is -H or -C^alkyl; and
Rk is -H, -C-Melkyl or monoyclic cycloalkyl group; or R1 and Rk taken together with the atoms to which they are attached form a monocyclic heterocycloalkyl ring; or
(b) two adjacent R° moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups;
(ii) a monocyclic heteroaryl group substituted with one, two, or three R0 moieties, where each R0 moiety is independent or two adjacent R° moieties together form -O(CH2)i.2O- unsubstituted or substituted with one or two fluoro groups; or (iii) a naphthyl or bicyclic heteroaryl group unsubstituted or substituted with one, two, or three R1 moieties; where each R1 moiety is independently -C-Malkyl, -OCi^alkyl, perhaloalkyl, perhaloalkoxy , -NO2, -CN, or halo; R2 is -H or methyl; and R3 is -H or methyl; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds of Formula (I); and (b) a pharmaceutically acceptable excipient.
39. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by FAAH activity, comprising administering to the subject in need of such treatment an effective amount of FAAH-modulating agent as defined in claim 38.
40. A compound selected from the group consisting of: 2-({6-[4-(Methyloxy)phenyl]pyrimidin-4-yl}amino)-1-phenyletharκ)l 2-{[6-(3-Methylphenyl)pyrimidin-4-yηamino}-1-phenytethanol 1-Phenyl-2-[(6-{3^(trifluoromethyl)oxy]phenyl}pyrimidin-4-yl)amino]ethanol
(1 S,2R)-1 -Phenyl-2-[(6-{4-[(trifluoromethyl)oxy]ptienyl}pyrimidin-4-yl)amino]propan-1 -ol (1 S)- 1 -Phenyt-2-[(6^4^(tιit1uoτomethyl)oxy]phenyt}pyrimidin-4-yl)amino]ethanol 1 -[4-{6-{[(2R)-2-Hydroxy-2-phenylethyl]amino}pyrimidin-4-yl)phenyl]ethanone; and (1 R)- 1 -Phenyt-2-[(6^4-[(tιit1uoromethyt)oxy]phenyl}pyrimidin-4-yl)amino]ethanol; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.
41. A method of preparing the compounds of Formulae (I) comprising the steps of: reacting a compound of Formula Il
R1
(") in a one-pot fashion by nucleophilic aromatic substitution, with an amino alcohol in the presence of a suitable base in a suitable polar solvent at a temperature from about 50 °C to about 180 °C; and performing a palladium-mediated cross-coupling reaction with a suitable boronic acid in the presence of a base and at least one palladium-mediated cross-coupling reagents at a temperature from about 50 °C to about 180 °C.
PCT/US2009/001043 2008-02-19 2009-02-18 Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase WO2009105220A1 (en)

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