MX2008008483A - Multicyclic amino acid derivatives and methods of their use - Google Patents

Multicyclic amino acid derivatives and methods of their use

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Publication number
MX2008008483A
MX2008008483A MXMX/A/2008/008483A MX2008008483A MX2008008483A MX 2008008483 A MX2008008483 A MX 2008008483A MX 2008008483 A MX2008008483 A MX 2008008483A MX 2008008483 A MX2008008483 A MX 2008008483A
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Mexico
Prior art keywords
amino
phenyl
alkyl
optionally substituted
aryl
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MXMX/A/2008/008483A
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Spanish (es)
Inventor
Ying Wang
Wenxue Wu
Arokiasamy Davasagayaraj
Haihong Jin
Qingyun Liu
Brett Marinelli
Lakshama Samala
Zhicai Shi
Ashok Tunoori
Chengmin Zhang
Haiming Zhang
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Lexicon Pharmaceuticals Inc*
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Application filed by Lexicon Pharmaceuticals Inc* filed Critical Lexicon Pharmaceuticals Inc*
Publication of MX2008008483A publication Critical patent/MX2008008483A/en

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Abstract

Compounds of formulae I and II are disclosed, as well as compositions comprising them and methods of their use to treat, prevent and manage serotonin-mediated diseases and disorders.

Description

DERIVATIVES OF MULTICICLIC AMINO ACIDS AND METHODS FOR USE This application claims the priority for the patent application of E.U. No. 60 / 754,955, filed on December 29, 2005. 1. FIELD OF THE INVENTION This invention relates to multiclick compounds, compositions that comprise them and their use in the treatment, prevention and management of diseases and disorders. 1. BACKGROUND The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is involved in multiple central nerve facets of mood control and regulation of sleep, anxiety, alcoholism, drug abuse, ingestion of food and sexual behavior. In peripheral tissues, serotonin has been reported to be involved in the regulation of vascular tone, intestinal motility, primary hemostasis and immune responses mediated by cells. Walther, D.J., et al., Science 299: 76 (2003). The enzyme tryptophan hydroxylase (TPH) catalyzes the step of limiting the rate of serotonin biosynthesis. Two isoforms of TPH have been reported: TPH1, which is expressed in the periphery, mainly in the gastrointestinal tract (Gl); and TPH2, which is expressed in the brain. Id. The TPH1 isoform is encoded by the gene tphl; TPH2 is encoded by the tph2 gene. Id. Genetically deficient mice have been reported for the tphl gene ("knockout mice"). In one case, mice reported normal amounts of serotonin in classic serotonergic regions of the brain, but were largely lacking serotonin in the periphery. Id. In another, the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin. Cote, F., et al., PNAS 100 (23): 13525-13530 (2003). Because serotonin is involved in so many biochemical processes, drugs that affect serotonin levels are frequently treated for their adverse effects. Therefore, there is a need for new ways to treat diseases and disorders that are affected by serotonin. 2. SUMMARY OF THE INVENTION This invention is directed, in part, to compounds of the formula I: I and pharmaceutically acceptable salts and solvates of the same, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond (ie, A is linked directly to D), -0-, -S-, -C (0) -, -C (R) =, = C (R4) -, -C (R3R) - , -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N (R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; D is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3. The invention also encompasses compounds of the formula II II and pharmaceutically acceptable salts and solvates of the same, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a link (i.e., A is directly linked to D), -0-, -S-, -C (0) -, -C (R4) =. = C (R4) -, -C (R3R4) ", -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N ( R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, - 0C (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S ( 02) C (R3R) -; D is optionally substituted aryl or heterocycle, E is optionally substituted aryl or heterocycle, Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl , alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3. Particular compounds inhibit the activity of TPH (e.g., TPH1). This invention is also directed to pharmaceutical compositions and methods for treating, preventing and managing a variety of diseases and disorders. 3. BRIEF DESCRIPTION OF THE FIGURE The aspects of the invention can be understood with reference to the appended figure. Figure 1 shows the effects of a potent TPH1 inhibitor of the invention, in the gastrointestinal tract and the brain of a mouse after oral administration. All data are presented as a percentage of the control group average (dosed with vehicle). The error bars are S.E.M. N = 5 per group. The symbols are *, p < 0.05 vs. control group. For the brain data, p = 0.5, one-way ANOVA. 4. DETAILED DESCRIPTION The invention is based, in part, on the discovery that deactivation of the tphl gene in mice significantly reduces serotonin Gl levels, causes still few, if any, measurable effects, in the central nervous system (CNS). ). This invention is also based on the discovery of compounds that inhibit TPH (e.g., TPH1). When administered to mammals, the preferred compounds of the invention reduce serotonin levels and can be used in the treatment, prevention and management of a wide range of diseases and disorders. 4.1 Definitions Unless otherwise indicated, the term "alkenyl" means a straight, branched and / or cyclic hydrocarbon having from 2 to 20 (eg, from 2 to 10 or from 3 to 6) carbon atoms , and that includes at least one carbon-carbon double bond. The alkenyl residues Representative include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl. Unless otherwise indicated, the term "alkyl" means a straight, branched and / or cyclic hydrocarbon ("cycloalkyl") having from 1 to 20 (eg, from 1 to 10 or from 1 to 14) carbon atoms. Alkyl residues having 1 to 4 carbons are referred to as "lower alkyl". Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2-trimethylpentyl, nonyl, decyl , undecilo and dodecilo. The cycloalkyl residues may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. Additional examples of alkyl residues have linear, branched and / or cyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl). The term "alkyl" includes saturated hydrocarbons as well as alkenyl and alkynyl residues. Unless otherwise indicated, the term "alkoxy" means an O-alkyl group. Examples of groups of alkoxy include -OCH3, -OCH2CH3, -0 (CH2) 2CH3, -0 (CH2) 3CH3, -0 (CH2) 4CH3 and -0 (CH2) 5CH3. Unless indicated otherwise, the term "alkylaryl" or "alkyl-aryl" means an alkyl residue bound to an aryl residue. Unless otherwise indicated, the term "alkylheteroaryl" or "alkyl heteroaryl" means an alkyl residue linked to a heteroaryl residue, unless otherwise indicated, the term "alkylheterocycle" or "alkyl heterocycle" "means an alkyl residue bound to a heterocycle residue." Unless otherwise indicated, the term "alkynyl" means a straight, branched or cyclic hydrocarbon having from 2 to 20 (eg, from 2 to 20). or from 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond Representative representative alkynyl residues include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, -methyl, 1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonnynyl , 2-noninyl, 8-noninyl, 1-decinyl, 2-decinyl and 9-decinyl Unless otherwise indicated, the term "aryl" means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen. An aryl residue may comprise multiple rings linked or fused together. Examples of aryl residues include anthracenyl, azulenyl, biphenyl, fluorenyl, indane, indenyl, naphthyl, phenanthrenyl, phenyl, 1, 2, 3, 4-tetrahydro-naphthalene and tolyl. Unless otherwise indicated, the term "arylalkyl" or "aryl-alkyl" means an aryl residue linked to an alkyl residue. Unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureido" and "biohydrolyzable phosphate" mean, amide, ester, carbamate, carbonate, ureido, or phosphate respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but may confer advantageous properties to that compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive but is converted in vivo into the biologically active compound. Examples of biohydrolyzable esters include lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable amides include lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkyl-carbonyl amides. Examples of carbamates Biohydrolyzables include lower alkylamines, substituted ethylene diamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines. Unless otherwise indicated, the phrases "peripheral serotonin-mediated disease or disorder" and "peripheral serotonin-mediated disease and disorder" mean a disease and / or disorder having one or more symptoms, the severity of which is affected by peripheral serotonin levels. Unless otherwise indicated, the terms "halogen" and "halo" encompass fluorine, chlorine, bromine and iodine. Unless indicated otherwise, the term "heteroalkyl" refers to an alkyl residue (eg, linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (eg, N, O, or S). Unless indicated otherwise, the term "heteroaryl" means an aryl residue wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O, or S). Examples include acridinyl, benzimidazolyl, benzofuranyl, benzisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl and triazinyl. Unless indicated otherwise, the term "heteroarylalkyl" or "heteroaryl-alkyl" means a heteroaryl residue linked to an alkyl residue. Unless otherwise indicated, the term "heterocycle" refers to an aromatic, partially aromatic, or non-aromatic, monocyclic or polycyclic ring or ring system comprising carbon, hydrogen and at least one heteroatom (eg, N, Or, or S). A heterocycle may comprise multiple rings (i.e., two or more) fused or linked together. The heterocycles include heteroaryls. Examples include benzo [1,3] dioxolyl, 2,3-dihydro-benzo [1,4] dioxinyl, cinolinyl, furanyl, hindantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl , tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl. Unless otherwise indicated, the term "heterocycloalkyl" or "heterocycloalkyl" refers to a heterocycle residue bound to an alkyl residue. Unless otherwise indicated, the term "heterocycloalkyl" refers to a non-heterocycle aromatic. Unless otherwise indicated, the term "heterocycloalkylalkyl" or "heterocycloalkyl-alkyl" refers to a heterocycloalkyl residue bound to an alkyl residue. Unless otherwise indicated, the terms "manage", "manage" and "manage" encompass the prevention of the recurrence of the specified disease or disorder, or of one or more of its symptoms, in a patient who has already suffered from the disease or disorder and / or the lengthening of the time in which the patient who has suffered from the disease or disorder remains in remission. The terms encompass the modulation of the threshold, development and / or duration of the disease or disorder, or the change in the manner in which the patient responds to the disease or disorder. Unless otherwise indicated, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids or bases. Suitable pharmaceutically acceptable base addition salts include metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts prepared from lysine, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( N-methylglucamine) and procaine Suitable non-toxic acids include inorganic and organic acids such as acetic acid, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, ethenesulfonic, formic, fumaric, furoic, galacturonic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric , tartaric and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts include, therefore, hydrochloride and mesylate salts. Others are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Easton PA, 1990) and Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy), 19th ed. (Mack Publishing, Easton PA, 1995). Unless otherwise indicated, the term "potent TPH1 inhibitor" is a compound having a TPH1_IC50 less than about 10 uM. Unless otherwise indicated, the terms "prevent", "prevent" and "prevention" contemplate an action that occurs before the patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder, or one or more of Your symptoms. The terms include prophylaxis.
Unless indicated otherwise, the term "prodrug" encompasses esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, conjugates of amino acid, phosphate esters, metal salts and pharmaceutically acceptable sulfonate esters of the compounds described herein. Examples of prodrugs include compounds comprising a biohydrolyzable residue (e.g., a biohydrolyzable amide analog, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ester, biohydrolyzable phosphate or biohydrolyzable ureido). The prodrugs of the compounds described herein are contemplated and readily prepared by those of ordinary skill in the art. see, e.g., Design of Prodrugs (Bundgaard, a., Ed. Elseview, 1985; Bundgaard H., "Design and Application of Prodrugs" A Textbook of Drug Design and Development, (Text of drug design and development), Krosgaard-Larsen and H. Bundgaard, Ed. 1991, Chapter 5 , p. 113-191; and Bundgaard H., Advanced Drug Delivery Review, 1992, 8, 1-38. Unless stated otherwise, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence. A prophylactically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" may encompass an amount that improves general prophylaxis or that improves the prophylactic efficacy of another prophylactic agent. Unless otherwise indicated, the term "Protection group" or "protecting group", when used to refer to part of a molecule subjected to a chemical reaction, means a chemical residue that is not reactive under the conditions of that chemical reaction, and which can be removed to provide a residue which is reactive under those conditions. Protection groups are well known in the art. See, e.g., Greene, T.W., and Wuts, P.G.M., Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis) (3rd ed., John Wiley &Sons, 1999); Larock R.C., Comprehensive Organic Transformations (2nd ed., John Wiley &Sons, 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl and phthalimido. Unless indicated otherwise, the term "pseudohalogen" refers to a polyatomic anion that is it resembles a halide ion in its acid-base, substitution and reduction chemistry, which generally has a low base capacity, and which forms a free radical under polymerization conditions of atom transfer radical. Examples of pseudohalogens include ions of azide, cyanide, cyanate, thiocyanate, thiosulfate, sulfonates and sulfonyl halides. Unless otherwise indicated, the term "TPHI selective inhibitor" is a compound that has a TPH2_IC5o that is at least approximately 10 times greater than its TPH1_IC50. Unless otherwise indicated, the term "stereomerically enriched composition" of a compound refers to a mixture of the named compound and its stereoisomer (s) containing (n) more of the named compound than of its ( s) stereoisomer (s). for example, a stereoisomerically enriched composition of (S) -butan-2-ol encompasses mixtures of (S) -butan-2-ol and (R) -butan-2-ol in proportions of eg, about 60/40, 70 / 30, 80/20, 90/10, 95/5, and 98/2. Unless indicated otherwise, the term "stereoisomeric mixture" encompasses racemic mixtures as well as stereomerically enriched mixtures (eg, R / S = 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and 70/30). Unless otherwise indicated, the term "Stereomerically pure" means a composition comprising a stereoisomer of a compound and which is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having a stereocenter will be substantially free of the opposite stereoisomer of the compound. A stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the stereoisomer of the compound. % by weight of the other stereoisomers of the compound, more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or more than about 99% by weight of a stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound. Unless otherwise indicated, the term "substituted", when used to describe a chemical structure or residue, refers to a derivative of that structure or residue wherein one or more of its hydrogen atoms is replaced with an atom, chemical residue or functional group such as, but not limited to, alcohol, aldehyde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (eg, methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-0C (0) alkyl), amide (-C (0) NH-alkyl- or -alkylNHC (0) alkyl), amidinyl (-C (NH) NH-alkyl or C (NR) NH2), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl , aryloxy, azo, carbamoyl (-NHC (O) O-alkyl or -OC (0) NH-alkyl), carbamyl (eg, C0NH2 as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl , carboxylic acid, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (eg, methoxy, ethoxy), guanidino, halo, haloalkyl (eg, -CCL3 , -CF3, C (CF3) 3), heteroalkyl, hemiacetal, imine (primary and secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxygen (ie, to provide an oxo group), phosphodiester, sulfide, sulfonamido ( eg, S02NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkysulfonyl), sulfoxide, thiol (eg, sulfhydryl, thioether) and urea (-NHCONH-alkyl-). Unless otherwise indicated, a "Therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A therapeutically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of the disease or condition. The term "therapeutically effective amount" may encompass an amount that improves therapy in general, reduces or avoids the symptoms or causes of a disease or condition, or improves the therapeutic efficacy of another therapeutic agent. Unless indicated otherwise, the term "TPH1_IC50" is the IC50 of a compound for TPH1 as determined using the in vitro inhibition assay described in the Examples, below. Unless indicated otherwise, the term "TPH2_IC50" is the IC5o of a compound for TPH2 as determined using the in vitro inhibition assay described in the Examples, below. Unless otherwise indicated, the terms"treat", "treating" and "treatment" contemplate an action that occurs while a patient suffers from the specified disease or disorder, which reduces the severity of the disease or disorder or one or more of its symptoms, or that retards or delays the progress of the disease or disorder. Unless otherwise indicated, the term "include" has the same meaning as "includes" and the term "includes" has the same meaning as "includes, but is not limited to". Similarly, the term "such as" has the same meaning as the term "such as, but not limited to." Unless otherwise stated, one or more adjectives that immediately precede a series of nouns should be interpreted to apply to each of the nouns. For example, the phrase "optionally substituted alkyl, aryl or heteroaryl" has the same meaning as "optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl". It should be noted that a chemical residue that is part of a larger compound can be described herein by using a name commonly commensurate with it when it exists as a single molecule or a name commonly according to its radical. For example, the terms "pyridine" and "pyridyl" are assigned the same meaning when they are used to describe a residue bound to other chemical residues. Therefore, it is assigned to the two phrases "XOH, where X is pyridyl" and "XOH, wherein X is pyridine" the same meaning and include the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol. It should also be noted that if the stereochemistry of a structure or a portion of a structure is not indicated, for example, with bold lines or hyphens, it must be interpreted that the structure or portion of the structure encompasses all of the stereoisomers thereof. . Similarly, the names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers, encompass pure stereoisomers and mixtures thereof. In addition, any atom shown in a drawing with unfilled valences is assumed to be attached to sufficient hydrogen atoms to satisfy the valences. Additionally, the chemical bonds represented with a solid line parallel to a line in dashes, include both single and double bonds (e.g., aromatics), if the valences permit. 4.2 Compounds This invention encompasses, inter alia, the compounds of the formula I: I and pharmaceutically acceptable salts and solvates of the same, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -0-, -S-, -C (0) -, -C (R4) =. = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N ( R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, - OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S ( 02) C (R3R) -; D is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3. The particular compounds are of the formula I (A): KA) The compounds of the formula II are also encompassed by the invention: II and pharmaceutically acceptable salts and solvates thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -0-, -S-, -C (0) -, - C (R4) =. = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, - N (R5) C (0) N ( R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, - OC (R3R4) ~, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S ( 02) C (R3R4) -; D is aryl or optionally substituted heterocycle; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3. The particular compounds are of the formula II (A): II (A) With respect to the formulas described herein (eg, I, I (A), II and II (A)), particular compounds include those wherein A is optionally substituted cycloalkyl (eg, of 6 members and of 5 members). In some, A is optionally substituted aryl (e.g., phenyl or naphthyl). In others, A is optionally substituted heterocycle (e.g., 6 member and 5 member). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, A is aromatic. In others, A is non-aromatic. In some, A is an optionally substituted bicyclic residue (e.g., indole, iso-indole, pyrrolo-pyridine or naphthylene). The particular compounds are of the formula: where: each of Ai and A2 is independently an optionally substituted monocyclic cycloalkyl, aryl or heterocycle. The compounds encompassed by this formula include those in which Ai and / or A2 are optionally substituted cycloalkyl (e.g., 6-membered and 5-membered). In some, Ai and / or A2 are optionally substituted aryl (e.g., phenyl or naphthyl). In others, Ai and / or A2 are optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, Ai and / or A2 are aromatic. In others, Ai and / or A2 are non-aromatic. With respect to the formulas described herein, particular compounds include those wherein D is optionally substituted aryl (e.g., phenyl or naphthyl). In others, D is optionally substituted heterocycle (e.g., 6 member and 5 member). Examples of 6-membered heterocycles include, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, D is aromatic. In others, D is non-aromatic. In some, D is an optionally substituted bicyclic residue (e.g., indole, iso-indole, pyrrolo-pyridine or naphthylene).
With respect to the formulas described herein, particular compounds include those wherein E is optionally substituted aryl (e.g., phenyl or naphthyl). In others, E is optionally substituted heterocycle (e.g., 6 member and 5 member). Examples of 6-membered heterocycles include, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, E is aromatic. In others, E is non-aromatic. In some, E is an optionally substituted bicyclic residue (e.g., indole, iso-indole, pyrrolo-pyridine or naphthylene). With respect to the various formulas described herein, particular compounds include those wherein Ri is hydrogen or optionally substituted alkyl. In some, R2 is hydrogen or optionally substituted alkyl. In some, n is 1 or 2. In some, X is a bond or S. In others, X is -C (R4) =, = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) - or -C = C-, and, for example, R4 is independently hydrogen or optionally substituted alkyl. In others, X is -O-, -C (R3R4) 0- or -OC (R3R4) - and, for example, R3 is hydrogen or optionally substituted alkyl, and R is hydrogen or optionally substituted alkyl. In some, R3 is hydrogen and R4 is trifluoromethyl. In some compounds, X is -S (02) -, S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) - or -S (02) C (R3R4) - and, for example, R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl and R5 is hydrogen or optionally substituted alkyl. In others, X is -N (R5) -, -N (R5) C (O) N (R5) -, C (R3R4) N (R5) -, or -N (R5) C (R3R4) - y, for example, R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl and each R5 is independently hydrogen or optionally substituted alkyl. Some compounds of the invention are encompassed by the formula: wherein, for example, R3 is trifluoromethyl. Others are covered by the formula: where, for example, R3 is hydrogen. Some compounds are covered by the formula: wherein: each of Zi f Z2, Z3 and Z4 is independently N or CR6: each R6 is independently hydrogen, cyano, halogen, OR7, NR8R9, amino, hydroxyl or alkyl, alkyl-aryl or optionally substituted alkyl-heterocycle; each R7 is independently hydrogen or alkyl-alkyl aryl or optionally substituted alkyl-heterocycle; each R8 is independently hydrogen or alkyl-aryl alkylaryl or optionally substituted alkyl-heterocycle; each Rg is independently hydrogen or alkyl-alkyl aryl or optionally substituted alkyl-heterocycle; and m is 1-4. Certain of such compounds are of the formula: Others are of the formula: wherein, for example, R3 is trifluoromethyl, others are of the formula: where, for example, R3 is hydrogen. With reference to the various formulas above, some compounds are such that all Zi, Z2, Z3 and Z4 are N. In others, only three of Zi, Z2, Z3 and Z4 are N. In others, only two of Zi, Z2, Z3 and Z4 are N. In others, only one of Zi, Z2, Z3 and Z4 is N. In others, none of the Zi, Z2, Z3 and Z4 is N. Some compounds are of the formula: wherein: each of Z'i, Z'2, and Z'3 is independently N, NH, S, O, or CRß: each Re is independently amino, cyano, halogen, hydrogen, 0R7, SR7, NR8R9, or alkyl, alkyl aryl or optionally substituted alkyl heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rg is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-3. Certain of such compounds are of the formula: Others are of the formula: wherein, for example, R3 is trifluoromethyl, others are of the formula: where, for example, R3 is hydrogen, With reference to the various formulas above, some compounds are such that all Z'i, Z'2, and Z'3 are N or NH. In others, only two of Z'i, Z'2, and Z'3 are N or NH. In others, only one of Z'i, Z'2, and Z'3 is N or NH. In others, none of the Z'i, Z'2, and Z'3 is N or NH. Some compounds are covered by the formula: wherein: each of Z '' ?, Z''2, Z''3 and Z''4 is independently N or CRio; each Rio is independently amino, cyano, halogen, hydrogen, ORu, SRn, NR? 2Ri3 or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ru is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle; each R 2 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle; and each Ri3 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle. Certain of such compounds are of the formula: Others are of the formula: wherein, for example, R3 is trifluoromethyl. Others are of the formula: where, for example, R3 is hydrogen, With reference to the various formulas above, some compounds are such that all Z '' ?, Z '' 2, Z '' 3 and Z '' 4 are N. in others, only three of Z '' ?, Z ' ', Z''3 and Z''4 are N. In others, only two of Z "?, Z''2, Z''3 and Z' 'are N. In others, only one of Z' '? , Z''2, Z''3 and Z''4 is N. In others, none of Z''x, Z "2, Z''3 and Z''4 is N. Some compounds are of the formula : wherein: each of Z '' ?, Z''2, Z''3 and Z''4 is independently N or CR? 0; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR? 2R? 3 or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 2 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle; and each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain of such compounds are of the formula: Others are of the formula: wherein, for example, R3 is trifluoromethyl, others are of the formula: where, for example, R3 is hydrogen. With reference to the various formulas above, some compounds are such that all Z '' ?, Z''2, Z''3 and Z''4 are N. In others, only three of Z '' ?, Z''2, Z''3 and Z''4 are N. In others, only two of Z '' ?, Z''2 , Z''3 and Z''4 are N. In others, only one of Z '' ?, Z''2, Z''3 and Z''4 is N. In others, none of Z ''? , Z''2, Z''3 and Z''4 is N. Some are of the formula: whose substituents are defined herein. Others are of the formula: whose substituents are defined herein, Others are of the formula: whose substituents are defined herein. Others are of the formula: whose substituents are defined herein. With reference to the various formulas described herein, particular compounds include those wherein both A and E are optionally substituted phenyl and, for example, X is -0-, -C (R3R4) 0-, or -OC (R3R ) - and, for example, R3 is hydrogen and R4 is trifluoromethyl and, for example, n is 1. With reference to the various generic chemical structures described herein, certain embodiments of the invention are such that one or more of the following conditions: 1) E and D are not both optionally substituted phenyl (ie, E is not phenyl optionally substituted with at least one residue in addition to D and the residue ~ [CH2] n- and D is not phenyl optionally substituted with minus a residue in addition to E and X). 2) E and D are not both phenyl optionally substituted when A is optionally substituted phenyl (i.e., A is phenyl optionally substituted with at least one residue in addition to X). 3) E and D are not both phenyl. 4) E and D are not both phenyl when A is phenyl optionally substituted. 5) E, D and A are not all phenyl. 6) When E is para-phenyl (i.e., D is attached in the para position to the residue - [CH2] n-), and n is 1, D is not optionally substituted pyridazin-3 [2H] -one. In a specific embodiment, when E is para-phenyl, n is 1, Ri is -C (0) (optionally substituted phenyl), and R 2 is H, D is not optionally substituted pyridazin-3 [2 H] -one. A more specific embodiment does not cover the compounds described in the international patent application WO 05/077915. 7) A is not optionally substituted pyrrolidine. In a specific embodiment, when E is para-phenyl, and n is 1, D is not optionally substituted 2,6-dimethoxyphenyl. In another specific embodiment, when E is para-phenyl, n is 1, X is -CH 2 -, and A is pyrrolidine, D is not optionally substituted pyridazin-3 [2 H] -one. A more specific embodiment does not cover the compounds described in the international patent application WO 05/068415. 8) When E is para-phenyl, and n is 1, D is not optionally substituted quinazoline. In a specific embodiment, when E is para-phenyl, n is 1, and X is -NH- or -CH2-, D is not optionally substituted quinazoline. In another specific embodiment, when E is para-phenyl, and n is 1, D is not quinazoline-2, - (I H, 3 H) -dione optionally substituted. In another specific modality, when E is para-phenyl, n is 1 and Ri is -C (0) (optionally substituted phenyl), D is not quinazoline-2,4 (H, 3 H) -dione optionally substituted. A more specific embodiment does not cover the compounds described in the international patent application WO 05/061466. 9) When E is optionally substituted phenyl (ie, E is phenyl optionally substituted with residues in addition to D and the residue - [CH2] n-), D is optionally substituted phenyl (ie, D is phenyl optionally substituted with residues in addition to X and E), n is 1, and X is -OCH2-, A is not phenyl. In a specific embodiment, when E is meta- (optionally substituted phenyl) (ie, E is phenyl optionally substituted with residues in addition to D and the residues - [CH2] n, and D is attached in the meta position to the residue ~ [ CH2] n-), D is optionally substituted phenyl, n is 1 and X is -OCH2-, A is not phenyl. In another specific embodiment, when E is meta- (optionally substituted phenyl), D is optionally substituted phenyl, n is 1, X is -OCH2-, and R2 is optionally substituted alkyl or alkylaryl, A is not phenyl. In another specific embodiment, when E is meta- (substituted phenyl) (ie, E is phenyl substituted with one or more residues in addition to D and the residue - [CH2] n, and D is attached in the meta position to the residue - [CH2] n_), D is substituted phenyl (ie, D is phenyl optionally substituted with at least one residue in addition to C and E), n is 1, and X is -OCH2-, A is not phenyl. A more specific modality does not covers the compounds described in the international patent application WO 05/058943, WO 05/033129, WO 04/012816 or WO 03/106480. 10) When E is para-phenyl, D is phenyl, n is 1, X is not O, or -OCH2-. In a specific embodiment, when E is para-phenyl, D is phenyl, n is 1, and X is O, or -OCH2-, A is not optionally substituted cycloalkyl or phenyl (ie, phenyl optionally substituted with at least one residue in addition of X). In another specific embodiment, when E is para-phenyl, D is para-phenyl (ie, X is attached in the para position to E) or ortho-phenyl (ie, X is attached in the ortho position to E), n is 1, and X is O, or -OCH2-, A is not cycloalkyl or optionally substituted phenyl. In another specific embodiment, when E is para-phenyl, D is phenyl, n is 1, X is O, or -OCH2-, and Ri is not H, A is not optionally substituted cycloalkyl or phenyl. In another specific embodiment, when E is para-phenyl, D is phenyl, n is 1, X is O, or -OCH2-, Ri is not H and R2 is methyl or H, A is not cycloalkyl or optionally substituted phenyl. A more specific embodiment does not cover the compounds described in the international patent application WO 05/014534, WO 05/014533, WO 05/014532 or WO 04/014844. 11) When E is para-phenyl, D is ortho-phenyl, n is 1, and X is -CH2-, A is not piperidine. A more specific modality does not cover the compounds described in the application International Patent WO 04/014844. 12) When E is para-phenyl, D is optionally substituted purine, n is 1 and X is -CH2-, A is not phenyl. In a specific embodiment, when E is para-phenyl, D is optionally substituted purine, n is 1, X is -CH2-, and at least one of Ri and R2 is H, A is not phenyl. A more specific embodiment does not cover the compounds described in the international patent application WO 04/094426. 13) When E is para-phenyl, D is optionally substituted purine, n is 1 and X is a bond, A is not optionally substituted tetrahydrofuran. In a specific embodiment, when E is para-phenyl, D is optionally substituted purine, n is 1, X is -CH2- and none of Ri and R2 is H, A is not optionally substituted tetrahydrofuran. A more specific embodiment does not cover the compounds described in the international patent application WO 04/094426. 14) When E is phenyl, D is optionally substituted phthalazine (ie, phthalazine optionally substituted with at least one residue other than E and X), and X is -CH2-, A is not optionally substituted pyridine (ie, pyridine optionally substituted with a residue other than X). In a specific embodiment, when E is phenyl, D is optionally substituted phthalazine, and X is -CH2-, A is not substituted pyridine. A more specific modality does not cover the compounds described in the international patent application WO 04/056798. 15) When E is para- (optionally substituted phenyl), D is meta- (optionally substituted phenyl) and n is 1, X is not a bond, -CH2-, -CH20-, -NR5-, or -CH2NR5-. A more specific embodiment does not cover the compounds described in the international patent application WO 04/046091. 16) E is not isoxazole. In a specific embodiment, when E is isoxazole, D is para-phenyl and n is 1, X is not -OCH2-. In another specific embodiment, when E is isoxazole, D is para-phenyl, n is 1, and X is -OCH2-, A is not optionally substituted quinoline (i.e., quinoline optionally substituted with one or more residues in addition to X). A more specific embodiment does not cover the compounds described in the international patent application WO 04/043349. 17) When E is para- (optionally substituted phenyl) and n is 1, D is not optionally substituted 1,4-piperazine (ie, piperazine optionally substituted with at least one residue in addition to E and X, which are bonded to the atoms of nitrogen in positions 1 and 4). In a specific embodiment, when E is para- (optionally substituted phenyl), n is 1, D is 1,4-piperazine optionally substituted, X is not a bond or -CH 2 -. A more specific modality does not cover the compounds described in the application International Patent WO 03/089410. 18) D is not optionally substituted 1, 1-dioxo-l, 2,5-thiadiazolidine. In a specific embodiment, when E is para-phenyl, D is not 1, 1-dioxo-l, 2,5-thiadiazolidine. In another specific embodiment, when E is para-phenyl, n is 1 and D is 1,1-dioxo-l, 2,5-thiadiazolidine, X is not -CH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is 1,1-dioxo-l, 2,5-thiadiazolidin-3-one, and X is -CH 2 -, A is not optionally substituted phenyl. A more specific embodiment does not cover the compounds described in the international patent application WO 03/082841. 19) When E is para-phenyl, and n is 1, D is not optionally substituted quinazoline or 1,2,3,4-tetrahydroquinazoline (eg, 3,4-dihydroquinazolin-2 (IH) -one, quinazoline-2, 4 (ÍH, 3H) -dione, 2-thioxo-2,3-dihydroquinazolin-4 (lH) -one, quinazolin-4 (3H) -one or 1H-benzo [c] [1, 2, 6] thiadiazin-4 (3 H) -one, any of which may be optionally substituted with residues in addition to E and X). In a specific embodiment, when E is para-phenyl, n is 1, and Ri is 2,6-dichlorobenzoyl, D is not optionally substituted quinazoline or 1,2,3,4-tetrahydroquinazoline. A more specific embodiment does not cover the compounds described in the international patent application WO 03/070709 or WO 02/016329. 20) D is not optionally substituted piperidine.
In a specific embodiment, when E is optionally substituted pyrimidin-2 (HH) -one (ie, pyrimidin-2 (HH) -one optionally substituted with residues in addition to D and the residue - [CH2] n-) and n is 1, D is not optionally substituted piperidine. In another specific embodiment, when E is optionally substituted pyrimidin-2 (HH) -one, n is 1 and D is optionally substituted piperidine, X is not -CH2- or -CH2NH-, A more specific embodiment does not encompass the compounds described in the international patent application WO 03/066624. 21) When E is meta-phenyl, substituted in the para position to the residue - [CH2] n with OH, n is 1 and D is optionally substituted ortho-phenyl, X is not -O-. In a specific embodiment, when E is meta- (optionally substituted phenyl), n is 1, D is optionally substituted ortho-phenyl, and X is -O-, A is not substituted tetrahydro-2H-pyran (ie, tetrahydro-2H) -piran substituted with at least one residue in addition to X). A more specific embodiment does not encompass the compounds described in the US patent. 6,951,840. 22) E is not optionally substituted quinazolin-4 (3H) -one. In a specific embodiment, when E is optionally substituted quinazolin-4 (3H) -one, n is 1, and D is phenyl, X is not -NH-. In another embodiment, when E is quinazolin-4 (3H) -one optionally substituted, n is 1, D is phenyl, and X is -NH-, A is not 4,5-dihydro-lH-imidazole. A more specific embodiment does not cover the compounds described in the international patent application WO 02/081467. 23) When E is para-phenyl, and n is 1, D is not optionally substituted isoindoline-1,3-dione. In a specific embodiment, when E is para-phenyl, n is 1 and D is optionally substituted isoindoline-1,3-dione, X is not -OCH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is isoindoline-1,3-dione, X is -OCH2-, and R2 is H, A is not phenyl. A more specific embodiment does not cover the compounds described in the international patent application WO 02/028830. 24) D is not piperidine. In a specific embodiment, when E is purine, n is 1 and D is piperidine, X is not a bond. In another specific embodiment, when E is purine, n is 1, D is piperidine and X is a bond, A is not 1, 2, 3, 4-tetrahydro-l, 8-naphthyridine. A more specific embodiment does not cover the compounds described in the international patent application WO 02/018384. 25) When E is meta- (optionally substituted phenyl), n is 1, D is optionally substituted phenyl, and C is O, A is not substituted phenyl. In a specific embodiment, when E is meta- (optionally substituted phenyl), n is 1, D is optionally substituted phenyl, Ri is acetyl, R 2 is ethyl and X is O, A is not substituted phenyl.
A more specific embodiment does not cover the compounds described in the international patent application WO 02/000245. 26) When E is para-phenyl, n is 1, and D is phenyl, X is not -NH-, -CH2NH-, or -NHCH2-, In a specific embodiment, when E is para-phenyl, n is 1 and D is meta-phenyl, X is not -NH-, -CH2NH-, or -NHCH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is meta-phenyl and R2 is H, X is not -NH-, -CH2NH-, or -NHCH2-. A more specific embodiment does not encompass the compounds described in the US patent. 6,677,360 or the international patent application WO 00/035864. 27) When E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl and X is -O-, A is not optionally substituted phenyl. In a specific embodiment, when E is meta- (substituted phenyl), n is 1, D is meta- (substituted phenyl) and X is -O-, A is not optionally substituted phenyl. In another specific embodiment, when E is meta- (substituted phenyl), n is 1, D is meta- (substituted phenyl), Ri is H, R2 is H and X is -O-, A is not optionally substituted phenyl. A more specific embodiment does not cover the compounds described in the international patent application WO 01/054486. 28) When E is para-phenyl, n is 1 and D is optionally substituted imidazolidin-4-one (i.e., imidazolidin-4-one optionally substituted with at least one residue in addition to X and A), X is not -CH2-. In a specific embodiment, E is para-phenyl, n is 1, D is optionally substituted imidazolidin-4-one (ie, imidazolidin-4-one optionally substituted with at least one residue in addition to X and A), and X is - CH2-, A is not pyridine. A more specific embodiment does not encompass the compounds described in the US patent. 6,903,128. 29) When E is para- (optionally substituted phenyl), n is 1 and D is optionally substituted pyridin-2 (HH) -one, X is not -CH 2 -. In a specific embodiment, when E is para- (optionally substituted phenyl), n is 1, D is optionally substituted pyridin-2 (HH) -one, and X is -CH 2 -, A is not phenyl. A more specific embodiment does not encompass the compounds described in the US patent. 6,916,933. 30) When E is para-phenyl and n is 1, D is not quinazoline-2, 4- (1H, 3H) -dione or 2,4-dimethyleneimidazolidine. In a specific embodiment, when E is para-phenyl, n is 1 and X is -CH 2 -, D is not quinazoline-2, 4- (1H, 3H) -dione or 2,4-dimethyleneimidazolidine. A more specific embodiment does not encompass the compounds described in the US patent. 6,855,706. 31) A is not optionally substituted piperidine. In another embodiment, when E is para-phenyl, and n is 1, D is not ortho-phenyl. In a specific modality, when E is para- phenyl, n is 1 and D is ortho-phenyl, X is not -CH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is ortho-phenyl and X is -CH2-, A is not optionally substituted piperidine. A more specific embodiment does not encompass the compounds described in the US patent. 6,469,047. 32) When E is para-phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is para-phenyl, n is 1 and D is optionally substituted phenyl, X is not -CH2-, -0- or -0CH2-, A more specific embodiment does not encompass the compounds described in the US Pat. USA 6,420,418. 33) When E is para-phenyl and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is para-phenyl, n is 1 and D is optionally substituted phenyl, X is not -CH2-, -0CH2-, -NH- or -CH2NH-. A more specific embodiment does not encompass the compounds described in Japanese Patent 2001089368. 34) E is not optionally substituted pyrimidin-2 (1H) -one (ie, pyrimidin-2 (1H) -one optionally substituted with at least one residue in addition to D and the residue - [CH2] n-). In a specific embodiment, when E is optionally substituted pyrimidin-2 (1 H) -one and n is 1, D is not piperidine or piperazine. In another specific embodiment, when E is optionally substituted pyrimidin-2 (1H) -one and n is 1, X is not -CH 2 -, -NH- or -CH 2 NH-. One more modality Specification does not cover the compounds described in the international patent application WO 00/061551. 35) D is not optionally substituted imidazolidin-4-one. In a specific embodiment, when E is para-phenyl, and n is 1, D is not optionally substituted imidazolidin-4-one. In another specific embodiment, when E is para-phenyl, n is 1 and D is optionally substituted imidazolidin-4-one, X is not -CH 2 - or a bond. A more specific embodiment does not encompass the compounds described in the US patent. 6,423,728; 6,806,365 or 6,229,011. 36) D is not optionally substituted phenyl. In a specific embodiment, D is not phenyl or 2,6-dimethoxyphenyl (i.e., phenyl substituted at positions 2 and 6 by methoxy in addition to its substitutions by E and X). In another specific embodiment, when E is para-phenyl, and n is 1, D is not optionally substituted phenyl. In another specific embodiment, when E is para-phenyl, n is 1 and D is optionally substituted phenyl, X is not -CH2-, -OCH2- or -CH2NH-. A more specific embodiment does not encompass the compounds described in the US patent. 6,855,843. 37) E is not indole optionally substituted. In a specific embodiment, when E is optionally substituted indole, and n is 1, D is not substituted tetrahydro-2H-pyran. A more specific embodiment does not encompass the compounds described in the US patent. 6,610,502. 38) E is not optionally substituted isoxazole (i.e., isoxazole optionally substituted with at least one residue in addition to D and ~ [CH2] n-). In a specific embodiment, when E is isoxazole, and n is 1, D is not phenyl. In another specific embodiment, when E is isoxazole, n is 1 and D is phenyl, X is not -OCH2- or -CH2-. A more specific embodiment does not encompass the compounds described in the US patent. 6,114,328 or 5,849,736 or international patent application WO 95/14683. 39) When E is phenyl, n is 1 and D is phenyl, X is not -OCH2-. In a specific embodiment, when E is phenyl, n is 1, D is phenyl and X is -OCH2-, A is not phenyl. A more specific embodiment does not encompass the compounds described in Japanese Patent 09118662. 40) E is not optionally substituted imidazolidine-2,4-dione (ie, imidazolidine-2,4-dione optionally substituted with at least one residue in addition to D and - [CH2] n-). A is not optionally substituted benzoimidazole (i.e., benzoimidazole optionally substituted with at least one residue in addition to X). In a specific embodiment, when E is optionally substituted imidazolidine-2,4-dione, n is not 2. In another embodiment, when E is optionally substituted imidazolidine-2,4-dione and n is 2, D is not phenyl. In another specific embodiment, when E is optionally substituted imidazolidine-2,4-dione, n is 2 and D is phenyl, A is not benzoimidazole A more specific embodiment does not encompass the compounds described in the US patent. 6,620,820. 41) E is not optionally substituted morpholine. In a specific embodiment, when E is optionally substituted morpholine and n is 1, D is not optionally substituted phenyl. In another specific embodiment, when E is optionally substituted morpholine, n is 1 and D is optionally substituted phenyl, C is not -OCH2-. A more specific embodiment does not encompass the compounds described in the US patent. 3,658,806. 42) When E is optionally substituted phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is optionally substituted phenyl, n is 1, and D is optionally substituted phenyl, A is not optionally substituted phenyl. In another specific embodiment, when E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl, and X is -O-, A is not optionally substituted phenyl. A specific modality does not encompass diisodithyrosine. A more specific embodiment does not cover the compounds described in the US patent application. 2005/233964 or 2005/074838 or in the international patent application WO 05/076972, WO 05/069845 or WO 04/094590. 43) When E is phenyl and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is phenyl, n is 1 and D is phenyl optionally replaced, X is not -0-. In another embodiment, when E is phenyl, A is not optionally substituted phenyl. A more specific embodiment does not cover the compounds described in the U.S. patent application. 2005/059705. 44) When E is optionally substituted pyrimidin-2 (HH) -one and n is 1, D is not piperidine or piperazine. In another embodiment, when D is piperidine and n is 1, X is not -NH- or -NHCH2-. In another embodiment, when D is piperazine, X is not -CH2-. A more specific embodiment does not cover the compounds described in the US patent application. 2004/077638 or 2004/063934. 45) When E is optionally substituted phenyl and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is optionally substituted phenyl, n is 1 and D is optionally substituted phenyl, A is not phenyl. In another specific embodiment, when E is optionally substituted phenyl, n is 1 and D is optionally substituted phenyl, X is not -OCH2-. A more specific embodiment does not cover the compounds described in Skaff O., et al., JOC 70 (18): 7353-7363 (2005). 46) D is not optionally substituted indoline. In a specific embodiment, when E is optionally substituted phenyl, and n is 1, D is not optionally substituted indoline. In another specific embodiment, when E is optionally substituted phenyl, n is 1 and D is indoline optionally substituted, X is not a link. A more specific embodiment does not encompass the compounds described in Nicolaou KC, et al., JACS 126 (40): 12897-12906 (2004) or Nicolaou KC, et al., Angew Chemie Int. Ed., 42 (15): 1753 -1758 (2003). 47) E is not optionally substituted triazole. In another embodiment, D is not optionally substituted tetrahydro-2H-pyran. In a specific modality, E is not triazole. In another specific embodiment, when E is optionally substituted triazole, D is not optionally substituted tetrahydro-2H-pyran. In another specific embodiment, when E is optionally substituted triazole, A is not phenyl. In another specific embodiment, when E is optionally substituted triazole, X is not -O- or -OCH2-. A more specific embodiment does not cover the compounds described in Kuijpers B.H.M., et al., Organic Let., 6 (18): 3123-3126 (2004). 48) E is not optionally substituted triazole or isoxazole. In another embodiment, D is not optionally substituted tetrahydro-2H-pyran. In a specific embodiment, when E is triazole or isoxazole, and n is 1, D is not optionally substituted tetrahydro-2H-pyran. In another specific embodiment, when E is triazole or isoxazole, n is 1 and D is optionally substituted tetrahydro-2H-pyran, X is not -OCH2- A more specific embodiment does not encompass the compounds described in Dondoni, A., et al. , Organic Let., 6 (17): 2929- 2932. 49) When E is optionally substituted phenyl, n is 1 and D is optionally substituted phenyl, A is not phenyl. In a specific embodiment, when E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl, and X is -OCH2-, A is not phenyl. A more specific embodiment does not cover the compounds described in Hutton CA, and Skaff 0., Tetrahedron Let., 44 (26): 4895-4898 (2003) and Yoburn JC, or Van Vranken DL, Organic Let., 5 (16) : 2817-2820 (2003). 50) When E is phenyl, n is 1, D is optionally substituted phenyl and C is -CH 2 -, A is not pyrrolidine. A more specific embodiment does not encompass the compounds described in Doherty G.A., et al., Bioorg. Med. Chem. Let. 13 (11) .1891-1895 (2003). 51) E is not optionally substituted pyrimidin-2 (1H) -one or 5, 6, 7, 8-tetrahydroquinazolin-2 (3H) -one. In another embodiment, D is not piperidine. In a specific embodiment, when E is optionally substituted pyrimidin-2 (HH) -one and n is 1, D is not piperidine. In another specific embodiment, when E is optionally substituted pyrimidin-2 (HH) -one, n is 1 and D is piperidine, X is not -NH-, -CH2-, or CH2NH-. A more specific embodiment does not cover the compounds described in Zechel C, et al., Bioorg. Med. Chem. Let., 13 (2): 165-169 (2003). 52) A is not optionally substituted piperazine.
In a specific embodiment, when E is phenyl, n is 1, D is phenyl, and X is -CH 2 -, A is not optionally substituted piperazine. A more specific embodiment does not cover the compounds described in Castañedo G.M., et al., Bioorg. Med. Chem. Let. 12 (20): 2913-2917 (2002). 53) E is not optionally substituted indole. In a specific embodiment, when E is optionally substituted indole, n is 1 and D is optionally substituted tetrahydro-2H-pyran, X is not -CH20-. In another specific embodiment, when E is optionally substituted indole, n is 1, D is optionally substituted tetrahydro-2H-pyran, and X is -CH20-, A is not phenyl. A more specific modality does not cover the compounds described in Nishikawa T., et al., Org. Biomol. Chem. 3 (4): 687-700 (2005). 54) E, D and A are not all phenyl. In a specific embodiment, when E, D and A are all phenyl, X is not -CH-. A more specific embodiment does not cover the compounds described in Sircar I., et al., Bioorg. Med. Chem 10 (6): 2051-2066 (2002). 55) A is not cyclopropyl. In a specific embodiment, when E is phenyl, n is 1, D is optionally substituted phenyl, and X is -O-, A is not cyclopropyl. In another embodiment, D is not 2H-imidazol-2-one. In a specific embodiment, when E is phenyl, n is 1, D is 2H-imidazol-2-one and C is -CH2-, A is not phenyl. One modality more specific does not cover the compounds described in Yang, G.X., et al., Bioorg. Med. Chem. Let. 12 (11): 1497-1500 (2002). 56) E is not purine. In another embodiment, D is not piperidine. In a specific embodiment, when E is purine, n is 1, D is piperidine and X is -CH2NH-, A is not imidazole. A more specific embodiment does not encompass the compounds described in Peyman A., et al., Angew Chemie 39 (16): 2874-2877 (2000). 57) When E is optionally substituted phenyl, n is 1 and D is optionally substituted phenyl, X is not -O-. In a specific embodiment, when E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl, and X is -O-, A is not optionally substituted phenyl. A more specific embodiment does not encompass the compounds described in Wu, W. et al., J Biol. Chem. 274 (36): 25933-25944 (1999) or Jacob, J.S. et al., J. Biol. Chem. 271 (33): 19950-19956 (1996). 58) E is not 4, 5-dihydroisoxazole (i.e., 4,5-dihydroisoxazole connected to D and the residue ~ [CH2] n-). In a specific embodiment, when E is 4, 5-dihydroisoxazole, n is 1 and A is phenyl, X is not -OCH2-. In another specific embodiment, when E is 4, 5-dihydroisoxazole, n is 1, A is phenyl and X is -OCH2-, A is not optionally substituted piperidine. A more specific modality does not cover the compounds described in Wityak J., et al., J. Med. Chem., 40 (l): 50-60 (1997). 59) When E is imidazole, n is 1 and D is optionally substituted phenyl, X is not -OCH2-. In a specific embodiment, when E is imidazole, n is 1, D is optionally substituted phenyl and X is -OCH2-, A is not phenyl. A more specific embodiment does not encompass the compounds described in Feldman K.S., et al., JOC 61 (19): 6656-6665 (1996). 60) E is not 3,4-dihydro-2H-benzo [b] [1,4] thiazine optionally substituted. In another embodiment, D is not optionally substituted 3,4-dihydro-2H-benzo [b] [1,4] thiazine. In another embodiment, A is not 3,4-dihydro-2H-benzo [b] [1,4] thiazine optionally substituted. In a specific embodiment, E, D and A are not all 3,4-dihydro-2H-benzo [b] [1,] thiazine optionally substituted. A more specific embodiment does not encompass the compounds described in Napolitano A., et al., JOC 61 (2): 598-604 (1996). 61) E is not dihydropyrimidine-2, - (ÍH, 3H) -dione. In a specific embodiment, when E is dihydropyrimidine-2, - (1H, 3H) -dione and n is 2, D is not optionally substituted tetrahydrofuran. A more specific embodiment does not encompass the compounds described in Nawrot B., et al., Nucleosides & Nucleotides 14 (1 and 2): 143-165 (1995). 62) E is not indoline. In a specific embodiment, when E is indoline, n is 1 and D is optionally substituted phenyl, A is not phenyl optionally replaced. In another specific embodiment, when E is indoline, n is 1, D is optionally substituted phenyl, and A is optionally substituted phenyl, X is not -0-. A more specific embodiment does not encompass the compounds described in Naruse N., et al., J. Antibiotics 46 (12): 1812-1818 (1993). 63) When E, A and D are all optionally substituted phenyl, X is not -0-. A more specific embodiment does not cover the compounds described in Fetterer R.H., et al., J. Parasit 79 (2): 160-166 (1993). 64) When E, A and D are all optionally substituted phenyl, X is not -0CH2-. A more specific embodiment does not encompass the compounds described in Schmidt U., et al., Synthesis 12: 1248-54 (1992), Schmidt U., et al., JACS. Chem. Comm. 13: 951-953 (1992) or Schmidt U., et al., JACS Chem. Comm. 5: 275-277 (1991). 65) When E is quinazoline and n is 1, D is not phenyl. In a more specific embodiment, when E is quinazoline, n is 1 and D is phenyl, X is not -NH-. A more specific embodiment does not cover the compounds described in Lawson, E.C. et al., Letters Drug Design & Disc. 1 (1): 14-18 (2004). 66) When E is phenyl, n is 1 and D is optionally substituted phenyl, C is not -CH 2 -. In a more specific embodiment, when E is phenyl, n is 1, D is optionally substituted phenyl, and X is -CH2-, A is not pyrrolidine.
A more specific embodiment does not encompass the compounds in Doherty G.A., et al., Bioorg. Med. Chem. Let. 13 (7): 2937-2938 (2003). 67) D does not include boron. A more specific embodiment does not encompass the compounds described in Shull, B.K., et al., J. Pharm. Sci., 89 (2): 215-222 (2000). 68) When E is phenyl and n is 1, D is not 2,5-dioxo-pyrrolidine. In a specific embodiment, when E is phenyl, n is 1, and D is 2,5-dioxo-pyrrolidine, A is not phenyl. A more specific embodiment does not encompass the compounds described in Tilley J.W., et al., Bioorg. Med. Chem. Let. ll (l): 1-4 (2001). 69) D is not optionally substituted tetrahydro-2H-pyran. In a specific embodiment, when a is phenyl, and n is 1, D is not optionally substituted tetrahydro-2H-pyran. A more specific modality does not cover the compounds described in Manabe S., and Ito Y., Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 41: 139-143 (1999). 70) E is not isoxazole. In a specific embodiment, when E is isoxazole, n is 1 and D is phenyl, X is not -OCH2-. A more specific embodiment does not encompass the compounds described in Wityak G., et al., JMC 40 (8): 1292 (1997). 71) E, D and A are not all indole optionally substituted. A more specific modality does not cover compounds described in Humphries K.A., et al., J. Electro. Chem. 346 (1-2): 377-403 (1993). 72) When E is substituted phenyl, n is 1 and D is substituted phenyl, A is not phenyl. A more specific embodiment does not encompass the compounds described in Schmidt U., et al., Synthesis 10: 1025-1030 (1992); Schmidt U., et al., JACS Chem. Comm. 10: 744 (1991); or Schmidt U., et al., Angewandte Chemie 101 (7): 946-948 (1989). 73) When E is oxadiazole, and n is 1, D is not phenyl. In a specific embodiment, when E is oxadiazole, n is 1 and D is phenyl, A is not phenyl. A more specific embodiment does not encompass the compounds described in Moussebois C, et al., Helv. Chimica Acta 60 (1): 237-242 (1977). 74) D is not lH-imidazol-2 (3H) -one. In a more specific embodiment, when E is phenyl, n is 1 and A is phenyl, D is not lH-imidazol-2 (3H) -one. 75) A is not cyclopropyl. In a specific embodiment, when E is phenyl, n is 1 and X is -O-, A is not cyclopropyl. 76) D is not optionally substituted purine. In a specific embodiment, when E is phenyl, n is 1 and A is phenyl, D is not purine. 77) When X is -CH2-, A is not phenyl. In a specific embodiment, when E is phenyl, n is 1 and X is -CH 2 -, D is not optionally substituted imidazole (e.g. imidazol-2 (3H) -one). 78) D is not optionally substituted phthalazine. In a specific embodiment, when E is phenyl, n is 1 and X is -CH 2 -, D is not optionally substituted phthalazine. 79) D is not optionally substituted 2-oxo-pyridine. In a specific mode, when E is phenyl, n is 1 and X is -CH 2 -, D is not optionally substituted 2-oxo-pyridine. 80) A is not optionally substituted morpholine. In a specific embodiment, when E is phenyl, n is 1 and X is -CH2-, A is not optionally substituted morpholine. 81) None of E, A or D is piperidine or piperazine optionally substituted. 82) When E is imidazole, n is 1 and D is optionally substituted triazole, X is not -NH-. In a specific embodiment, when E is imidazole, n is 1, D is optionally substituted triazole and X is -NH-, A is not optionally substituted phenyl. This invention encompasses stereomerically pure compounds and stereomerically enriched compositions thereof. The stereoisomers can be synthesized or dissolved asymmetrically using standard techniques such as chiral columns, chiral dissolving agents, or enzymatic dissolution. See, e.g., Jacques J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen S.H., et al., Tetrahedron 33: 2725 (1977); Eliel E.L., Stereochemistry of Coal Compounds (McGraw Hill NY, 1962); and Wilen S.H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN, 1972). The particular compounds of the invention are potent inhibitors of TPH1. The specific compounds have a TPH1_IC50 less than about 10, 5, 2.5, 1, 0.75, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.05 uM. The particular compounds of the invention are selective inhibitors of TPH1. The specific compounds have a TPH1_IC50 which is about 10, 25, 50, 100, 250, 500 or 1000 times lower than their TPH2_IC50. The particular compounds do not significantly inhibit human tyrosine hydroxylase (TH). For example, the specific compounds have an IC50 for TH greater than about 100, 250, 500 or 1000 uM. The particular compounds do not significantly inhibit human phenylalanine hydroxylase (PAH). For example, the specific compounds have an IC50 for PAH greater than about 100, 250, 500 or 1000 uM. The particular compounds of the invention do not bind significantly (e.g., are inhibited with an IC50 greater than about 10, 25, 50, 100, 250, 500, 750 or 1000 uM) to one or more of the following: enzyme conversion angiotensin, erythropoietin receptor (EPO), factor IX, factor XI, integrin (eg, alpha4), fibrinogen receptor isoxazoline or isoxazole, metalloprotease, neutral endopeptidase (NEP), phosphatase (eg, tyrosine phosphatase), phosphodiesterase (eg, PDE) -4), polymerase, PPARy, TNF-alpha, vascular cell adhesion molecule 1 (VCAM-1), or the vitronectin receptor. The ability of a compound to bind to (e.g., inhibit) any of these objectives can be easily determined using methods known in the art, as described in the aforementioned references. The specific compounds of the invention do not inhibit cell adhesion. When administered to mammals (e.g., mice, rats, dogs, monkeys or humans), certain compounds of the invention do not readily cross the blood / brain barrier (e.g., less than about 5, 2.5, 2, 1.5, 1, 0.5, or 0. 01 percent of the compound in the blood goes to the brain).
The ability or inability of a compound to cross the blood / brain barrier can be determined by methods known in the art. See, e.g., Riant P. et al., Journal of Neurochemistry 51: 421-425 (1988); Kastin A.J., Akerstrom V., J. Pharmacol. Exp. Therapeutics 294: 633-636 (2000); W.A. Banks, W.A. et al., J. Pharmacol. Exp. Therapeutics 302: 1062-1069 (2002). 4.3 Synthesis of Compounds The compounds of the invention can be prepared by methods known in the art and by the methods described herein. For example, with reference to formula I, compounds in which E is phenyl and D is pyrazine, pyridiazine, pyridine or optionally substituted phenyl, can be prepared by the method shown in the Scheme Q m-Q-s, Pd (PPh3) 2CI2, Na2C03 AcCN H20 = 1 I, microwave Scheme 1 where, for example: Compounds wherein X is -OCR3- can generally be prepared using the method shown in Scheme 2, wherein R3 is CF3 and D is pyrimidine: Scheme 2 wherein, for example, A is phenyl, biphenyl or optionally substituted naphthyl.
The compounds of the invention can also be prepared using the procedure shown below in Scheme 3: Kb) Scheme 3 where Pi is Ri or a protection group; P2 is a protection group; P3 is 0R2 or a protection group; X 'is, for example, 0 or N: Yi and Y3 are halogen (e.g., Br, Cl) or an appropriate pseudohalide (e.g., triflate); and each R 'is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl or heterocycle or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane (e.g., 4, 4, 5, 5-tetramethyl-l, 3,2-dioxaborlane). The groups A, Ri, R2, R3, R6 and m are defined elsewhere herein. Also defined herein are the residues Z '' ?, Z''2 / Z''3 and Z''4, although it should be understood that with respect to the scheme shown above, one of them is attached to the phenyl ring. For example, Z ''? and Z''4 may independently be CRio (which is defined herein) while Z''2 is N and Z''3 is a carbon atom bonded to the adjacent phenyl ring. The individual reactions shown above can be carried out using conditions known in the art. for example, palladium catalysts and suitable conditions for Suzuki coupling of the boron and halogen-containing residues are well known, and the examples are provided below. Additionally, the appropriate types and uses of the groups of protection, as well as methods for their removal and replacement with residues such as, but not limited to, hydrogen (e.g., hydrolysis under acidic or basic conditions). The residue A can be bicyclic (e.g., optionally substituted biphenyl). In such cases, the starting material containing A can be prepared as shown below: wherein Y2 is halogen or pseudohalogen, and each R is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a dioxaborolane cyclic (eg,,, 5, 5-tetramethyl-l, 3, 2-dioxaborolane). Another procedure for the preparation of the compounds wherein D is optionally substituted pyrimidine or triazine, is shown below in Scheme 4: Scheme 4 where, for example, X is N, O, or S and FG is defined below: FG = B (OH) 2 when E is optionally substituted phenyl FG - H when E is: The ester derivatives of these and other compounds of the invention can be easily prepared using methods such as that shown below in Scheme 5, wherein E is optionally substituted phenyl: Scheme 5 An alternative procedure for the preparation of triazine-based compounds is shown below in Scheme 6: n-BuOH dry / tBuOK 3.5 eq. 160 ° C, sealed tube, 2 days Scheme 6 Cyclic residue D may be any of a variety of structures that are easily incorporated into the compounds of the invention. For example, the compounds wherein D is oxazole can be prepared as shown below in Scheme 7: Using the methods known in the art, the synthetic procedures shown above are easily modified to obtain a wide range of compounds. For example, chiral chromatography and other techniques known in the art can be used to separate the stereoisomers from the final product. See, e.g., Jacques J et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen S.H., et al., Tetrahedron 33: 2725 (1977); Eliel E.L., Stereochemistry of Carbon Compounds (McGraw Hill NY, 1962); and Wilen S.H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN, 1972). Additionally, as shown in some of the above schemes, the synthesis can use chiral starting materials to produce stereomerically enriched or pure products. 4.4 Methods of Use This invention encompasses a method for inhibiting TPH, which comprises contacting the TPH with a compound of the invention (i.e., a compound described herein). In a particular method, the TPH is TPH1. In another, the TPH is TPH2. In a particular method, the inhibition is in vitro. In another, the inhibition is in vivo. One embodiment encompasses a method for inhibiting TPH1 in a mammal, which comprises administering to the mammal a Composite of the invention. In a particular method, TPH2 is not significantly inhibited. In one method, the compound does not easily cross the blood / brain barrier. In another, the compound is a selective inhibitor of TPHl. This invention encompasses methods for treating, preventing and managing various diseases and disorders mediated by peripheral serotonin, which comprise inhibiting TPHI activity in a patient in need of such treatment, prevention or management. In a particular embodiment, the inhibition is achieved by administering to the patient a therapeutically or prophylactically effective amount of a potent TPHI inhibitor. Examples of potent TPHI inhibitors are described herein. Particular diseases and disorders include carcinoid syndrome and gastrointestinal diseases and disorders. Examples of specific diseases and disorders include abdominal pain (eg, associated with medullary carcinoma of the thyroid (, anxiety, carcinoid syndrome, celiac disease, constipation (eg, constipation that has an iatrogenic cause, and idiopathic constipation), Crohn's disease, depression , diabetes, diarrhea (eg, biliary acid diarrhea, enterotoxin-induced secretory diarrhea, diarrhea that has an iatrogenic cause, idiopathic diarrhea (eg, idiopathic secretory diarrhea) and traveler's diarrhea), emesis, abdominal pain functional dyspepsia, irritable bowel syndrome (IBS), lactose intolerance, MEN types I and II, Ogilvie syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder and Zollinger-Ellison syndrome. In particular methods of the invention, the treatment, management and / or prevention of a disease or disorder is achieved while avoiding the adverse effects associated with the alteration of serotonin levels in the central nervous system (CNS). Examples of such adverse effects include agitation, anxiety disorders, depression and sleep disorders (e.g., insomnia and sleep disturbance). 4.5 Pharmaceutical Compositions This invention encompasses pharmaceutical compositions comprising one or more compounds of the invention. Certain pharmaceutical compositions are single unit dose forms suitable for oral, mucosal (e.g., sublingual nasal, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, rapid, intramuscular or intraarterial) or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; tablets; capsules, such as soft elastic gelatin capsules; sachets; dragees; pills; dispersions; suppositories; ointments; poultices (cataplasms); pasta; powder; dressings; creams; poultices; solutions; patches; aerosols (e.g., rubbers or nasal inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. The formulation must be adapted to the mode of administration. For example, oral administration of a compound susceptible to degradation in the stomach should be achieved using an enteric layer. Similarly, a formulation may contain ingredients that facilitate the delivery of the active ingredient (s) to the site of action. For example, the compounds can be administered in liposomal formulations in order to protect them from degrading enzymes, facilitate transport in the circulatory system and effect their delivery through cell membranes. Similarly, compounds low in solubility in liquid dosage forms (and in dosage forms suitable for reconstitution) can be incorporated with the help of solubilizing agents, emulsifiers and surfactants such as, but not limited to cyclodextrins (eg, alpha-cyclodextrin, beta-cyclodextrin, Captisol® and Encapsin ™ (see, eg, Davis and Brewster, Nat. Rev. Drug Disc, 3: 1023- 1034 (2004)), Labrasol®, Labrafil®, Labrafac®, creamfor, and non-aqueous solvents, such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, dimethyl formamide, dimethyl sulfoxide (DMSO), biocompatible oils (eg, cottonseed oils, tiger nut, corn, germ, olive, castor and sesame seeds), glycerol, alcohol tetrahydrofurfurilic, polyethylene glycols, sorbitan fatty acid esters and mixtures thereof (eg, DMSO: corn oil). Low solubility compounds can also be incorporated into suspensions using other techniques known in the art, for example, they can be suspended. Particles of a compound in a liquid to provide a nanosuspension (see, e.g., Rabinow, Nature Rev. Drug Disc, 3: 785-796 (2004)). The nanoparticulate forms of the compounds described herein can be prepared by the methods described in the U.S. Patent Publications. Nos. 2004-0164194, 2004-0195413, 2004.0251332, 2005.0042177 Al, 2005-0031691 Al and the US Patents Nos. 5,145,684, 5,510,118, 5,518,187, 5,534,270, 5,543,133, 5,662,883, 5,665,331, 5,718,388, 5,718,919, 5,834,025, 5,862,999, 6,431,478, 6,742,734, 6,745,962, all of which are incorporated herein by reference. In one embodiment, the nanoparticulate form comprises particles having an average particle size less than about 2000 nm, less than about 1000 nm, or less than about 500 nm. The composition, form and type of a dosage form will typically vary depending on the use. For example, a dosage form used in the acute treatment of a disease may contain greater amounts of one or more of the active ingredients comprising, than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain minor amounts of one or more of the active ingredients that it comprises, than an oral dosage form used in the treatment of the same disease. How to take into account such differences will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed. Mack Publishing, Easton PA (1990). 4.5.1 Oral Dosage Forms The pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), tablets, capsules and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and can be prepared by pharmacy methods well known to those skilled in the art. See, generally Remington's Pharmaceutical Sciences, 18th ed. Mack Publishing, Easton PA (1990). Typical dosage forms are prepared by combining the active ingredient (s) in an intimate mixture with at least one excipient according to conventional pharmaceutical composition techniques. The excipients may take a variety of forms depending on the form of preparation desired for administration. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by conventional pharmacy methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers or both, and then shaping the product into the desired presentation if required. Disintegrants may be incorporated in the solid dosage forms to facilitate rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets). 4.5.2 Parenteral Dosage Forms Parenteral dosage forms can be administered to patients by several routes including subcutaneous, intravenous / including rapid injection), intramuscular, and intraarterial. Because their administration typically circulates through the patient's natural defenses against contaminants, the parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection and emulsions. Suitable carriers that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include: water for injection USP; aqueous vehicles such as sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection: water miscible vehicles such as ethyl alcohol, cottonseed, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate. 5. EXAMPLES 5.1. Production of Fractured Gen tphl Mice Exon 3 of the murine TPHI gene was removed by targeting the gene essentially as described by Wattler et al., Biotechniques 26 (6): 1150-6 (1999). The resulting knockout animals displayed a normal TPH activity in the brain but a drastically reduced TPH expression in the intestine. 5.2. Physiological Effects of tphl Gene Fracture Homologous (- / -) mice for tphl fracture were studied in conjunction with heterozygous (+/-) mice for gene fracture, in conjunction with wild-type littermates (+ / +). During this analysis, the mice underwent medical examination using an integrated set of medical diagnostic procedures designed to achieve the function of the major organ systems in a mammalian subject. By studying homologous (- / -) knockout mice in the numbers described and in conjunction with heterozygous (+/-) and wild-type (+ / +) littermates, more reliable and repeatable data were obtained. The tphl gene fracture mainly affected the the isoform in the gastrointestinal tract of TPH (TPHl), and had little or no effect on the isoform in the brain of TPH (TPH2). The fracture of the gene did not cause measurable adverse effects in the central nervous system. This was confirmed by serotonin immunochemistry, which showed that serotonin was greatly reduced or found absent in the stomach, duodenum, jejunum, ileus, caecum and colon, while serotonin levels were not affected in raphe neurons. Homologous (- / -) mice for the tphl gene had a decrease in thrombosis without a significant increase in bleeding or other adverse indications. 5.3. Characterization of HPLC In some of the following synthetic examples, the retention times of high performance liquid chromatography (HPLC) are provided. Unless noted otherwise, the various conditions used to obtain those retention times are described below: Method A: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 4 minutes; flow rate = 2 ml / minute; Observation wavelength = 220 nm. Method B: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 10 to 100% for 4 minutes; flow rate = 3 ml / minute; Observation wavelength = 220 nm. Method C: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 5 minutes; flow rate = 2 ml / minute; Observation wavelength = 220 nm. Method D: Shim VP ODS 4.6 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 4 minutes; flow rate = 3 ml / minute; Observation wavelength = 220 nm. Method E: Shim VP ODS 4.6 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 4 minutes; flow rate = 3 ml / minute; Observation wavelength = 254 nm. Method F: YMC-PACK ODS-A 4.6 x 33 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 4 minutes; flow rate = 3 ml / minute; Observation wavelength = 220 nm. Method G: YMC-PACK ODS-A 4.6 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 2 minutes; flow rate = 2.5 ml / minute; Observation wavelength = 220 nm. Method H: C18 4.6 x 20 mm; Solvent A = water at 90%, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% for 2 minutes; flow rate = 2 ml / minute; Observation wavelength = 220 nm. Method I: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 10 to 100% for 4 minutes; flow rate = 2 ml / minute; Observation wavelength = 220 nm. Method J: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = H20, 0.1% TFA; Solvent B = MeOH, 0.1% TFA; B% from about 10 to about 90% for 4 minutes; flow rate = 2 ml / minute; Observation wavelength = 220 nm. Method K: Sunfire C18 50 mm x 4.6 mm x 3.5 um; Solvent A = 10 mM NH4OAc in water; Solvent B = MeCN; B% from 10 to 95% for 2 minutes; flow rate = 4.5 ml / minute; Observation wavelength = 220 nm. Method L: Sunfire C18 50 mm x 4.6 mm x 3.5 um; Solvent A = 10 mM NH4OAc; Solvent B = MeCN; B% of 2 a % for 0.8 minutes, then 95% B for 2 minutes; flow rate = 4.5 ml / minute; Observation wavelength = 220 nm. Method M: YMC-PACK ODS-A 4.6 x 33 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = MeOH at 90%, water at 10%, TFA at 0.1%; B% from 0 to 100% for 5 minutes; flow rate = 2.5 ml / minute; Observation wavelength = 254 nm. Method N: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = H20, 0.1% TFA; Solvent B = MeOH, 0.1% TFA; B% from 10 to 90% for 4 minutes; flow rate = 2 ml / minute; observation wavelength = 220 and 254 nm. Method O: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = 90% water, 10% MeOH with 0.1% TFA; Solvent B = 90% MeOH, 10% water with 0.1% TFA; B% from 0 to 100% for 4 minutes; flow rate = 2 ml / minute; observation wavelength = 220 and 254 nm. Method P: Shim-PACK VP ODS 4.6 x 50 mm; Solvent A = 90% H20, 10% MeOH, 0.1% TFA; Solvent B = 10% H20, 90% MeOH, 0.1% TFA; B% from 0 to 100% for 2 minutes; flow rate = 3.5 ml / minute; observation wavelength = 220 and 254 nm. Method Q: Shim VP ODS 4.6 x 50 mm; Solvent A = H20 with 0.1% TFA; Solvent B = MeOH with 0.1% TFA; B% from 0 to 100% for 4 minutes; flow rate = 3 ml / minute; length | Observation wave = 254 nm. Method R: YMC-PACK ODS-A 4.6 x 33 mm; Solvent A = H20, 0.1% TFA; Solvent B = MeOH with 0.1% TFA; B% from 10 to 90% for 3 minutes; flow rate = 2 ml / minute; observation wavelength = 220 and 254 nm. Method S: YMC-PACK ODS-A 3.0 x 50 mm; Solvent A = 90% H20, 10% MeOH, 1% TFA; Solvent B = 10% H20, 90% MeOH, 1% TFA; B% from 10 to 90% for 4 minutes; flow rate = 2 ml / minute; observation wavelength = 220 and 254 nm. 5.4. Synthesis of (S) -2-amino-3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-acid il) phenyl) propanoic A mixture of 2-amino-4,6-dichloro- [1, 3, 5] triazine (200 mg, 1.21 mol), (R) - (+) -1- (2-naphthyl) ethylamine (207 mg, 1.21 mol) and diisopropyl-ethylamine (3.63 mol) was dissolved in 150 ml of 1,4-dioxane. The solution was refluxed at 90 ° C for 3 hours. After completion of the reaction (monitored by LCMS), the solvent was removed and the reaction mixture was extracted with CH2C12 (100 ml) and H20 (100 ml). The organic layer was separated and washed with H20 (2 x 100 ml), dried over Na 2 SO 4, and concentrated in vacuo to provide the crude intermediate. The crude compound was dissolved in 5 ml of MeCN and 5 ml of H20 in a 20 ml microwave reaction vial. To this solution was added L-p-borono-phenylalanine (253 mg, 1.21 mol), sodium carbonate (256 mg, 2.42 mol) and a catalytic amount of dichlorobis (triphenylphosphine) -palladium (II) (42.1 mg, 0.06 mol). The mixture was sealed and stirred in the microwave reactor at 150 ° C for 5 minutes, followed by filtration through celite. The filtrate was concentrated and dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using a solvent system of MeOH / H20 / TFA. The combined pure fractions were evaporated in vacuo and further dried in a lyophilizer to give 238 mg of 2-amino-3- acid. { 4- [4-amino-6- (l-naphthalen-2-yl) -ethylamino) - [1, 3,5] triazin-2-yl] phenyl} -propionic (yield: 46%, LC: Column: YMC-Pack ODS-A 3.0 x 50 mm, B% = 0-100%, slope time = 4 minutes, Flow rate = 2 ml / minute, wavelength = 220, Solvent A = 90:10 water: MeOH weight / 0.1% TFA, Solvent B = 90:10 MeOH: water weight / 0.1% TFA, RT = 2785 minutes, MS: M + 1 = 429). NMR: ^ -NMR (400 MHz, CD3OD): d 1.65 (d, 3H), 3.22-3.42 (m, 2H), 4.3 (m, ÍH), 5.45 (m, ÍH), 7.4 (m, ÍH), 7.6 (m, 4H), 7.8 (m, 4H), 8.2 (m, 2H). 5.5 Alternative Synthesis of (S) -2-amino-3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazine- 2- il) phenyl) propanoic (R) -1- (naphthalen-2-yl) ethyl) cyanoguanidine was prepared by forming a mixture of naphthalene amine (1 equivalent), sodium dicyanide (0.95 equivalents) and followed by 5N HCl (1). equivalent) in n-BuOH: H20 (1: 1). The mixture was refluxed for 1 day in a sealed tube at 160 ° C and the progress of the reaction was monitored by LCMS. After completion of the reaction, the solvent (n-BuOH) was removed under reduced pressure and INN of HCl was added to adjust the pH to a range of 3-5. The aqueous solution was extracted with EtOAc (2 x 100) and the combined organic phase was dried over Na 2 SO 4. The solvent was removed in vacuo to provide the crude product. The compound was purified by ISCO column chromatography using as the solvent system EtOAc: hexane (7: 3 and 1: 1), to obtain a white solid yield 48-71% for 1 g at a scale of 22.5 grams. NMR: XH-NMR (400 MHz, CD3OD): d 1.5 (d, 3H), 5.1 (m, HH), 7.5 (m, 4H), 7.8 (s, HH), 7.9 (m, 2H); LCMS: RT 1.69, M + l: 239, Yield: 71%. The title compound was prepared from (R) -1- (1-naphthalen-2-yl) ethyl) cyanoguanidine according to the method shown in Scheme 6. 5.6. Synthesis of (S) -2-amino-3- (4- (4-amino-6- ((4'-methyl-biphenyl-4-yl) -methylamino) -1,3,5-triazin-2-yl) -phenyl acid propanoic A mixture of 2-amino-4,6-dichloro- [1, 3, 5] triazine (100 mg, 0.606 mol), 4'-methyl-biphenyl-4-yl-methylamine (142 mg, 0.606 mol), and cesium carbonate (394 mg, 1.21 mol) was dissolved in 1,4-dioxane (1.5 ml. ) and H20 (1.5 ml) in a 5 ml microwave vial. The mixture was stirred in the microwave reactor at 100 ° C for 15 minutes. The solvent was removed and the residue was dissolved in CH2C12 (20 ml) and washed with H20. (2 x 20 ml), dried over Na 2 SO 4 and then removed in vacuo. The crude intermediate was then dissolved in 1.5 ml of MeCN and 1.5 ml of H20 in a 5 ml microwave vial.
To this solution was added L-p-borono-phenylalanine (126 mg, 0. 606 mol), sodium carbonate (128 mg, 1.21 mol) and a catalytic amount of dichlorobis (triphenylphosphine) -palladium (II) (21.1 mg, 0.03 mol). The mixture was sealed and stirred in the microwave reactor at 150 ° C for 5 minutes, followed by filtration through celite. The filtrate was concentrated and dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using a solvent system of MeOH / H20 / TFA. The combined pure fractions were evaporated in vacuo and further dried in a lyophilizer to give 21.6 mg of 2-amino-3- acid. { 4- [4-amino-6- [(4'-methyl-biphenyl-4-ylmethyl) -amino] - [1,3,5] triazin-2-yl] phenyl} -propionic (LC: Column: YMC-Pack ODS-A 3.0 x 50 mm, B% = 0-100%, slope time = 4 minutes, Flow rate = 2 ml / minute, wavelength = 220, Solvent A = 90:10 water: MeOH weight / 0.1% TFA, Solvent B = 90:10 MeOH: water weight / 0.1% TFA, RT = 3096 minutes, MS: M + 1 = 455). ^ -NMR (400 MHz, CD3OD): d 2.33 (s, 3H), 3.24-3.44 (m, 2H), 4.38 (m, ÍH), 7.02 (d, 2H), 7.42 (m, 2H), 7.50- 7.60 (m, 6H), 8.22 (m, 2H). 5.7. Synthesis of (S) -2-amino-3- (4- (4-morpholino-6- (naphthalen-2-ylmethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid A mixture of 2, 4-dichloro-6-morpholin-4-yl- [1, 3, 5] triazine hydrochloride (121 mg, 0.516 mol), C-naphthalen-2-yl-methylamine (100 mg, 0.516 mol ), cesium carbonate (336 mg, 1.03 mol) was dissolved in 1,4-dioxane (1.5 ml) and H20 (1.5 ml) in a 5 ml microwave vial. The mixture was stirred in a microwave reactor at 180 ° C for 600 seconds. The solvent was removed and the residue was dissolved in CH2C12 (10 ml) and washed with H20 (2 x 10 ml), dried over Na2SO4 and then in vacuo. The residue was purified by preparative HPLC to provide 20 mg of the intermediate (yield 11%, M + 1 = 356). The intermediate was then dissolved in 0.5 ml of MeCN and 0.5 ml of H20 in a 2 ml microwave vial. To this solution was added L-p-borono-phenylalanine (11.7 mg, 0.0562 mol), sodium carbonate (11.9 mg, 0.112 mol) and a catalytic amount of dichlorobis (triphenylphosphine) -palladium (II) (2.0 mg, 5%). The mixture was sealed and stirred in the microwave reactor at 150 ° C for 5 minutes, followed by filtration through celite. The filtrate was concentrated and dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using a solvent system of MeOH / H20 / TFA. The combined pure fractions were evaporated in vacuo and further dried in a lyophilizer to give 17 mg of 2-amino-3- acid. { 4- [4-morpholin-4-yl-6- [(1-naphthalen-2-ylmethyl) -amino] - [1,3,5] triazin-2-yl] phenyl} -propionic (yield: 63%, LC: Method B, RT = 3,108 minutes, MS: M + 1 = 486). 5.8. Synthesis of (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (2- (trifluoromethyl) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic Tetrabutylammonium fluoride (0.1 ml, 1.0 M solution in tetrahydrofuran) was added to a solution of 2-trifluoromethyl-benzaldehyde (1.74 g, 10 mol) and trifluoromethyltrimethylsilane (TMSCF3) (1.8 ml, 12 mol) in 10 ml of THF at 0 ° C. The formed mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of IN of HCl and stirred overnight. The product was extracted with ethyl acetate (3 x 20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to provide 2.2 g of 1- (2-trifluoromethylphenyl) -2,2,2-trifluoro-ethanol, yield 90%. NaH (80 mg, 60%, 3.0 mol) was added to a solution of 1- (2-trifluoromethylphenyl) -2,2, 2-trifluoro-ethanol (244 mg, 1 mol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mole) was added and then the reaction mixture was heated at 70 ° C for 1 hour. After cooling, 5 ml of water were added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by a rotovap to provide 267 mg of 4-chloro-6- [2,2,2-trifluoro-1- (2-trifluoromethylphenyl) -ethoxy] -pyrimidin-2-ylamine, yield 71%. In a microwave vial, 4-chloro-2-amino-6- [1- (2-trifluoromethylphenyl) -2,2, 2-trifluoroethoxy] pyrimidine (33 mg, 0.1 mol), 4-borono-L- was charged. phenylalanine (31 mg, 0.15 mol) and 1 ml of acetonitrile, 0.7 ml of water, 0.3 ml of IN of aqueous sodium carbonate were added to the previous solution followed by 5 mole percent of dichlorobis (triphenylphosphine) -palladium (II) . The reaction vessel was sealed and heated at 150 ° C for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and then purified by LC preparation to provide 5.6 mg of 2-amino-3- (4-. {2-amino-6- [2,2,2-trifluoro- 1- (2-trifluoromethylphenyl) -ethoxy] -pyrimidin-4-yl.} - phenyl) -propionic acid. XH NMR (400 MHz, CD3OD) d 7.96 (m, 3H), 7.80 (d, J = 8.06 Hz, HH), 7.74 (t, J = 7.91 Hz, HH), 7.63 (t, J = 8.06 Hz, HH ), 7.41 (d, J = 8.3 Hz, 2H), 7.21 (m, HH), 6.69 (s, HH), 3.87 (m, HH), 3.34 (m, HH), 3.08 (m, HH). 5.9. Synthesis of (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1-p-tolylethoxy) pyrimidin-4-yl) phenyl) propanoic acid Tetrabutylammonium fluoride (0.1 ml, 1.0 M solution in tetrahydrofuran) was added to a solution of 4-methyl-benzaldehyde (1.2 g, 10 mol) and TMSCF3 (1.8 ml, 12 mol) in 10 ml of THF at 0 ° C. The formed mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of IN of HCl and stirred overnight. The product was extracted with ethyl acetate (3 x 20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to provide 1.6 g of 1- (4-methylphenyl) -2,2,2-trifluoro-ethanol, 86% yield. NaH (80 mg, 60%, 3.0 mol) was added to a solution of 1- (4-methylphenyl) -2,2,2-trifluoro-ethanol (190 mg, 1 mol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mole) was added and then the reaction mixture was heated at 70 ° C for 1 hour. After cooling, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by a rotovap to provide 209 mg of 4- chloro-6- [(4-methylphenyl) -2,2, 2-trifluoro-ethoxy] -pyrimidin-2-ylamine, yield 66%. A microwave vial was loaded with 4-chloro-2-amino-6- [1- (4-methylphenyl) -2,2, 2-trifluoro-ethoxy] -pyrimidine (33 mg, 0.1 mol), 4-borono-L-phenylalanine (31 mg, 0.15 mol) and 1 ml of acetonitrile, 0.7 ml of water, and aqueous sodium carbonate (0.3 ml, IN) were added to the above solution followed by 5 mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated to 150 ° C for 5 minutes with microwaves. After cooling, the reaction mixture was evaporated to dryness.
The residue was dissolved in 2.5 ml of methanol, then purified by LC preparation to provide 14.6 mg of 2-amino-3- (4-. {2-amino-6- [2, 2, 2-trifluoro- 1- (4-methylphenyl) -ethoxy] -pyrimidin-4-yl.} - phenyl) -propionic acid. 1H NMR (300 MHz, CD3OD) d 7.94 (d, J = 8.20 Hz, 2H), 7.47 (d, J = 7. 24 Hz, 4H), 7.27 (d, J = 8.01 Hz, 2H), 6.80 (s, ÍH), 6.75 (m, ÍH), 4.30 (t, ÍH), 3.21-3.44 (m, 2H), 2.37 (s, 3H). 5.10. Synthesis of (2S) -2-amino-3- (4- (2-amino-6- (1-cyclohexyl-2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid Cyclohexanecarbaldehyde (0.9 g, 5 mol) was dissolved in 10 ml of aqueous 1,4-dioxane to which 200 mg (10 mol) of sodium borohydride was added. The reaction was carried out overnight at room temperature. After completing the reaction, 5 ml of 10% HCl solution was added and the product was extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.8 g of 1-cyclohexyl-2,2,2-trifluoro-ethanol, yield 88%. NaH was added to the solution of l-cyclohexyl-2,2,2-trifluoro-ethanol (182 mg, 1 mol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 2-amino-4 was added, 6-dichloro-pyrimidine (164 mg, 1 mol) and then the reaction mixture was heated at 70 ° C for 1 hour. After cooling, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by a rotovap to provide 202 mg of 4-chloro-6- [1-cyclohexyl-2,2,2-trifluoro-ethoxy] -pyrimidin-2-ylamine, 65% yield. Into a microwave vial was charged 4-chloro-2-amino-6- [l-cyclohexane-2,2,2-trifluoro-ethoxy] pyrimidine (33 mg, 0.1 mol), 4-borono-L-phenylalanine (31 mg, 0.15 mol) and 1 ml of acetonitrile, 0.7 ml of water, 0.3 ml of aqueous sodium carbonate (1M) were added to the previous solution followed by 5 mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes with microwaves. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and the product was purified by LC preparation to provide 4.9 mg of 2-amino-3- (4-. {2 -amino-6- (1-cyclohexyl-2,2,2-trifluoro-ethoxy] -pyrimidin-4-yl.} - phenyl) -propionic XH NMR (300 MHz, CD3OD) d 7.95 (d, J = 8.39 Hz, 2H), 7.49 (d, J = 8.39 Hz, 2H), 6.72 (s, ÍH), 5.90 (m, ÍH), 4.33 (t, ÍH), 3.21-3.44 (m, 2H), 1.73- 2.00 (m, 6H), 1.23-1.39 (m, 5H) 5.11 Synthesis of (S) -2-amino-3- (4- (6- (2-fluorophenoxy) pyrimidin-4-yl) phenyl) propanoic NaH (80 mg, 60%, 3.0 mol) was added to a solution of 2-fluorophenol (112 mg, 1 mol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 4,6-dichloro- pyrimidine (149 mg, 1 mol) and then the reaction mixture was heated at 70 ° C for 1 hour. After cooling, 5 ml of water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by a rotovap to provide 146 mg of 4-chloro-6- (2-fluorophenoxy) -pyrimidine, 65% yield. One microwave vial (2 ml) was charged with 4-chloro-6- [2-fluorophenyl] pyrimidine (33 mg, 0.1 mol), 4-borono-L-phenylalanine (31 mg, 0.15 mol) and 1 ml of acetonitrile , 0.7 ml of water, 0.3 ml of aqueous sodium carbonate (1M) were added to the previous solution followed by 5 mol% of dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and the product was purified by LC preparation to provide 4.9 mg of 2-amino-3- acid. { -. { 2-amino-6- (1-2-fluorophenyl-2,2,2-trifluoro-ethoxy] -pyrimidin-4-yl.} - phenyl) -propionic acid. XH NMR (400 MHz, CD3OD) d 8.74 (s, ÍH), 8.17 (d, J = 8.06 Hz, 2H), 7.63 (s, ÍH), 7.50 (d, J = 8.06 Hz, 2H), 7.30 (m , 5H), 4.33 (m, ÍH), 3.34 (m, ÍH). 5.12. Synthesis of (2S) -2-amino-3- (4- (4- (3- (4-chlorophenyl) piperidin-1-yl) -1,3,5-triazin-2-yl) phenyl) propanoic acid 3- (4-chlorophenyl) piperidine (232 mg, 1 mol) was added to a solution of 2,4-dichlorotriazine (149.97 mg, 1 mol) and 300 mg of diisopropylethyl amine in 10 ml of THF at 0 ° C. The formed mixture was warmed to room temperature and stirred for 1 hour. The product was extracted with ethyl acetate (3 x 20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to provide 328 mg of 2-chloro-4- [3- (4-chlorophenyl) -piperidin-1-yl] - [1, 3,5] triazine. A microwave vial was loaded with 2-chloro-4- [3- (4-chlorophenyl) -piperidin-2-yl] - [1, 3, 5] triazine (62 mg, 0.2 mol), 4-borono-L phenylalanine (60 mg, 0.3 mol), 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.6 ml, 1M) was added to the solution, followed by 5 mole percent of dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes with microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, then purified by LC from Preparation to provide 5.1 mg of 2-amino-3- acid. { -. { 4- [3- (4-chlorophenyl) -piperidin-1-yl] - [1,3, 5] triazil-2-yl} phenyl) -propionic. ? H NMR (400 MHz, CD3C1) d 8.58 (d, 2H), 8. 05 (d, 2H), 7.47 (m, 5H), 4.96 (m, ÍH), 4.23 (m, 2H), 3.21- 3.44 (m, 4H), 2.37 (m, 5H). 5.13. Synthesis of (2S) -2-amino-3- (4- (4-amino-6- (2,2,2-trifluoro-1-phenylethoxy) -1,3,5-triazin-2-yl) phenyl ester propanoic NaH (80 mg, 60%, 3.0 mol) was added to a solution of 2,2,2-trifluoro-1-phenyl-ethanol (176 mg, 1 mol) in 10 ml of anhydrous 1,4-dioxane. The mixture was stirred for 20 minutes, then added to a solution of 2-amino-4,6-dichloro-triazine (164 mg, 1 mol) in 30 ml of 1,4-dioxane at 0 ° C for 1 hour. The reaction mixture was then heated to room temperature. After completing the reaction, 5 ml of water were added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by a rotovap to provide 198 mg of 4-chloro-6- [2,2,2-trifluoro-1-phenyl-ethoxy] - [1, 3, 5] triazine-2-ylamine, 65% yield .
A microwave vial was loaded with 4-chloro-6- [2,2,2-trifluoro-1-phenyl-ethoxy] - [1,3,5] triazine-2-ylamine (33 mg, 0.1 mol), 4 -boron-L-phenylalanine (31 mg, 0.15 mol) and 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to the previous solution followed by mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol then purified by LC preparation to provide 3.2 mg of 2-amino-3- acid. { 4-. { 4-amino-6- (1-phenyl-2,2,2,2-trifluoro-ethoxy] - [1,3,5] triazin-2-yl] phenyl) -propionic acid. XH NMR (300 MHz, CD3OD) d 8.22 (d, J = 8.20 Hz, 2H), 7.52 (m, 2H), 7.33 (m, 5H), 6.62 (m, ÍH), 4.19 (t, ÍH), 3.1 -3.33 (m, 2H). 5.14. Synthesis of (S) -2-amino-3- (5- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-acid il) pyridin-2-yl) propanoic A microwave vial was loaded with 6-chloro-N- [1-naphthalen-2-yl-ethyl] - [1, 3, 5] triazine-2,4-diamine (30 mg, 0.1 mol), protected 2-boc amino-3- acid. { 5- [4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyridin-2-yl] propionic (50 mg, 0.15 mol), 1 ml of acetonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to the solution, followed by 5 mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol then purified by LC preparation to provide 7 mg of boc protected acid 2-amino-3-. { 5- [4-amino-6- (1-naphthalen-2-y1-ethylamino) - [l, 3,5] triazin-2-yl] -pyridin-2-yl} -propionic The above product (7.0 mg) was dissolved in 0.1 ml of 10% TFA / DCM solution for 2 hours to provide 1.1 mg of 2-amino-3- acid. { 3- [4-amino-6- (1-naphthalen-2-yl-ethylamino) - [1,3,5] triazin-2-yl] pyridin-2-ylpropionic acid. XH NMR (300 MHz, CD3C1) d 9.35 (d, HH), 8.57 (m, HH), 7.85 (m, 4H), 7.45 (m, 4H), 6.94 (s, HH), 5.58 (m, HH) , 4.72 (m, 2H), 4.44 (m, ÍH), 1.42 (d, 3H). 5.15. Synthesis of (S) -2-amino-3- (3- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-acid il) -lH-pyrazol-1-yl) propanoic 6-chloro-N- [l-naphthalen-2-yl-ethyl] - [1,3,5] triazine-2,4-diamine (30 mg, 0.1 mol), boc-prptegido amino-3- acid. { 3- [4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyrazol-1-yl] -propionic acid (50 mg, 0.15 mol), 1 ml of acetonitrile and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml and IN) was added to a microwave vial, followed by 5 mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol then purified by LC preparation to provide 6.8 mg of protected boc acid 2-amino-3-. { 3- [4-amino-6- (l-naphthalen-2-yl-ethylamino) - [1,3,5] triazin-2-yl] -pyrazol-2-yl} -propionic The above product (6.8 mg) was stirred in 0.1 ml of 10% TFA / DCM solution for 2 hours to provide 3 mg of 2-amino-3- acid. { 3- [4-amino-6- (1-naphthalen-2-yl-ethylamino) - [1, 3,5] triazin-2-yl] pyrazol-2-yl} propionic 1 H NMR (300 MHz, CD 3 Cl) d 8.52 (s, H H), 8.21 (s, H H), 7.74 (m, 4 H), 7.36 (m, 3 H), 5.35 (m, H H), 4.72 (m, 2 H) , 4.44 (m, ÍH), 1. 55 (d, 3H). 5.16. Synthesis of (S) -2-amino-3- (4 '(3- (cyclopentyloxy) -4-methoxybenzylamino) biphenyl-4-yl) propanoic acid Sodium triacetoxyl borohydride (470 mg, 2.21 mol) was added to a solution of 4-bromo-phenylamine (252 mg, 1.47 mol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (324 mg, 1.47 mol) was added. 10 ml of 1,2-dichloroethane (DCE), 0.5 ml of HOAc. The mixture was stirred overnight at room temperature, followed by the addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed by a rotovap to provide 656 mg of crude (4-bromo-phenyl) - (3-cyclopentyloxy-4-methoxy-benzyl) -amine. This was used for the next step without further purification. An Emrys process vial (2-5 ml) was charged for microwaves, with (4-bromo-phenyl) - (3-cyclopentyloxy-4-methoxy-benzyl) amine (84 mg, 0.22 mol), 4-borono-L -phenylalanine (46 mg, 0.22 mol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 mL, 1M) was added to the above solution, followed by 5 mole percent dichlorobis- (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol was purified by LC preparation to provide 5 mg of 2-amino-3- [4 '- (3-cyclopentyloxy-4-methoxy-benzylamino) -biphenyl-4-yl] - Propionic, yield 5%. X H NMR (400 MHz, DMSO-d 6): d 1.46 (m, 2 H), 1.62 (m, 4 H), 3.01 (m, 2 H), 3.64 (s, 3 H), 4.14 (s, 3 H), 4.66 (m , ÍH), 6.61 (d, 2H), 6.82 (s, 2H), 6.88 (s, ÍH), 7.18 (d, 2H), 7.31 (d, 2H), 7.44 (d, 2H), 7.60 (m, ÍH), 8.19 (s, 3H). 5.17. Synthesis of (S) -2-amino-3- (4- (6- (3- (cyclopentyloxy) -4-methoxybenzylamino) pyrimidin-4-yl) phenyl) propanoic acid Sodium triacetoxyl borohydride (985 mg, 4.65 mol) was added to a solution of 6-chloro-pyrimidin-4-ylamine (200 mg, 1.55 mol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (682 mg, 3.1 mol) in 25 ml of DCE. 1 ml of HOAc was added and the mixture was stirred overnight at 50 ° C followed by the addition of 25 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane: EtOAc 5: 1) to provide 64 mg of (6-chloro-pyrimidin-4-yl) - (3-cyclopentyloxy-4) -methoxy-benzyl) -amine, yield 12%. An Emrys process vial (2-5 ml) was charged for microwaves, with (6-chloro-pyrimidin-4-yl) - (3-cyclopentyloxy-4-methoxy-benzyl) amine (64 mg, 0.19 mol), 4 -boron-L-phenylalanine (40 mg, 0.19 mol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 mL, 1M) was added to the above solution, followed by 5 mole percent dichlorobis- (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified by LC preparation to provide 5.3 mg of 2-amino-3- acid. { 4 '- [6- (3-cyclopentyloxy-4-methoxy-benzylamino) -pyrimidin-4-yl] -phenyl} -propionic, 6% yield. X H NMR (400 MHz, DMSO-d 6): d 1.46 (m, 2 H), 1.62 (m, 4 H), 3.01 (m, 2 H), 3.08 (m, 2 H), 3.65 (s, 3 H), 4.20 (m , ÍH), 4.46 (d, 2H), 4.68 (m, ÍH), 6.82 (t, 2H), 6.87 (d, 2H), 7.40 (d, 2H), 7.90 (s, 2H), 8.25 (s, 2H), 8.6 (s, ÍH). . 18 Synthesis of (S) -2-amino-3- (4- (6- (3- (cyclopentyloxy) -4-methoxybenzylamino) pyrazin-2-yl) phenyl) propanoic acid Sodium triacetoxyl borohydride (1315 mg, 6.2 mol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mol) in 50 ml of DCE. 1 ml of HOAc was added and the mixture was stirred overnight at 50 ° C followed by the addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane: EtOAc 6: 1) to give 50 mg of (6-chloro-pyrazin-2-yl) - (3-cyclopentyloxy-4) -methoxy-benzyl) -amine, yield 10%. An Emrys process vial (2-5 ml) was charged for microwaves, with (6-chloro-pyrazin-2-yl) - (3-cyclopentyloxy-4-methoxy-benzyl) amine (50 mg, 0.15 mol), 4 -boron-L-phenylalanine (31 mg, 0.15 mol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to the solution, followed by 5 mole percent dichlorobis- (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and the product was purified by LC preparation to provide 5.5 mg of 2-amino-3- acid. { 4- [6- (3-Cyclopentyloxy-4-methoxy-benzylamino) -pyrazin-2-yl] -phenyl} -propionic, 6% yield. H NMR (400 MHz, DMSO-d6): d 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.0 (m , ÍH), 4.45 (d, 2H), 4.65 (m, ÍH), 6.90 (s, 2H), 6.95 (s, ÍH), 7.32 (d, 2H), 7.60 (t, ÍH), 7.90 (s, ÍH), 7.95 (d, 2H), 8.25 (s, ÍH). 5.19. Synthesis of (S) -2-amino-3- (4- (5- ((4-methylbiphenyl-2-yl) methylamino) pyrazin-2-yl) phenyl) propanoic acid Sodium triacetoxyl borohydride (215 mg, 1.02 mol) was added to the solution of 4 '-methyl-biphenyl-2-carbaldehyde and 5-bromo-pyrazin-2-ylamine in 5 ml of DCE, 0.1 ml of HOAc was added and the mixture was stirred overnight at room temperature environment, followed by the addition of 5 ml of DCE. The organic phase was washed with water, and purified by column (silica gel, hexane: EtOAc 6: 1) to give 100 mg of (5-bromo-pyrazin-2-yl) - (4'-methyl-biphenyl) 2-ylmethyl) -amine, 55% yield. An Emrys process vial (2-5 ml) was charged for microwaves, with (5-bromo-pyrazin-2-yl) - (4'-methyl-biphenyl-2-ylmethyl) -amine (25 mg, 0.071 mol) , 4-borono-L-phenylalanine (22 mg, 0.11 mol) and 1 ml of acetonitrile. Aqueous sodium carbonate (1 ml, 1M) was added to the solution, followed by 5 mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and the product was purified by LC preparation to provide 19 mg of acid 2-amino-3-. { - [6- (3-cyclopentyloxy-4-methoxy-benzylamino) -pyrazin-2-yl] -phenyl} -propionic, 63% yield. 1H NMR (400 MHz, CD3OD): d 2.22 (s, 3H), 3.09 (m, ÍH), 3.25 (m, ÍH), 4.18 (t, ÍH), 4.40 (s, 2H), 7.07 (d, 2H), 7.14 (m 3H), 7.24 (m, 4H), 7.36 (m, ÍH), 7.72 (d, 2H), 7.84 (s, ÍH), 8.20 (d, ÍH). 5.20. Synthesis of (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1-phenylethoxy) -pyrimidin-4-yl) phenyl) propanoic acid NaH (60%, 120 mg, 3.0 mol) was added to a solution of 2,2,2-trifluoro-1-phenyl-ethanol (350 mg, 2.03 mol) in 5 ml of THF. The mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (300 mg, 2.03 mol) was added and then the reaction mixture was heated at 70 ° C for 1 hour. After cooling, the THF was evaporated to give a residue which was dissolved in 15 ml of EtOAc and then washed with water, and dried over sodium sulfate. The solvent was removed by a rotovap to provide 550 mg of 4-chloro-6- (2,2,2-trifluoro-1-phenyl-ethoxy) -pyrimidine, 95% yield. An Emrys process vial (2-5 ml) was charged for microwave, with 4-chloro-6- (2, 2, 2-trifluoro-1-phenyl-ethoxy) -pyrimidine (30 mg, 0.11 mol), 4-borono-L-phenylalanine (32 mg, 0.16 mol), 1 ml of acetonitrile and 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, 1M) was added to the above solution, followed by 10 mole percent of POPd2 (dihydrogen di-u-chlorodichlorobis (di-tert-butylphosphinite-kP) dipaladate. was heated at 120 ° C for 30 minutes by microwaves.
After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and the product was purified by LC preparation to provide 4.8 mg of 2-amino-3- acid. { 4- [6- (2, 2, 2-trifluoro-1-phenyl-ethoxy) -pyrimidin-4-yl] -phenyl} -propionic, performance 11% LH NMR (400 MHz, CD3OD): d 3.20 (m, ÍH), 3.40 (m, ÍH), 4.25 (t, ÍH), 6. 82 (dd, ÍH), 7.43 (m, 5H), 7.57 (s, ÍH), 7.60 (m, 2H), 8.10 (d, 2H), 8.75 (s, ÍH). 5.21. Synthesis of (2S) -2-amino-3- (4- (6- (1- (3, 4-difluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid Tetrabutylammonium fluoride (TBAF: 0.1 ml, 1M) in THF was added to a solution of 3,4-difluoro-benzaldehyde (1.42 mg, 10 mol) and (trifluoromethyl) trimethylsilane (1-70 g, 12 mol) in 10 ml. of THF at 0 ° C. The mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was treated with 12 ml of 1M HCl and stirred overnight. The product was extracted with dichloromethane (3 x 20 ml) the organic layer was combined and passed through a pad of silica gel. The organic solvent is evaporated to provide 1.9 g of 1- (3,4-difluoro-phenyl) -2,2,2-trifluoro-ethanol, yield 90%. NaH (80%, 60 mg, 3.0 mol) was added to a solution of 1- (3,4-difluoro-phenyl) -2,2,2-trifluoro-ethanol (212 mg, 1 mol) in 5 ml of THF , the mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (149 mg, 1 mol) was added and then the reaction mixture was heated at 70 ° C for 1 hour. After cooling, the THF was evaporated. The residue which was dissolved in 15 ml of EtOAc and then washed with water, and dried over sodium sulfate. The solvent was removed by a rotovap to provide 230 mg of 4-chloro-6- [1- (3,4-difluoro-phenyl) -2,2,2-trifluoro-ethoxy] -pyrimidine, yield 70%. An Emrys process vial (2-5 ml) was charged for microwaves, with 4-chloro-6- [1- (3,4-difluoro-phenyl) -2,2,2-trifluoro-ethoxy) -pyrimidine (33 mg, 0.1 mol), 4-borono-L-phenylalanine (31 mg, 0.15 mol), 1 ml of acetonitrile and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to the above solution, followed by 5 mol% of dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 ° C for 5 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and the product was purified by LC preparation to provide 10 mg of 2-amino-3- (4-. {6- [1- (3, 4- difluoro-phenyl) -2,2, 2-trifluoro-ethoxy] -pyridin-4-yl} -phenyl} -propionic, yield 21%. XH NMR (400 MHz, CD3OD): d 3.11 (m, HH), 3.27 (m, HH), 4.19 (dd, HH), 6.78 (q, HH), 7.26 (m, 2H), 7.35 (d, 3H) ), 7.49 (m, 2H), 8.02 (d, 2H), 8.66 (s, ÍH). . 22. Synthesis of (S) -2-amino-3- (4- (5- (3- (cyclopentyloxy) -4-methoxybenzylamino) -pyrazin-2-yl) phenyl) propanoic acid A mixture of 3-cyclopentyloxy-4-methoxy-benzaldehyde (417 mg, 1895 mol), 2-amino-5-bromopyrazine (300 mg, 1724 mol), sodium triacetoxyborohydride (1.5 equivalents) and glacial acetic acid (e equivalents) in dichloromethane (10 ml) was stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated to give the crude product which was purified by ISCO (flash column chromatography of SiO2) (hexane / ethyl acetate = 100/9 to 3/2) to provide approximately 400 mg of 6-bromo- pyrazin-2-yl- (3-cyclopentyloxy-4-methoxy-benzyl) -amine. Yield: 61%. To a 5 ml microwave vial, the above were added 6-bromo-pyrazin-2-yl- (3-cyclopentyloxy-4-methoxy-benzyl) -amine (50 mg, 0.132 mol), 4-borono-L- phenylalanine (30 mg, 0.144 mol), Na2CO3 (31 mg, 0.288 mol), acetonitrile (2 ml) and water (2 ml), dichlorobis (triphenylphosphine) -palladium (5 mg, 0.007 mol). The vial was capped and stirred at 150 ° C for 5 minutes under microwave radiation. The reaction mixture was cooled, was filtered through a syringe filter and then separated by reverse phase preparation HPLC using a 100 x 30 mm ID column YMC-Pack ODS (MeOH / H20 / TFA solvent system). The pure fractions were concentrated in vacuo. The product was then suspended in 5 ml of water, frozen and lyophilized to provide the title compound as a trifluoro salt (12 mg, 20%). XH NMR (CD3OD) d 8.41 (s, ÍH), 7.99 (s, ÍH), 7.83 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 6.0 Hz, 2H), 6.90-6.95 (m, 3H), 4.78 (m, ÍH), 4.50 (s, 2H), 4.22-4.26 (m, ÍH), 3.79 (s, 3H), 3.12-3.39 (m, 2H), 1.80-1.81 (m, 6H) , 1.60 (m, 2H). M + 1 = 463. 5.23. Synthesis of (S) -2-amino-3- (4- (5- ((3- (cyclopentyloxy) -4-methoxybenzyl) - (methyl) amino) pyrazin-2-yl) phenyl) propanoic acid To a solution of (6-bromo-pyrazin-2-yl) - (3-cyclopentyloxy-4-methoxy-benzyl) -amine (70 mg, 0.185 mol) in acetonitrile (10 ml) was added formaldehyde (18.5 mol) and sodium cyanoborohydride (17 mg, 0.278 mol). Aqueous concentrated HCl was then added dropwise until the pH = 2. The mixture was stirred for about 6 hours at room temperature. It was then diluted with ethyl acetate, washed with water (3 x 5 ml), dried over MgSO4. The solvent was removed in vacuo to provide 70 mg of the crude product 5- (bromo-pyrazin-2-yl) - (3-cyclopentyloxy-4-methoxy-benzyl) -methyl-amine (95% crude yield), which was used in the next stage without further purification. 5- (Bromo-pyrazin-2-yl) - (3-cyclopentyloxy-4-methoxy-benzyl) -methyl-amine (37 mg, 0.094 mol) was subjected to a Suzuki coupling reaction as described above to produce 6 mg of the title compound. Yield: 13%. 1R NMR (CD3OD) d 8.59 (s, ÍH), 8.12 (s, ÍH), 7.85 (d, 2H), 7.39 (d, 2H), 6.81-6.91 (m, 3H), 4.72 (m, ÍH), 4.30 (m, ÍH), 3.79 (s, 3H), 3.20-3.40 (m, 2H), 3.18 (s, 3H), 3.79 (s, 3H), 1.80 (m, 6H), 1.58 (m , 2H). M + 1 = 477. 5.24. Synthesis of (S) -2-amino-3- (4- (5- ((1,3-dimethyl-lH-pyrazol-4-yl) methylamino) pyrazin-2-yl) phenyl) propanoic acid A mixture of 1,3-dimethyl-lH-pyrazole-4-carbaldehyde (142 mg, 1145 mol), 2-amino-5-bromopyrazine (200 mg, 1149 mol), borane trimethylamine complex (126 mg, 1.73 mol) and glacial acetic acid (137 mg, 2.29 mol) in anhydrous methanol (3 ml) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed with water, dried with MgSO 4 and filtered. The filtrate was concentrated to provide 300 mg of (5-bromo-pyrazin-2-yl) - (1,3-dimethyl-lH-pyrazol-4-ylmethyl) amine as crude product, which was used for the next step without purification additional. Crude yield: 93%. The (5-bromo-pyrazin-2-yl) - (1,3-dimethyl-lH-pyrazol-4-ylmethyl) amine (40 mg, 0.142 mol) was used in the above-described Suzuki coupling reaction to provide 19 mg of the title compound. Performance: 36.5%. : H NMR (CD3OD) d 8.48 (s, ÍH), 8.05 (s, ÍH), 7.87 (d, 2H), 7.39 (d, 2H), 6. 10 (s, ÍH), 4.81 (s, 2H), 4.30 (m, ÍH), 3.83 (s, 3H), 3.11- 3.38 (m, 2H), 2.10 (s, 3H). M + 1 = 367. 5.25. Synthesis of (S) -2-amino-3- (4- (4-amino-6 ((S) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yloxy acid phenyl) propanoic To a 250 ml flask was added R - (+) - l- (2-naphthyl) ethylamine (400 mg, 2.424 mol), 2-amino-4,6-dichloro triazine (373 mg, 2181 mol), , Anhydrous 4-dioxane (40 ml) and N, N-diisopropylethylamine (1 ml, 5.732 mol) and heated to gentle reflux for about 4 hours. The reaction was carefully monitored in order to avoid the formation of the disubstituted product. (It was observed that the longer the reaction, the more the disubstituted product formed).
After 4 hours, the reaction mixture was cooled and the solvent was removed under reduced pressure. Water was added to the residue, and the solution was sonic for 2-3 minutes. The solvent was then filtered, washed with water and dried to provide 540 mg (83% crude yield) of the mono-chloride, 6-chloro-N- (1-naphthalen-2-yl-ethyl) - [1,3,5] triazine-2, 2-diamine, which was used for the next step of the reaction without further purification. A mixture of 6-chloro-N- (l-naphthalen-2-yl-ethyl) - [1, 3, 5] triazine-2, 2-diamine (90 mg, 0.300 mol), tert-butyl ester of 2-acid 3-tert-butoxycarbonylamino-3- (4-hydroxy-phenyl) -propionic acid (102 mg, 0.303 mol) and potassium carbonate (82 mg, 0.594 mol) in isopropanol (8 ml) was refluxed overnight. The solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. The solid was filtered and washed with ethyl acetate. The filtrate was concentrated and then redissolved in a methanol / water mixture (90:10) and purified by a preparative LC using a 100 x 30 mm ID column Sunfire C18 OBD (MeOH solvent system / H20 / TFA ). The pure fractions were combined and concentrated to provide 50 mg of the crude product, tert-butyl ester of 3- acid. { 4- [4-amino-6- (1-naphthalen-2-yl-ethylamino) - [1,3,5] triazin-2-yloxy] -phenyl} 2-tert-butoxycarbonylamino-propionic, (28% yield). The above product (50 mg, 0.083 mol) was dissolved in trifluoroacetic acid / dichloromethane (8 ml / 2 ml) and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was then redissolved in a methanol / water mixture (90:10) and purified by a preparation LC using a 100 x 30 mm ID column Sunfire C18 OBD (MeOH / H20 / TFA solvent system). The pure fractions were combined and concentrated to provide about 4 ml, which were frozen and lyophilized to give 4 mg of the title compound as a TFA salt (11% yield). XH NMR (CD3OD) d 7.37-7.81 (m, 8H), 7.19 (m, 2H), 6.98 (m, HH), 5.37 (m, HH), 4.19 (m, HH), 3.17-3.38 (m, 2H) ), 1.56 (m, 3H). M + 1 = 445. 5.26 Synthesis of (S) -2-amino-3- (4- (4-amino-6- ((R) -1- (biphenyl-2-yl) -2, 2, 2 acid -trifluoroethoxy) -1, 3, 5-triazin-2-yl) phenyl) propanoic A mixture of l-biphenyl-2-yl-2,2,2-trifluoro-ethanone (300 mg, 1.2 mol), complexes of borane tetrahydrofuran (1.2 ml, 1M in THF, 1.2 mol) and S-2-methyl- CBS-oxazaborolidine (0.24 ml, 1M in toluene, 0.24 mol) in THF (8 ml) was stirred at room temperature overnight.
Several drops of concentrated HCl were added and the mixture was stirred for 30 minutes. The product was purified by Si02 chromatography (hexane / ethyl acetate = 100/0 in 3/1) to give 290 mg of l-biphenyl-2-yl-2,2,2-trifluoroethanol (96% yield). The above alcohol (290 mg, 1151 mol) was dissolved in anhydrous THF (10 ml). Sodium hydride (55 mg, 1375 mol) was added in one portion and the mixture was stirred at room temperature for 30 minutes. The solution was then transferred to a flask containing a suspension of 2-amino-4,6-dichloro-triazine (190 mg, 1152 mol) in THF (20 ml). The mixture was stirred at room temperature overnight. Water was added and the mixture was then diluted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and then concentrated to give 400 mg of the crude product 2-amino-4- (1-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-). chloro-triazine The 2-amino-4- (1-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine (40 mg, 0.105 mol) was subjected to the same coupling reaction Suzuki as described above to provide 5 mg of the title compound Yield: 9.4% XH NMR (CD3OD) d 8.18 (d, 2H), 7.86 (m, ÍH), 7.40-7.52 (m, 9H), 7.32 ( m, HH), 7.07 (m, HH), 4.32 (m, HH), 3.22-3.41 (m, 2H), M + 1 = 510. 5.27 Synthesis of (2S) -2-amino-3- ( 4- (4-amino-6- (1- (6,8-difluoronaphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid In a three neck flask, copper iodide (299 mg, 1515 mol) and lithium chloride (LiCl) (145 mg, 3452 mol) were added under nitrogen to anhydrous THF (60 ml). The mixture was stirred at room temperature until a pale yellow solution was obtained. After cooling to 0 ° C, methyl vinyl ketone and chlorotrimethylsilane were added and the mixture was stirred until an orange color was observed (-20 minutes). After cooling to about -40 ° C, a solution of 3,5-difluorophenylmagnesium bromide (27.65 mL, 13.8 mol) in THF (0.5 M) was slowly added. The reaction mixture was stirred at about -40 ° C for 0.5 hours, then the cold bath was removed and the temperature was allowed to rise slowly to room temperature. The solvent was evaporated and the residue was extracted with hexane (4 x 20 ml). The collected extractions were washed with 10% aqueous NaHC03 and dried over Na2SO4. The solvent was evaporated under reduced pressure to produce 3,5-difluorophenyl-1-trimethylsilyloxyalkene (2.03 g, 7.929 mol, crude yield 57%), which was used in the successive reaction without further purification. Energized calcium carbonate (3,806 g, 38. 06 mol) and ethyl vinyl ether (2184 g, 30,329 mol) were added to a solution of ceric ammonium nitrate (10,430 g, 19,033 mol) in methanol (40 ml) under a nitrogen atmosphere. To the resulting suspension was added a solution of the 3,5-difluorophenyl-1-trimethylsiloxyalkene prepared above (2.03 g, 7.929 mol) in ethyl vinyl (6 ml, 4.518 g, 62.75 mol) by dripping under vigorous stirring, and the mixture was added dropwise. stirred at room temperature overnight. The solid was filtered through a celite layer, and the filtrate was concentrated to a quarter of its initial volume. The resulting thick mixture was slowly emptied, under vigorous stirring, in 1: 1 v / v 10% aqueous diethyl ether-NaHCO 3. The precipitate was filtered, the ether solution was separated and the solvent was evaporated under reduced pressure to provide a clear liquid. The resulting liquid solution (a mixture of acyclic and cyclic acetates) in methanol (4 ml) was added dropwise to a suspension of dichlorodicyanobenzoquinone (1.77 g, 7.797 mol) in 80% aqueous sulfuric acid at 0 ° C. After completing the addition, the ice bath was removed and stirring continued for 30 minutes. The mixture was poured into ice water and the resulting brown precipitate was filtered and dissolved in acetone. Silica gel was added to form a stopper and the crude product was purified by chromatography (hexane / ethyl acetate = 100/0 in 3/1) to provide 760 mg of 1- (5,7-difluoro-naphthalene-2-yl) -etanone (48% two stage yield) as a light yellow solid. The above ketone (760 mg, 3,689 mol) was dissolved in methanol (40 ml). Then, ammonium acetate (2.841 g, 36.896 mol), sodium cyanoborohydride (232 mg, 3.389 mol) and molecular sieves (3 A, 7.6 g) were added. The mixture was stirred at room temperature for two days. The solid was filtered and the filtrate was concentrated. The residue was dissolved in water and aqueous concentrated HCl was added by dropping to a pH = 2. The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other by-products. The water layer was basified to a pH = 10 with aqueous sodium hydroxide (1M) and extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to yield 290 mg of 1- (5M). , 7-difluoronaphthalen-2-yl) -ethylamine (38% yield). The freshly prepared amine (290 mg, 1,401 mol) was added directly to a suspension of 2-amino-4,6-dichloro triazine (277 mg, 1678 mol) in anhydrous 1,4-dioxane (60 ml), and followed by addition of N, N-diisopropylethylamine (1 ml, 5.732 mol). The mixture was heated to gentle reflux for about 3 hours. The reaction mixture was then cooled and the solvent was removed under reduced pressure. Water was added to the residue and the mixture was sonicated for 2-3 minutes. The resulting solid was filtered and washed with water, and dried to provide 395 mg (crude yield 60%) of 6-chloro-N- [1-6, 8-difluoro-naphthalen-2-yl-ethyl] - [1, 3, 5] triazine-2, 4 -diamine, which was used for the next reaction stage directly without further purification. The above-prepared monochloride (48 mg, 0.144 mol) was subjected to the same Suzuki coupling reaction as described above to produce .12 mg of the title product. Yield: 17.9%. ? ti NMR (CD3OD) d 8.14-8.22 (m, 2H), 8.05 (m, ÍH), 7.92 (m, ÍH), 7.63 (m, ÍH), 7.32-7.51 (m, 3H), 7.11 (m, ÍH), 5.48 (m, ÍH), 4.13 (m, ÍH), 3.13-3.41 (m, 2H), 1.66 (d, 3H). M + 1 = 465. 5.28. Synthesis of (2S) -2-amino-3- (4- (4-amino-6- (2, 2, 2-trifluoro-1- (3 '-methylbiphenyl-2-yl) ethoxy) -1, 3 , 5-triazin-2-yl) phenyl) propanoic To a mixture of 3 '-methyl-1-biphenyl-2-carbaldehyde (500 mg, 2551 mol) and trifluoromethyl trimethylsilane (435 mg, 3. 061 mol) in THF (3 ml) was added terabutil ammonium fluoride (13 mg, 0.05 mol) at 0 ° C. The temperature was allowed to warm to room temperature. The mixture was stirred during hours at room temperature, then diluted with ethyl acetate, washed with water and brine and dried by MgSO4. The solvent was removed under reduced pressure to provide 660 mg (crude yield 97%) of 2,2,2-trifluoro-1- (3'-methyl-biphenyl-2-yl) -ethanol as crude product which was used for the next stage without further purification. The above alcohol (660 mg, 2.481 mol) was dissolved in anhydrous 1,4-dioxane (10 ml). Sodium hydride (119 mg, 60% in mineral oil, 2975 mol) was added at once and the mixture was stirred at room temperature for 30 minutes. The solution was transferred to a flask containing a suspension of 2-amino-, 6-dichloro-triazine (491 mg, 2,976 mol) in 1,4-dioxane (70 ml). The mixture was stirred at room temperature for 6 hours. The solvent was removed and the residue was suspended in ethyl acetate, which was washed with water, dried over MgSO4 and then concentrated to provide 790 mg of the crude product containing about 57% of the desired product 2-amino-4- (1 - (3'-methyl-biphenyl-2-yl-2,2,2,2-trifluoro-ethoxy-6-chloro-triazine and approximately 43% by-products (the bisubstituted product) The crude product was used without further purification The 2-amino-4- (l- (3'-methyl-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine (98 mg, 57% purity, 0.142. mol) was used to effect the same Suzuki coupling reaction as described above to provide 9 mg of the title compound. Yield: 12.0%. XH NMR (CD3OD) d 8.09 (m, 2H), 7.85 (m, 1H), 7.50 (m, 2H), 7.28-7.43 (m, 5H), 7.17-7.26 (m, 2H), 7.18 (m, 1H) ), 3.85 (m, ÍH), 3.08-3.44 (m, 2H), 2.33 (s, 3H). M + 1 = 524. 5.29. Synthesis of (S) -2-amino-3- (4- (5- (3,4-dimethoxyphenylcarbamoyl) -pyrazin-2-ylphenyl) propanoic acid To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mol) and triethylamine (0.557 ml, 4 mol) in dichloromethane (20 ml) was added 5-chloro-pyrazine-2-carbonyl chloride (0.354 g, mol) at 0-5 ° C. The mixture was allowed to stir at room temperature for 3 hours. The mixture was diluted with methylene chloride (20 ml), washed with saturated NaHCO 3 (20 ml), brine (20 ml), dried (anhydrous Na 2 SO 4) and concentrated to obtain 0.42 g of 5-chloro-pyrazine- Crude 2-carboxylic acid (3,4-dimethoxy-phenyl) -amide, which was used directly in the next reaction.
The crude 5-chloro-pyrazine-2-carboxylic acid (3,4-dimethoxy-phenyl) -amide (0.18 g, 0.61 mol), Lp-bromo phenylalanine (0.146 g, 0.70 mol), CH 3 CN (2.5 ml) were combined. , H20 (2.5 ml), Na2CO3 (0.129 g, 1.22 mol) in a microwave vial. The mixture was sealed and maintained at 150 ° C for 5 minutes. The mixture was filtered and concentrated. The residue was dissolved in methanol / water (1: 1) and purified by preparative HPLC using MeOH / H20 / TFA as a solvent system to produce 2-amino-3- acid. { - [5- (3, 4-dimethoxy-phenylcarbonyl) -pyrazin-2-yl] -phenyl} -propionic as TFA salt (HPLC: Method A, Retention time = 2846 minutes, LCMS M + l 423). XH NMR (400 MHz, DMSO-d6) d 3.10-3.30 (m, 2H), 3.72 (d, 6H), 4.05 (m, ÍH), 7.42-7.62 (m, 4H), 8.22 (m, 3H), 9.30 (m, 2H). 5.30. Synthesis of (S) -2-amino-3- (4- (2-amino-6- (4- (2- (trifluoromethyl) phenyl) -piperidin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid 2-Amino-4,6-dichloro pyrimidine (0.164 g, 1 mol), 4- (2-trifluoromethyl-phenyl) hydrochloride - was dissolved piperidine (0.266 g, 1 mol), and cesium carbonate (0.684 g, 2.1 mol) in a mixture of 1,4-dioxane (5 ml) and H20 (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210 ° C for 20 minutes in a microwave reactor. The solvent was removed and the residue was dissolved in 5% methanol in CH2C12 (20 ml), dried over Na2SO and concentrated to obtain the crude intermediate 4-chloro-6- [4- (2-trifluoromethyl-phenyl) - piperidin-1-yl] -pyrimidin-2-ylamine (0.42 g) which was used directly in the next step. The crude intermediate (0.42 g), Lp-borono-phenylalanine (0.209 g, 1 mol), sodium carbonate (0.210 g, 2 mol) and dichlorobis (triphenylphosphine) -palladium (II) (35 mg, 0.05 mol) were dissolved in a mixture of MeCN (2.5 ml) and H20 (2.5 ml) in a 10 ml microwave vial. The vial was sealed and stirred in a microwave reactor at 150 ° C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using MeOH / H20 / TFA as the solvent system to provide 2-amino-3- (4-. {4- (2 -trifluoromethyl-phenyl) -piperidin-1-yl] -pyrimidin-4-yl.} - phenyl) -propionic acid as a TFA salt. HPLC: Method A, Retention time = 3,203 minutes. LCMS M + l 486.: H NMR (400 MHz, CD3OD) d 1.80-2.20 (m, 5H), 3.0-3.16 (m, 2H), 3.22-3.42 (m, 2H), 4.22 (t, ÍH), 4.42-4.54 (m, ÍH), 5.22-5.34 (m, ÍH), 6.80 (s, ÍH), 7.40 (t, ÍH), 7.50-7.60 (m, 4H), 7.68 (d, 1H9, 7.82 (d, 2H). 5.31- Synthesis of (S) -2-amino-3- (4- (2-amino-6- ((R)) acid 1-naphthalen-2-yl) ethylamino) pyrimidin-4-yl) phenyl) propanoic acid 2-Amino-4,6-dichloro pyrimidine (0.164 g, 1 mol), (R) - (+) -1- (2-naphthyl) -ethylamine (0.171 g, 1 mol), and cesium carbonate ( 0.358 g, 1.1 mol) in a mixture of 1,4-dioxane (4 ml) and H20 (4 ml) in a 20 ml microwave vial. The vial was sealed and stirred at 210 ° C for 20 minutes in a microwave reactor. The solvent was removed and the residue was dissolved in CH2C12 (50 ml), washed with water (20 ml), brine (20 ml), dried (Na2SO4) and concentrated to obtain the crude intermediate 6-chloro-N- 4- (naphthalen-2-yl-ethyl) -pyrimidine-2,4-diamine (0.270 g) which was used directly in the next step. The crude intermediate (0.27 g), Lp-borono-phenylalanine (0.210 g, 1 mol), sodium carbonate (0.210 g, 2 mol) and dichlorobis (triphenylphosphine) -palladium (II) (25 mg, 0.036 mol) were dissolved in a mixture of MeCN (2.5 ml) and H20 (2.5 ml) in a microwave vial. The vial was sealed and stirred in a microwave reactor at 150 ° C for 6 hours. minutes The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using MeOH / H20 / TFA as the solvent system to provide 2-amino-3- acid. { 4- [2-amino-6- (naphthalen-2-yl-ethylamino) -pyrimidin-4-yl] -phenyl} -propionic as a salt of TFA. HPLC: Method A, Retention time = 3.276 minutes. LCMS M + l 428. XH NMR (400 MHz, CD3OD) d 1.68 (d, 3H), 3.22-3.40 (m, 2H), 4.30 (t, ÍH), 5.60 (q, ÍH), 6.42 (s, ÍH) ), 7.42-7.54 (m, 5H), 7.72 (m, 2H), 7.82-7.84 (m, 4H). 5.32. Synthesis of (S) -2-amino-3- (4- (2-amino-6- (methyl ((R) -1- (naphthalen-2-yl) ethyl) amino) pyrimidin-4-yl) phenyl ester propanoic 2-Amino-4,6-dichloro pyrimidine (0.327 g, 2 mol), methyl- (1-naphthalen-2-yl-ethyl) -amine (0.360 g, 2 mol), and cesium carbonate (0.717 g) were dissolved. , 2.2 mol) in a mixture of 1,4-dioxane (7.5 ml) and H20 (7.5 ml) in a 20 ml microwave vial. The vial was sealed and stirred at 210 ° C for 20 minutes in a microwave reactor. The solvent was removed and the residue was dissolved in CH2C12 (50 ml), washed with water (20 ml), brine (20 ml), dried (Na2SO4) and concentrated to obtain the crude intermediate 6-chloro-N-4-methyl-N-4- (l-naphthalene-2-yl-ethyl) ) -pyrimidine-2,4-diamine (0.600 g) which was used directly in the next step. The crude intermediate (0.30 g), Lp-borono-phenylalanine (0.210 g, 1 mol), sodium carbonate (0.210 g, 2 mol) and dichlorobis (triphenylphosphine) -palladium (II) (25 mg, 0.036 mol) were dissolved in a mixture of MeCN (2.5 ml) and H20 (2.5 ml) in a microwave vial. The vial was sealed and stirred in a microwave reactor at 150 ° C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using MeOH / H20 / TFA as the solvent system to provide 2-amino-3- acid. { 4-. { 2-amino-6- [methyl- (1-naphthalen-2-yl-ethyl) amino] -pyrimidin-4-yl} -phenyl} -propionic as a salt of TFA. (HPLC: Method C, Retention time = 2945 minutes LCMS M + l 442.? H NMR (400 MHz, CD3OD) d 1.70 (m, 3H), 2.92 (s, 3H), 3.22-3.42 (m, 2H ), 4.28 (m, ÍH), 6.60 (s, ÍH), 6.72 (m, ÍH), 7.40-7.92 (m, 11H) 5.33 Synthesis of (S) -2-amino-3- (4-) acid (2-amino-6- ((S) -2,2, 2-trifluoro-1- (6-methoxynaphthalen-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic 2-Amino-4,6-dichloro pyrimidine (0.096 g, 0.6 mol), 2, 2, 2-trifluoro-1- (6-methoxy-naphthalen-2-yl) ethanol (0.140 g, 0.55 mol) was added, NaH (96 mg, 0.60 mol) to anhydrous dioxane (20 ml under a nitrogen atmosphere) The reaction was stirred at 80 ° C for 12 hours, cooled to room temperature and satiated with water (0.2 ml). The reaction mixture was concentrated and the residue was dissolved in CH2C12 (50 ml), washed with water (20 ml), brine (20 ml), dried (Na2SO4) and concentrated to obtain the crude intermediate 4-chloro-6-. [2,2,2-trifluoro-1- (6-methoxy-naphthalen-2-yl) -ethoxy] -pyrimidin-2-ylamine (0.22 g) which was used directly in the next step The crude intermediate (0.22 g) ), Lp-borono-phenylalanine (0.126 g, 0.6 mol), sodium carbonate (0.126 g, 1.2 mol) and dichlorobis (triphenylphosphine) -palladium (II) (15 mg, 0.021 mol) were dissolved in a mixture of MeCN ( 2.0 ml) and H20 (2.0 ml) in a microwave vial The vial was sealed and stirred in a microwave reactor. microwave at 150 ° C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using MeOH / H20 / TFA as the solvent system to provide 2-amino-3- acid. { 4-. { 2-amino-6- [2,2,2-trifluoro-1- (6-methoxy-naphthalen-2-yl) -ethoxy] -pyrimidin-4-yl} -phenyl} -propionic as a salt of TFA.
(HPLC: Method C, Retention time = 3.190 minutes LCMS M + 1 513. XH NMR (400 MHz, CD3OD) d 3.22-3.42 (m, 2H), 3.86 (s, 3H), 4.32 (ÍH), 6.88 (m, ÍH), 6.92 (ÍH), 7.29 (dd, ÍH), 7.26 (s, ÍH), 7.50 (d, 2H), 7.63 (d, ÍH) , 7.80-7.90 (m, 4H), 8.05 (s, ÍH). 5.34. Synthesis of (S) -2-amino-3- (4- (5- (biphenyl-4-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid 4-phenylbenzaldehyde (0.3 g, 1.65 mol) and 2-amino-5-bromopyrazine (0.24 g, 1.37 mol) were treated with Na (OAc) 3BH (0.44 g, 2.06 mol) in dichloromethane (7.0 ml) and acetic acid ( 0.25 ml) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSO4 and concentrated. Chromatography (Si02, EtOAc: Hex, 1: 1) gave 0.18 g of N- (biphenyl-4-ylmethyl) -5-bromopyrazin-2-amine. N- (biphenyl-4-ylmethyl) -5-bromopyrazin-2-amine (60 mg, 0.176 mol), Lp-boronophenylalanine (37 mg, 0.176 mol), palladium triphenyl phosphine dichloride (3.6 mg, 0.0052 mol), Na2C03 was heated. (37 mg, 0.353 mol), acetonitrile (1.25 ml) and water (1.25 ml) in a microwave reactor at 150 ° C for 5 minutes. The mixture was concentrated, dissolved in 1.0 N HCl, washed twice with ether, concentrated and purified by preparative HPLC to provide 41 mg of the title compound. M + 1 = 425; 1 H NMR (CD3OD) d 8.42 (s, HH), 8.05 (s, HH), 7.92 (d, 2H), 7.58 (d, 4H), 7.40 (m, 7H), 4.60 (s, 2H), 4.25 ( m, ÍH), 3.40 (m, ÍH), 3.20 (m, ÍH). 5.35. Synthesis of (S) -2-amino-3- (4- (5-naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid 2-naphthaldehyde (0.6 g, 3.84 mol) and 2-amino-5-bromopyrazine (0.56 g, 3,201 mol) were treated with Na (OAc) 3BH (1.02 g, 4.802 mol) in dichloromethane (15.0 ml) and acetic acid (0.5 ml) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N of NaOH, washed with brine, dried over MgSO4 and concentrated. Chromatography (Si02, EtOAc: Hex, 1: 1) gave 0.49 g of 5-bromo-N- (naphthalen-2-ylmethyl) pyrazin-2-amine. 5-Bromo-N- (naphthalen-2-ylmethyl) pyrazin-2-amine (0.2 g, 0.637 mol), Lp-boronophenylalanine (0.13 g, 0.637 mol), palladium triphenyl phosphine dichloride (13 mg, 0.019 mol) were heated. Na 2 CO 3 (0.13 mg, 1.27 mol), acetonitrile (5 ml) and water (5 ml) in a microwave reactor at 150 ° C for 5 minutes. The mixture was concentrated, dissolved in 1.0 N HCl, washed twice with ether, concentrated, dissolved in methanol, filtered and concentrated to provide 0.12 g of the captioned compound. M + 1 = 399; 1H NMR (CD3OD) d 8.51 (s, ÍH), 8.37 (s, ÍH), 7.90 (m, 6H), 7.50 (m, 5H), 4.85 (s, 2H), 4.30 (t, ÍH), 3.38 ( m, ÍH), 3.22 (m, ÍH). 5.36. Synthesis of (S) -2- (tert-butoxycarbonylamino) -3- (4- (5- (naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid The (S) -2-amino-3- (4- (5- (naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid (0.15 g, 0.345 mol) was treated with triethylamine (87 mg, 0.862 mol). ) and boc-anhydride (84 mg, 0.379 mol) in dioxane (3 ml) and H20 (3 ml) at 0 ° C. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated and partitioned between EtOAc and H20. The aqueous phase was acidified to pH = 1 with 1.0 N HCl and extracted with EtOAc. The organics were combined, washed with brine, dried over MgSO4 and concentrated to yield 48 mg of the captioned compound. 5.37. Synthesis of (S) -2-morpholinoethyl-2-amino-3- (4- (5- (naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoate The (S) -2- (tert-butoxycarbonylamino) -3- (4- (5- (naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid (48 mg, 0.090 mol), 4- was stirred. (2-hydroxyethyl) morpholine (12 mg, 0.090 mol), triethylamine (18 mg, 0.180 mol) and benzotriazole-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP, 18 mg, 0.090 mol), in dichloromethane (3.0 ml ) at room temperature for 5 hours. Additional triethylamine (18 mg, 0.180 mol) and BOP (18 mg, 0.090 mol) were added and the mixture was stirred overnight. The mixture was concentrated and purified by HPLC of Preparation to provide 2 mg of the compound taken up. 5.38. Synthesis of (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3'-fluorobiphenyl-4-yl) ethoxy) pyrimidin-4 acid il) phenyl) propanoic To 4 '-bromo-2, 2,2-trifluoroacetophenone (5.0 g, 19.76 mol) in THF (50 ml) at 0 ° C was added NaBH4 (1.5 g), 39.52 mol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was completed by TLC (CH2C12). The mixture was satiated with H20, rotary evaporated to remove most of the THF and extracted twice with CH2C12. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2C12 to elute the product, and the resulting solution was concentrated to provide 4.65 g of l- (4-bromophenyl) -2,2,2-trifluoroethanol. Yield 92%. To Pd (PPh3) 4 (2.1 g, 1823 mol) was added 3-fluorophenylmagnesium bromide (55 ml, 1.0 M in THF, 55 mol) at 0 ° C for 15 minutes. The ice bath was removed and the mixture it was stirred for 30 minutes. 1- (4-Bromophenyl) -2,2,2-trifluoroethanol (4.65 g, 18.23 mol) in THF (50 ml) was added over 10 minutes. The mixture was heated to reflux for 3 hours and was complete by LC (Sunfire column, TFA). The mixture was cooled, satiated with H20, rotary evaporated to remove most of the THF and extracted three times with CH2CL2. The organics were combined and washed with brine, dried over MgSO4 and concentrated. Chromatography (Si02, CH2C12) gave 4.64 g of 2,2,2-trifluoro-1- (3'-fluorobiphenyl-4-yl) ethanol. Yield 94%. To 2, 2, 2, -trifluoro-1- (3'-fluorobiphenyl-4-yl) ethanol (1.4 g, 5.18 mol) in THF (50 ml) at 0 ° C was added NaH (60% in mineral oil, 0.31 g, 7.77 mol). The ice bath was removed and the mixture was stirred for 30 minutes. One-time 2-amino-4,6-dichloropyrimidine (1.0 g, 6.22 mol) in THF (25 ml) was added. The mixture was heated at 50 ° C for 5 hours. The reaction was completed by LCMS (Sunfire, TFA). The mixture was cooled, satiated with brine and extracted three times with CH2CL2. The organics were combined, washed with brine, dried over MgSO4 and concentrated. Chromatography (Si02, CH2C12) afforded 1.48 g of 4-chloro-6- (2,2,2-trifluoro-1- (3'-fluorobiphenyl-4-yl) ethoxy) pyrimidin-2-amine. Performance 73%. 4-Chloro-6- (2, 2, 2-trifluoro-1- (3 '- fluorobiphenyl-4-yl) ethoxy) pyrimidin-2-amine (0.75 g, 1.89 mol), L-p-boronophenylalanine (0.47 g, 2.26 mol), Pd (PPh3) 2Cl2 (79 mg, 0.113 mol), Na 2 CO 3 (0.44 g, 4.15 mol), acetonitrile (10 ml, and H20 (10 ml) in a 20 ml microwave reactor and heated in the microwave at 150 ° C for 7 minutes.The reaction was completed by LCMS (Sunfire, neutral) .The mixture was concentrated, dissolved in NaOH (20 ml, 0.5 N), filtered, extracted with ether three times and cooled to 0 ° C. 0 ° C, 1.0 N of HCl was added slowly until obtaining a pH of 6.5. The mixture was stirred at 0 ° C for 30 minutes and the product was filtered, dried in the air, treated with an excess of 2.0 N of HCl in ether, concentrated, then triturated with CH2C12 to provide 1.12 g, 99% (purity 95.5%). 385 mg were purified by preparative HPLC (Sunfire, TFA), concentrated, treated with an excess of 1.0 N HCl (aqueous), concentrated to a small volume and lyophilized to provide 240 mg of the captioned compound. M + 1 = 527; 1H NMR d (CD3OD) 7.86 (d, 2H), 7.64 (s, 4H), 7.49 (d, 2H), 7.36 (m, 2H), 7.28 (m, ÍH), 7.02 (m, ÍH), 6.95 ( s, ÍH), 6.75 (q, ÍH), 4.26 (t, ÍH), 3.32 (m, ÍH), 3.21 (m, ÍH). . 39. Synthesis of (S) -2-amino-3- (4- (2-amino-6- (benzylthio) pyrimidin-4-yl) phenyl) propanoic acid The benzylmercaptan (0.14 g, 1.11 mol) was treated with NaH (60% in mineral oil, 67 mg, 1.66 mol) in dry THF (15 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (0.2 g, 1.22 mol) was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with water, then brine, dried over MgSO4 and concentrated to provide 0.11 g of 4- (benzylthio) -6-chloropyrimidin-2-amine. 4- (Benzylthio) -6-chloropyrimidin-2-amine was heated (0.1 g, 0.397 mol), Lp-boronophenylalanine (0.1 g, 0.477 mol), Pd (PPh3) 2Cl2 (17 mg, 0.024 mol), Na2C03 (93 mg, 0.874 mol), MeCN (2.5 ml) and water (2.5 ml) at 150 ° C for 5 minutes in a microwave. The mixture was concentrated and purified by preparative HPLC to provide 0.42 g of the title compound. M + 1 = 381; XH NMR (CD3OD) d 7.8 (d, 2H), 7.37 (t, 4H), 7.23 (m, 2H), 7.16 (m, ÍH), 6.98 (s, ÍH), 4.43 (s, 2H), 4.20 ( t, ÍH), 3.29 (m, ÍH), 3.13 (M, ÍH). 5.40. Synthesis of (S) -2-amino-3- (4- (2-amino-6- (naphthalen-2-ylmethylthio) pyrimidin-4-yl) phenyl) propanoic acid 2-mercaptonaphthalene (0.2 g, 1148 mol) was treated with NaH (60% in mineral oil, 92 mg, 2.30 mol) in dry THF (10 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (0.21 g, 1.26 mol) was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with water, then with brine, dried over MgSO4 and concentrated to give 0.18 g of 4-chloro-6- (naphthalen-2-ylmethylthio) pyrimidin-2-amine. 4-Chloro-6- (naphthalen-2-ylmethylthio) pyrimidin-2-amine (0.1 g, 0.331 mol), Lp-bromophenylalanine (83 mg, 0.397 mol), Pd (PPh3) 2Cl2 (14 mg, 0.020 mol) were heated. ), Na2CO3 (77 mg, 0.729 mol), MeCN (2.5 ml) and water (2.5 ml) at 150 ° C for 5 minutes in a microwave. The mixture was concentrated and purified by preparative HPLC to provide 57 mg of the title compound. M + 1 = 431; XH NMR (CD3OD) d 7.85 (s, ÍH), 7.79 (d, 2H), 7.22 (d, 3H), 7.46 (dd, ÍH), 7.35 (m, 4H), 6.95 (s, ÍH), 4.58 ( s, 2H), 4.17 (m, ÍH), 3.26 (m, ÍH), 3.11 (m, ÍH). 5.41. Synthesis of (2S) -2-amino-3- (4- (2-amino-6- (1- (3, 4-difluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic 3, 5-Difluorophenyl-trifluoromethyl ketone was treated with NaBH 4 (0.18 g, 4.76 mol) in THF (5 ml) for 2 hours. The mixture was satiated with water, extracted with methylene chloride (2 x). The organics were combined, filtered through silica gel and concentrated to provide 0.46 g of 1- (3,4-difluorophenyl) -2,2,2-trifluoroethanol. 1- (3,4-difluorophenyl) -2,2,2-trifluoroethanol (0.1 g, 0.471 mol) was treated with NaH (60% in mineral oil, 38 mg, 0.943 mol) in dry THF (3 ml) during 30 minutes. 2-Amino-4,6-dichloropyrimidine (77 mg, 0.471 mol) was added and the mixture was stirred at 50 ° C for 6 hours. The mixture was satiated with water and extracted with methylene chloride (2 x). The organics were combined, washed with water, then with brine, dried over MgSO4 and concentrated to give 0.14 g of 4-chloro-6- (1- (3,4-difluorophenyl) -2,2,2-trifluoroethoxy. ) -pyrimidin-2-amine. 4-Chloro-6- (1- (3,4-difluorophenyl) -2,2,2-trifluoroethoxy) pyrimidin-2-amine (0.14 g, 0.421 mol) was heated, L-p- bromophenylalanine (110 mg, 0.505 mol), Pd (PPh3) 2Cl2 (18 mg, 0.025 mol), Na2C03 (98 mg, 0.926 mol), MeCN (2.5 ml) and water (2.5 ml) at 150 ° C for 5 minutes in a microwave. The mixture was concentrated and purified by preparative HPLC to provide 74 mg of the title compound. M + 1 = 469; "NMR (CD3OD) d 7.83 (d, 2H), 7.47 (m, ÍH), 7.38 (m, 4H), 7.28 (m, ÍH), 4.21 (t, ÍH), 3.29 (m, ÍH), 3.15 (m, ÍH) 5.42 Synthesis of (2S) -2-amino-3- (4- (2-amino-6 (2,2,2-trifluoro-1- (3'-methylphenyl-2-yl) acid ) ethoxy) pyrimidin-4-yl) phenyl) propanoic To 4 '-bromo-2, 2,2-trifluoroacetophenone (5.0 g, 19.76 mol) in THF (50 ml) at 0 ° C was added NaBH4 (1.5 g, 39.52 mol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was completed by TLC (CH2C12). The mixture was satiated with H20, rotary evaporated to remove most of the THF and extracted 2 times with CH2CL2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica it was washed with CH2C12 to elute the product and the resulting solution was concentrated to provide 4.65 g of l- (4-bromophenyl) -2,2,2-trifluoroethanol. Yield 92%. Combined 1- (4-bromophenyl) -2,2,2-trifluoroethanol (0.13 g, 0.525 mol), m-tolylboronic acid (0.1 g, 0.736 mol), Fibercat (4.28% Pd, 47 mg, 0.0157 mol Pd) , K2C03 (0.22 g, 1576 mol), EtOH (3 ml), and H20 (0.5 ml) and heated at 80 ° C for 4 hours. The reaction was complete by TLC (CH2C12). The mixture was cooled, filtered, concentrated, mixed in CH2C12 and chromatographed on silica gel (CH2C12) to provide 0.1 g of 2,2,2-trifluoro-1 (3'-methyl-biphenyl-2-yl) ethanol. . Performance 72%. Alternatively, 1- (4-bromophenyl) -2,2,2-trifluoroethanol (0.98 g, 3.86 mol), m-tolylboronic acid (0.63 g, 4.63 mol), Pd (PPh3) 2 Cl2 (0.16 g, 0.232 mol Pd ), Na2C03 (0.90 g, 8.49 mol), AcCN (10 ml) and H20 (10 ml) were combined and heated in the microwave at 150 ° C for 10 minutes.
The reaction was complete by TLC (CH2C12). The mixture was cooled, concentrated, mixed in CH2C12, filtered and chromatographed on silica gel (CH2C12) to give 0.80 g of 2,2,2-trifluoro-1- (3'-methylbiphenyl-2-yl) ethanol. Performance: 79%. Alternatively, tetrabutylammoniofluoride (TBAF 1.0 N in THF 13 uL, 3.3 mg, 0.013 mol) was added to a mixture of 3-methyl-biphenyl-2-carboxyaldehyde (0.25 g, 1.27 mol) and trifluoromethyltrimethyl silane (0.25 g, 1.53 mol) in THF (1.5 ml) at 0 ° C. The reaction was warmed to room temperature and stirred for 3 hours. HCl (3.0 N, 2.0 ml) was added and the mixture was added for 3 hours. The mixture was concentrated, dissolved in methylene chloride, filtered through silica gel and concentrated to give 0.15 g of sodium chloride., 2, 2-trifluoro-1- (3 '-methylbiphenyl-2-yl) ethanol. 2, 2, 2-trifluoro-1- (3 '-methylbiphenyl-2-yl) ethanol (0.15 g, 0.563 mol) was treated with NaH (60% in mineral oil, 45 mg, 1.12 mol) in dry THF (5%). ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (92 mg, 0.5633 mol) was added and the mixture was stirred at 50 ° C for 6 hours. The mixture was satiated with water and extracted with methylene chloride (2 x). The organics were combined, washed with water, then with brine, dried over MgSO4 and concentrated to give 0.16 g of 4-chloro-6- (2,2,2-trifluoro-1- (3'-methylbiphenyl-2). -yl) ethoxy) pyrimidin-2-amine. 4-Chloro-6- (2,2,2-trifluoro-1- (3-methyl-biphenyl-2-yl) ethoxy) pyrimidin-2-amine (0.16 g, 0.406 mol), Lp-boronophenylalanine (10 mg, 0.487 mol), Pd (PPh3) 2Cl2 (0.17 g, 0.024 mol), Na2C03 (95 mg, 0.894 mol), MeCN (2.5 ml) and water (2.5 ml) at 150 ° C for 10 minutes in a microwave.
The mixture was concentrated and purified by preparative HPLC to give 105 mg of the compound of Title. M + 1 = 523; XH NMR (CD3OD) d 7.85 (d, 2H), 7.70 (d, ÍH), 7.44 (m, 4H), 7.31 (t, ÍH), 7.21 (m, 2H), 7.10 (m, 2H), 6.87 (m, 4H), 7.31 (m, 2H), 6.87 ( q, ÍH), 6.84 (s, ÍH), 4.25 (t, ÍH), 3.30 (m, ÍH), 3.18 (m, ÍH). 5.43. Synthesis of (S) -2-amino-3- (4- (5- (3- (cyclopentyloxy) -4-methoxybenzylamino) pyridin-3-yl) phenyl) propionic acid Triacetoxyl borohydride (245 mg, 1.16 mol) was added to the solution of 5-bromo-pyridine-3-amine (100 mg, 0.57 mol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (127 mg, 0.57 mol) in 10 ml of 1,2-dichloroethane (DCE), of HOAc (66 uL, 2 equivalents, 1.16 mol), the mixture was stirred overnight at room temperature, followed by the addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure to provide 200 mg of 5-bromo-N- (3- (cyclopentyloxy) -4-methoxybenzyl) pyridin-3-amine, which was used for the next step without further purification. An Emrys process vial (2-5 ml) was charged for microwaves, with 5-bromo-N- (3- (cyclopentyloxy) -4- methoxybenzyl) pyridin-3-amine (40 mg, 0.106 mol), 4-borono-L-phenylalanine (22 mg, 0.106 mol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 mL, 1M) was added to the above solution, followed by 10 mole percent of dichlorobis- (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 180 ° C for 10 minutes with microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified by LC preparation to provide 20 mg of (S) -2-amino-3- (4- (5-3-cyclopentyloxy-4-methoxy-benzylamino) pyridine) acid. 3-yl) phenyl) propanoic. NMR: 1 H NMR (400 MHz, CD3OD): d 1.59 (m, 2H), 1.7 (m, 6H), 3.17 (m, HH), 3.3 (m, HH), 3.75 (s, 3H), 4.2 (dd) , ÍH), 4.39 (s, 2H), 4.7 (m, ÍH), 6.9 (m, 3H), 7.4 (d, 2H), 7.6 (d, 2H), 7.7 (s, ÍH), 7.9 (s, ÍH), 8.15 (s, ÍH): Analytical HPLC: RT 2.69 M + l: 462 (RT: 1285). 5.44. Synthesis of 2-amino-3 (3- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-trlazin-2-yl) phenyl) propanoic acid To a solution of tert-butyl-2- (diphenylmethylene-amino) acetate (400 mg, 1.35 mol) in THF (25 ml) was added a solution of LDA (1.8 M in THF, 2 equivalents, 2.7 mol, new Aldrich bottle) for 5 minutes at -78 ° C and the resulting mixture was stirred for 20 minutes. A solution of 2- (3- (bromomethyl) phenyl) -5,5-dimethyl-1,3,2-dioxaborinone (460 mg, 1.2 equivalents, 1.62 mol) in THF (10 ml) was added dropwise to the mixture of reaction for 5 minutes. The reaction was continued at the same temperature (-78 ° C) for 30 minutes and left for 3 hours at room temperature. The reaction was quenched with saturated NH 4 Cl, followed by the addition of water (30 ml) and extracted with EtOAc (2 x 40 ml). The organic fractions were combined and dried over Na2SO4. The solvent was then concentrated under reduced pressure and crude tert -butyl-3- (3- (5,5-dimethyl-1,2,4-dioxaborinan-2-yl) phenyl) -2- (diphenylmethyleneamino) propionate was purified by column chromatography to provide the product as a semi-solid. An Emrys process vial (20 ml) was charged for microwaves, with (R) -6-chloro-N2- (1- (naphthalene-2-yl) ethyl) -1,3,5-triazine-2, 4- diamine (100 mg, 0.33 mol), tert-butyl-3- (3- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) phenyl) -2- (diphenyl methyleneamino) propanoate (248 mg , 0.5 mol, 1.5 equivalents) and 6 ml of acetonitrile, plus 6 ml of aqueous sodium carbonate (1 M) were added to the previous solution followed by 10 mole percent dichlorobis- (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 190 ° C for 10 minutes with microwaves. After cooling, the The reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml of THF to which 5N of HCl (5 ml) was added. The mixture was refluxed for 2 hours in order to deprotect the benzofone and tert-butyl groups. The reaction mixture was concentrated and dissolved in methanol (8 ml) and purified by LC preparation to provide 15 mg of 2-amino-3- (4- (4-amino-6- ((R) -1) acid. -naphthalene-2-yl) ethylamino) -1, 3,5-triazin-2-yl) phenyl) propanoic acid. NMR: * H NMR (400 MHz, CD3OD): d 1.85 (d, 3H), 3.2-3.45 (m, 2H), 4.37 (m, ÍH), 5.5 (m, ÍH), 7.4 (m, ÍH), 7.6 (m, 4H), 7.9 (m, 4H), 8.18 (m, 2H), analytical HPLC: RT 2.79 M + l: 429 (RT: 1.35). 5.45. Synthesis of 2-amino-3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) -2 acid -fluorophenyl) propanoic To a solution of tert-butyl 2- (diphenylmethylene-amino) acetate (1.1 g, 3.73 mol) in THF (30 ml) was added a solution of LDA (1.8 M in THF, 1 equivalent, 3.73 mol, new bottle of Aldrich ) for 5 minutes at -78 ° C and the resulting mixture was stirred for 20 minutes. A solution of 4-bromo-l- (bromomethyl) -2-fluorobenzene (1 g, 3.74 mol) in THF (10 mL) was added dropwise to the reaction mixture for 5 minutes. The reaction was continued at -78 ° C for 30 minutes, after which it was left at room temperature for 3 hours. The reaction was quenched with saturated NH 4 Cl, after which water (30 ml) was added. The product was extracted with EtOAc (2 x 4 mL) and the organic fractions were combined and dried over Na2SO4. The solvent was concentrated under reduced pressure and crude tert -butyl-3- (4-bromo-2-fluorophenyl) -2- (diphenylmethyleneamino) -propanoate was purified by column chromatography. The product was obtained as a solid. An Emrys process vial (20 ml) was charged for microwaves with tert-butyl 3- (4-bromo-2-fluorophenyl) -2- (diphenylmethylene-amino) propanoate (600 mg, 1.24 mol), Pd (dba) 2 (71 mg, 0.124 mol), PCy3 (35 mg, 0.124 mol), 4, 4, 4 ', 4', 5, 5.5 ', 5' -octamethyl-2, 2 '-bi (1, 3, 2-dioxaborolane (346 mg, 1.1 equivalents, 1.36 mol) and KOAc (182 mg, 1.5 equivalents, 1.86 mol) 20 ml in DMF The reaction vessel was sealed and heated at 160 ° C for 20 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in H20 (30 ml), extracted with EtOAc (2 x 40 ml) and purified with preparative LC to give 220 mg of ter- butyl 2- (diphenylmethyleneamino) -3- (2-fluoro-4- (4, 4, 5, 5-tetamethyl-1,3, 2-dioxaborolan-2-yl) phenyl) propanoate.
An Emrys process vial (5 ml) for microwaves was charged with (R) -6-chloro-N2- (1- (naphthalen-2-yl) ethyl) -1,3,5-triazine-2,4-diamine (67 mg, 0.22 mol), tert-butyl-2- (diphenylmethyleneamino) -3- (2-fluoro-4- (4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) phenyl) propanoate (120 mg, 0.22 mol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 mL, 1M) was added to the above solution followed by 10 mole percent dichlorobis (triphenylphosphine) -palladium (II). The reaction vessel was sealed and heated at 190 ° C for 10 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml of THF, to which 5M of HCl (2 ml) was then added. The mixture was refluxed for 2 hours (deprotection of the benzophenone and tert-butyl groups). After deprotection of two groups, the mixture was concentrated, dissolved in methanol (5 ml), and purified with LC preparation to yield 10 mg of 2-amino-3- (4- (4-amino-6) acid. ((R) -1- (naphthalene-2-yl) amino) -1,3,5-triazin-2-yl) -2-fluorophenyl) propanoic acid. NMR: X H NMR (400 MHz, CD 3 OD): d 1.6 (s, 3 H), 3.07 (m, H H), 3.45 (m, H H), 3.8 (m, H H), 5.45 (m, H H), 7.4 (m , 4H), 7.6 (m, ÍH), 7.8 (m, 4H), 8.08 (m, ÍH), analytical HPLC: RT 2.88, M + l: 447 (RT: 1.44). 5.46. Synthesis of (2S) -2-amino-3- (4- (4-amino-6- (1-adamantyl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid A solution to aaamancin amine? equivalent), 2-amino-4,6-dichloro- [1, 3, 5] triazine (1 equivalent) and diisopropyl ethyl amine (5 equivalents, Aldrich) in anhydrous 1,4-dioxane was refluxed at 130 ° C for 3 hours. After completing the reaction, the dioxane was removed under reduced pressure. The reaction was then cooled to room temperature, water was added and the product was extracted with dichloromethane (2 x 40 ml). The combined organic solution was dried over Na2SO4 and concentrated to produce the product, which was used in the next step without purification. A vial of Emrys process (20 ml) for microwave was loaded with adamantine triazine chloride (200 mg, 0.65 mol), 4-borono-L-phenylalanine (135 mg, 0.65 mol) and 5 ml of acetonitrile. Aqueous sodium carbonate (5 ml, 1M) was added to the above solution followed by 5 mole percent dichlorobis (triphenylphosphine) palladium (II). The reaction vessel was sealed and heated at 190 ° C for 20 minutes by microwaves. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 4 ml of methanol and purified with LC preparation to provide 60 mg (21% yield) of the coupled product. NMR: XH NMR (400 CD3OD): d 1.22 (m, 3H), 1.6-1.8 (m, 12H), 2.01 (d, 3H), 3.25-3.42 (m, 2H), 4.0 (m, ÍH), 4.40 (m, ÍH), 7.6 (d, 2H), 8.2 (d, 2H), analytical HPLC: RT 3.11, M + l: 437 (RT: 1.76). 5.47. Alternative synthesis of (2S) -2-amino-3- (4- (4-amino-6- (1- (adamantyl) ethylamine) -1, 3, 5-triazin-2-yl) phenyl) propanoic acid was prepared adamantane (2-yl) ethyl cyanoguanidine forming a solution of cyanoguanidine (1 equivalent), (S) -2-amino-3- (4-cyanophenylpropanoic acid (1 equivalent) and tertiary potassium butaoxide (3.5 equivalents, Aldrich) in n-BuOH dried, they were vigorously refluxed in a sealed tube for 2 days.After completion of the reaction, the mixture was allowed to cool to room temperature, and the reaction was quenched with water.The solvent was removed under reduced pressure. After allowing to cool to room temperature, the reaction mixture was brought to a pH of 12-14 by adding IN of NaOH, then the impurities were removed while it was extracted with ether: EtOAc (9: 1, 2 x 100 ml). The aqueous solution was cooled to 0 ° C, then 1M of HCl was added to adjust the pH to 7. The light yellow product was slowly emptied into H20, the mixture it was kept in a refrigerator for 30 minutes and the solid was obtained by filtration with 92% purity. The compound was crystallized from MeOH to yield a white solid (> 98% pure, 48-78% yield). XH NMR (400 MHz, CD3OD): d 1.0 (d, 3H), 1.45-1.6 (m, 6H), 4.62-4.8 (m, 4H), 2.0 (m, 2H), 3.3 (m, ÍH), 3.5 (m , ÍH); Analytical HPLC: RT 2.69; M + l: 462 (RT: 1285). The title compound was prepared from adamantane (2-yl) ethyl cyanoguanidine using the method shown in Scheme 6. 5.48. Synthesis of (S) -2-amino-3- (4- (5-fluoro-4- ((R) -1- (naphthalen-2-yl) ethylamino) pyrimidin-2-yl) phenyl) propanoic acid A mixture of (R) - (+) - 1 - (2-naphthyl) ethylamine (102.6 mg, 0.599 mol), 2,4-dichloro-5-fluoro-pyrimidine (100 mg, 0.599 mol) and cesium carbonate (390 mg, 1.2 mol) was dissolved in 1,4-dioxane (3 ml) and H20 (3 ml) in a 10 ml microwave vial. The mixture was stirred in the microwave reactor at 80 ° C for 10 minutes. The residue was dissolved in CH2C12 (50 ml), washed with water (20 ml) and brine (20 ml), dried (Na 2 SO) and concentrated to obtain the crude intermediate 2-chloro-5-fluoro-pyrimidin-4-yl) - (1-naphthalen-2-yl-ethyl) -amine. The crude intermediate (250 mg, 0.83 mol) is dissolved in 6.0 ml of MeCN and 6 ml of H20 in a 20 ml microwave vial. To this solution was added Lp-borono-phenylalanine (173.6 mg, 0.83 mol), sodium carbonate (173.6 mg, 1.66 mol) and a catalytic amount of dichlorobis (triphenylphosphine) -palladium (II) (11-6 mg, 0.0166 mol ). The reaction vial was then sealed and stirred in the microwave reactor at 150 ° C for 7 minutes. The contents were then filtered, and the filtrate was concentrated and dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using MeOH / H20 / TFA as the solvent system. The combined pure fraction was evaporated in vacuo and further dried in a lyophilizer to provide 154 mg of 2-amino-4- acid. { 4- [5-fluoro-4- (naphthalen-2-yl-ethylamino) -pyrimidin-2-yl] -phenyl} propionic NMR: 1 H NMR (400 Mhz, CD 3 OD) d 1.8 (d, 3 H), 3.2-3.4 (m, 2 H), 4.35 (m, H H), 5.7 (q, H H), 7.5 (m, 4 H), 7.6 ( d, ÍH), 7.8-7.9 (m, 4H), 8.1 (d, 2H), 8.3 (d, ÍH), LCMS: M + 1 = 431. 5.49. Synthesis of (S) -2-amino-3- (4- (2-amino-6- (4- (trifluoromethyl) -benzylamino) pyrimidin-4-yl) phenyl) propanoic acid A mixture of trifluoromethyl benzylamine (106.8 mg, 0. 610 mol), 2-amino-4,6-dichloropyrimidine (100 mg, 0.610 mol) and cesium carbonate (217 mg, 1.2 mol) was dissolved in 1,4-dioxane (6 ml) and H20 (6 ml) in a 20 ml microwave vial. The mixture was stirred in the microwave reactor at 210 ° C for 25 minutes. The solvent was then removed. The residue was dissolved in CH2C12 (50 ml), washed with water (20 ml) and brine (20 ml), dried (Na2SO4) and concentrated to obtain the crude intermediate 6-chloro-N-4 '- (trifluoromethyl) -benzyl) -pyrimidine-2,4-diamine. The crude intermediate (150 mg, 0.497 mol) was then dissolved in 3.0 ml of MeCN and 3 ml of H20 in a 10 ml microwave vial. To this solution was added L-p-borono-phenylalanine (104 mg, 0.497 mol), sodium carbonate (150 mg, 0.994 mol) and a catalytic amount of dichlorobis (triphenylphosphine) -palladium (II) (6.9 mg, 0.00994 mol). The reaction vial was then sealed and stirred in the microwave reactor at 150 ° C for 5 minutes. The contents were then filtered, and the filtrate was concentrated and dissolved in MeOH and H20 (1: 1) and purified by preparative HPLC using a solvent system of MeOH / H20 / TFA. The combined pure fractions were evaporated in vacuo and further dried in a lyophilizer to give 2-amino-3- acid. { - [2-amino-6 (4-trifluoromethyl-benzylamino) -pyrimidin-4-yl] -phenyl} propionic NMR: 1 H NMR (300 Mhz, CD 3 OD) d 1-3.3 (m, 2 H), 4.2 (t, 1 H), 4.7 (s, 2 H), 6. 3 (s, ÍH), 7.4-7.5 (m, 4H), 7.6 (d, 2H), 7.7 (d, 2H). LCMS: M + 1 = 432. 5.50. Synthesis of 2-amino-3- (5- (5-phenylthiophen-2-yl) -lH-indol-3-yl) propanoic acid 2-Amino-3- (5-bromo-lH-indol-3-yl) propionic acid (0.020 g, 0.071 mol) was added to a 5 ml microwave vial, which contained 5-phenyl-thiophene-2-acid boronic (0.016 g, 0.078 mol), Na2C03 (0.015 g, 0.142 mol), acetonitrile (1.5 ml) / water (1.5 ml) and dichlorobis (triphenylphosphine) -palladium (3 mg, 0.003 mol). The microwave vial was capped and stirred at 150 ° C for 5 minutes under microwave radiation. The reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparation HPLC using a 100 x 30 mm ID column YMC-Pack ODS (MeOH / H20 / TFA solvent system ). The pure fractions were concentrated in vacuo. The product was then suspended in 5 ml of water, frozen and lyophilized to yield 5 mg of the pure product, 2-amino-3- [5- (5-phenyl-thiophen-2-yl) -lH-indole 3-yl] propionic. ÍH NMR (300 MHz, CD3OD): 3.21-3.26 (m, 2H), 4.25 (q, ÍH), 7.15-7.35 (m, 8H), 7.58 (d, 2H), 7.82 (d, ÍH). . 51. Synthesis of (S) -2-amino-3- (4- (4- (4-phenoxyphenyl) -1H-1,2,3-triazol-1-yl) phenyl) propanoic acid A mixture of l-ethynyl-4-phenoxy-benzene (126 mg, 0. 65 mol) and (S) -3- (4-azido-phenyl) -2-tert-butoxycarbonylamino-propionic acid (200 mg, 0.65 mol) and (S) -3- (4-azido-phenyl) -2 acid -ter-butoxycarbonylamino-propionic acid (200 mg, 0.65 mg) in H20: dioxane (5: 1) was heated at 100 ° C in a sealed tube overnight. After the reaction was complete, 3N HCl (5 ml) was added and the mixture was stirred for 2 hours at 50 ° C. Removal of the solvent gave a crude product which was dissolved in MeOH and purified by preparative HPLC to provide 45 mg of the desired product (yield: 29%). XH NMR (400 MHz, CD3OD): d (ppm) 3.2 (m, HH), 3.4 (m, HH), 4.3 (m, HH), 6.9 (d, 2H), 7.0 (d, 2H), 7.2 ( m, ÍH), 7.3 (d, 2H), 7.4-7.55 (m, 6H), 8.0 (s, ÍH). 5.52. Synthesis of (S) -2-amino-3- (4- (4- (4- (thiophene-2-carboxamido) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) propanoic acid and (S) -2-amino-3- (4- (5- (4- (thiophene-2-carboxamido) phenyl) -lH-l, 2,3-triazol-l-yl) phenyl) propanoic acid A mixture of thiophene-2-carboxylic acid, (4-ethyl-phenyl) amide (117 mg, 0.49 mol) and (S) -3- (4-azido-phenyl) -2-tert-butoxycarbonylamino-propionic acid (150 mg, 0.49 mg) in 5 ml of H20: dioxane (5: 1) was heated at 100 ° C in a sealed tube overnight. After completing the reaction, 3N HCl (5 ml) was added and the mixture was stirred for 2 hours at 50 ° C. Removal of the solvent gave the crude product which was dissolved in MeOH and purified by preparative HPLC. According to LCMS (retention time) and NMR, two regio-isomers were obtained (total yield: 70 mg, 66%). The main product is (S) -2-amino-3- (4- (4- (4- (thiophene-2-carboxamido) phenyl) -1H-1,2,3-triazol-1-yl) phenyl) propanoic NMR: H NMR (400 MHz, CD3OD): d 3.2 (m, HH), 3.4 (m, HH), 4.3 (m, HH), 7.15 (m, HH), 7.3 (d, 2H), 7.6 (m , 4H), 7.0 (m, 3H), 7.95 (d, ÍH), 8.0 (s, ÍH). the product minor is (S) -2-amino-3- (4- (5- (4- (thiophene-2-carboxamido) phenyl) -1 H-1,2,3-triazol-1-yl) phenyl) propanoic acid. XH NMR (400 MHz, CD3OD): d 3.2 (m, HH), 3.4 (m, HH), 4.35 (m, HH), 7.2 (m, HH), 7.3 (d, 2H), 7.5-7.6 (m , 4H), 7.75 (m, 3H), 7.95 (d, ÍH), 8.05 (s, ÍH). 5.53. Synthesis of (S) -2-amino-3- (4- (2-amino-6- (phenylethynyl) pyrimidin-4-yl) phenyl) propanoic acid 2-amino-4,6-dichloro pyrimidine (0.180 g, 1.1 mol), trimethyl-phenylethynyl-stannane (0.264 g, 1 mol) was dissolved in THF (20 ml) and the mixture was stirred at 65 ° C for 12 hours . The LCMS indicated that the reaction was complete. The solvent was removed and the residue was used directly in the next step. The crude intermediate (0.42 g), Lp-borono-phenylalanine (0.210 g, 1 mol), sodium carbonate (0.210 g, 2 mol) and dichlorobis (triphenylphosphine) -palladium (II) (25 mg, 0.036 mol) were dissolved. in a mixture of MeCN (3 ml) and H20 (3 ml) in a 10 ml microwave vial. The vial was sealed and stirred in the microwave reactor at 150 ° C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue it was purified by preparative HPLC using MeOH (H20) TFA as the solvent system to obtain (S) -2-amino-3- [4- (2-amino-6-phenylethynyl-pyrimidin-4-yl) phenyl] propionic acid. as a salt of TFA. 1tt NMR (400 MHz, CD3OD): d (ppm) 3.20-3.42 (m, 2H), 4.31 (m, ÍH), 7.40-7.51 (m, 6H), 7.62 (d, 2H), 8.18 (d, 2H ). 5.54. Additional Compounds Additional compounds using methods known in the art and / or described herein are listed below: . 55. Inhibition assays of TPHI, TPH2, tyrosine hydroxylase (TH) and human phenylalanine hydroxylase (PH) were all generated using genes having the following access numbers, respectively: X52836, AY098914, X05290 and U49897. The total length coding sequence of human TPHI was cloned into the bacterial expression vector pET24 (Novagen, Madison, Wl, USA). A single colony of BL21 (DE3) cells harboring the expression vector was inoculated in 50 ml of L (LB) broth medium -canamicin and cultured at 37 ° C overnight with shaking. Half of the culture (25 ml) was then transferred in 3 1 of the medium containing 1.5% yeast extract, 2% bacto peptone, 0.1 mM tryptophan, 0.1 mM ferrous ammonium sulfate, and 50 mM phosphate buffer (pH, 7.0), and cultured at OD600 = 6 at 371C with oxygen supplemented at 40%, the pH was maintained at 7.0 and glucose was added. The expression of TPHI was induced with 15% D-lactose over a period of 10 days. hours at 25 ° C. The cells were turned and washed once with phosphate-buffered saline (PBS). TPHI was purified by affinity chromatography based on its binding to pterin. The cell pill was resuspended in a lysis buffer (100 mg / 20 g) containing 50 mM Tris-Cl, pH 7.6, 0.5 M NaCl, 0.1% Tween-20, 2 mM EDTA, 5 mM DTT, protease inhibitor mixture (Roche Applied Science, Indianapolis, IN, USA) and 1 mM phenylmethanesulfonyl fluoride (PMSF), and the cells were used with a microfluidizer. The lysate was centrifuged and the supernatant was centrifuged. loaded onto a 4B column of sepharose coupled to pterin which was equilibrated with a buffer containing 50 mM Tris, pH 8.0, 1 M NaCl, 0.1% Tween-20, 0.5. mM EDTA and 2 mM DTT. The column was washed with 50 ml of this buffer and TPHI was eluted with a buffer containing 30 mM NaHCO3, pH 10.5, 0.5 M NaCl, 0.1% Tween-20, 0.5 mM EDTA, 2 mM DTT and glycerol 10% The eluted system was immediately neutralized with 200 mM KH2P04, pH 7.0, 0.5 M NaCl, 20 mM DTT, 0.5 mM EDTA and 10% glycerol and stored at -80 ° C. Human tryptophan hydroxylase type II (TPH2), tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PAH) were expressed and purified in essentially the same manner, except that the cells were supplemented with tyrosine for TH and phenylalanine for PAH during culture. The activities of TPHl and TPH2 were measured in a reaction mixture containing 50 mM of 4-morpholinepropanesulfonic acid (MOPS), pH 7.0, 60 uM of tryptophan, 100 mM of ammonium sulfate, 100 uM of ferrous ammonium sulfate., 0.5 mM of tris (2-carboxyethyl) phosphine (TCEP), 0.3 mM of 6-methyl tetrahydropterin, 0.05 mg / ml of catalase, and 0.9 mM of DTT. The reactions were initiated by adding TPHI to a final concentration of 7.5 nM. The initial velocity of the reactions was determined by following the fluorescence change at 360 nm (excitation wavelength = 300 nm). The inhibition of TPH1 and TPH2 was determined by measuring their activities at various concentrations of the compound, and the potency of a given compound was calculated using the equation: where v is the initial velocity at a given concentration C of the compound, v0 is the v, when C = 0, b is the background signal, D is the slope Hill that is approximately equal to, and IC50 is the concentration of the compound which inhibits half the maximum enzymatic activity. The activities of TH and PAH were determined by measuring the amount of 3H20 generated using L- [3,4-3H] -tyrosine and L- [4-3H] -phenylalanine, respectively. The enzyme (100 nM) was first incubated with its substrate at 0.1 mM for approximately 10 minutes, and added to a reaction mixture containing 50 mM MOPS, pH 7.2, 100 mM ammonium sulfate, 0.05% T-20, 1.5 mM of TCEP, 100 uM of ferrous ammonium sulfate, 0.1 mM of tyrosine or phenylalanine, 0.2 mM of 6-methyl tetrahydropterin, 0.05 mg / ml of catalase and 2 mM of DTT. The reactions were allowed to proceed for 10-15 minutes and were stopped by the addition of 2 M HCl. The mixtures were then filtered through activated charcoal and the radioactivity in the filtrate was determined by scintillation count. The activities of the compounds in TH and PAH were determined using this analysis and calculated in the same manner as for TPH1 and TPH2. 5.56 Cell-Based Inhibition Analysis Two types of cell lines were used for visualization: RBL2H3 is a rat mastocytoma cell line that contains TPHI and produces 5-hydroxytryptamine (5HT) spontaneously; BON is a human carcinoid cell line that contains TPHI and produces 5-hydroxytryptophan (5HTP). The CBAs were carried out in a 96-well plate format. The mobile phase used in the HPLC contained 97% 100 nM sodium acetate, pH 3.5 and 3% acetonitrile. A C18 Waters column (4.6 x 50 mm) was used with Waters HPLC (model 2795). A multi-channel fluorometer (model 2475) was used to monitor the flow path adjusting to 280 nm as the excitation wavelength and to 360 nm as the emission wavelength. RBL CBA: The cells were cultured in complete medium (containing 5% bovine serum) for 3-4 hours to allow the cells to bind to the wells of the plate (7K cells / well). The compounds were then added to each well in the concentration range of 0.016 uM to 11.36 uM. The controls were cells in complete medium without any compound present. The cells were harvested after 3 days of incubation at 37 ° C. The cells were > 95% confluent without a compound present. The medium was removed from the plate and the cells were used with an equal volume of 0.1 N NaOH. A large portion of the cell lysate was treated by mixing with an equal volume of 1M TCA and then filtered through glass fiber. The filtrates were loaded on reverse phase HPLC to analyze the 5HT concentrations. A small portion of the cell lysate was also taken to measure the protein concentration of the cells that reflects the cytotoxicity of the compounds in the concentration used. Protein concentration was measured using the BCA method. The average of the 5HT level in the cells without compound treated, was used as the maximum value in the IC50 derivation according to the equation previously provided. The minimum value of 5HT is either set to 0 or from the cells treated with the highest compound concentration if a compound is non-toxic at that concentration. BON CBA: The cells were cultured in equal volume of DMEM and F12K with 5% bovine serum for 3-4 hours (20K cells / well) and the compound was added at a concentration range of 0.07uM to 50uM. The cells were incubated at 37 ° C overnight. Fifty μM of the culture supernatant were then taken for the measurement of 5HTP. The supernatant was mixed with an equal volume of 1M TCA, then filtered through glass fiber. The filtrate was loaded on reverse phase HPLC for measurement of the concentration of 5HTP. Cell viability was measured by treating the cells with a Promega Celltiter-Glo luminescent cell viability assay. The potency of the compound was then calculated in the same manner as in the RBL CBA. 5.57. In vivo effects The in vivo effects of a potent TPHI inhibitor of the invention, were evaluated in several studies determining the change of 5HT levels in the intestines and brains of mice after oral administration of the compound. The compound was formulated in different vehicles to provide either a suspension or a solution.
Generally, male C57 albino mice of 14 weeks of age were dosed once daily by oral delivery at 5 ml / kg for four consecutive days. Five hours after the last dose, the animals were quickly sacrificed. Several regions of the intestinal tract and whole brain were taken and immediately frozen. The 5HT was extracted from the tissues and measured by HPLC. Blood samples were taken for exposure analysis. It was found that the potent inhibitor of TPHl reduces the levels of 5HT in the intestine, both thin and thick, but not in the brain. In one study, the compound was formulated in H20 and administered to the mice at four different dose levels: 15, 50, 150 and 500 mg / kg, once daily by oral delivery. As shown in Figure 1, the compound caused a significant reduction of 5HT in the jejunum and ileus in a dose-dependent manner. In the colon, a statistically significant reduction of 5HT was observed at the dose levels of 50, 150 and 500 mg / kg / day. No significant change in 5HT levels was observed in the brain at any of the dose levels.

Claims (202)

  1. CLAIMS 1. A potent inhibitor of TPHl of formula I I or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -0-, -S-, -C (0) -, -C (R4) =, = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N (R5) -, - C ( R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, -OC (R3R) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R) -; D is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or alkyl or optionally substituted aryl; and n is 0-3. 2. The potent TPH1 inhibitor of claim 1, which is of formula I (A): IA 3. A potent inhibitor of TPHl of formula II II or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -O-, -S-, -C (O) -, -C (R4) =. = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (O) N (R5) -, -C ( R3R4) N (R5) -, -N (R5) C (R3R4) -, -ONC (R3) -, -C (R3) NO-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; D is aryl or optionally substituted heterocycle; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl- heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3. 4. The potent TPHI inhibitor of claim 3, which is of formula II (A): 11A 5. The potent TPHI inhibitor of claim 1 or 3, wherein A is optionally substituted cycloalkyl. 6. The potent TPHI inhibitor of claim 5, wherein the cycloalkyl is 6 members. 7. The potent TPHI inhibitor of claim 5, wherein the cycloalkyl is 5 membered. 8. The potent TPHI inhibitor of claim 1 or 3, wherein A is aryl optionally replaced. 9. The potent TPHI inhibitor of claim 8, wherein the aryl is phenyl or naphthyl. 10. The potent TPHI inhibitor of claim 1 or 3, wherein A is optionally substituted heterocycle. 11. The potent TPHI inhibitor of claim 10, wherein the heterocycle is 6 members. The potent TPHI inhibitor of claim 11, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. The potent TPHI inhibitor of claim 10, wherein the heterocycle is 5 members. 14. The potent TPHI inhibitor of claim 13, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 15. The potent TPHI inhibitor of claim 1 or 3, wherein A is aromatic. 16. The potent TPHI inhibitor of claim 1 or 3, wherein A is non-aromatic. 17. The potent TPHI inhibitor of claim 1 or 3, wherein A is an optionally substituted bicyclic residue. 18. The potent TPHI inhibitor of claim 17, wherein the bicyclic residue is indole, isoindol, pyrrolo-pyridine or naphthylene. 19. The potent TPHI inhibitor of claim 3, which is of the formula: wherein: each of Ai and A2 is independently a cycloalkyl, aryl or optionally substituted monocyclic heterocycle. 20. The potent TPHI inhibitor of claim 19, wherein Ai is optionally substituted cycloalkyl. 21. The potent TPHI inhibitor of claim 20, wherein the cycloalkyl is 6 members. 22. The potent TPHI inhibitor of claim 20, wherein the cycloalkyl is 5 membered. 23. The potent TPHI inhibitor of claim 19, wherein Ai is optionally substituted aryl. 24. The potent TPHI inhibitor of claim 23, wherein the aryl is phenyl. 25. The potent TPHI inhibitor of claim 19, wherein Ai is optionally substituted heterocycle. 26. The potent TPHI inhibitor of
  2. Claim 25, wherein the heterocycle is 6 members. 27. The potent TPHI inhibitor of claim 26, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. 28. The potent TPHI inhibitor of claim 25, wherein the heterocycle is 5 members. 29. The potent TPHI inhibitor of claim 28, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 30. The potent TPHI inhibitor of claim 19, wherein Ai is aromatic. 31. The potent TPHI inhibitor of claim 19, wherein Ai is non-aromatic. 32. The potent TPHI inhibitor of claim 19, wherein A2 is optionally substituted cycloalkyl. 33. The potent TPHI inhibitor of claim 32, wherein the cycloalkyl is 6 members. 34. The potent TPHI inhibitor of claim 32, wherein the cycloalkyl is 5 membered. 35. The potent TPHI inhibitor of claim 19, wherein A2 is optionally substituted aryl. 36. The potent TPHI inhibitor of claim 35, wherein the aryl is phenyl. 37. The potent TPHI inhibitor of claim 19, wherein A2 is optionally substituted heterocycle. 38. The potent TPHI inhibitor of claim 37, wherein the heterocycle is 6 members. 39. The potent TPHI inhibitor of claim 38, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. 40. The potent TPHI inhibitor of claim 37, wherein the heterocycle is 5 members. 41. The potent TPHI inhibitor of claim 40, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 42. The potent TPHI inhibitor of claim 19, wherein A2 is aromatic. 43. The potent TPHI inhibitor of claim 19, wherein A2 is non-aromatic. 44. The potent TPHI inhibitor of claim 1 or 3, wherein D is optionally substituted aryl. 45. The potent TPHI inhibitor of claim 44, wherein the aryl is phenyl or naphthyl. 46. The potent TPHI inhibitor of claim 1 or 3, wherein D is optionally substituted heterocycle. 47. The potent TPHI inhibitor of claim 46, wherein the heterocycle is 6 members. 48. The potent TPHI inhibitor of claim 47, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. 49. The potent TPHI inhibitor of claim 46, wherein the heterocycle is 5 members. 50. The potent TPHI inhibitor of claim 49, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 51. The potent TPHI inhibitor of claim 1 or 3, wherein D is aromatic. 52. The potent TPHI inhibitor of the claim. 1 or 3, where D is non-aromatic. 53. The. potent TPHI inhibitor of claim 1 or 3, wherein D is an optionally substituted bicyclic residue. 54. The potent TPHI inhibitor of claim 53, wherein the bicyclic residue is indole, isoindole, pyrrolo-pyridine or naphthylene. 55. The potent TPHI inhibitor of claim 3, wherein E is optionally substituted aryl. 56. The potent TPHI inhibitor of claim 55, wherein the aryl is phenyl or naphthyl. 57. The potent TPHI inhibitor of claim 3, wherein E is optionally substituted heterocycle. 58. The potent TPHI inhibitor of claim 57, wherein the heterocycle is 6 members. 59. The potent TPHI inhibitor of claim 58, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. 60. The potent TPHI inhibitor of claim 57, wherein the heterocycle is 5 members. 61. The potent TPHI inhibitor of claim 60, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 62. The potent TPHI inhibitor of claim 3, wherein E is aromatic. 63. The potent TPHI inhibitor of claim 3, wherein E is non-aromatic. 64. The potent TPHI inhibitor of claim 3, wherein E is an optionally substituted bicyclic residue. 65. The potent TPHI inhibitor of claim 64, wherein the bicyclic residue is indole, isoindole, pyrrolo-pyridine or naphthylene. 66. The potent TPHI inhibitor of claim 1 or 3, wherein Ri is hydrogen or alkyl optionally substituted. 67. The potent TPHI inhibitor of claim 1 or 3, wherein R2 is hydrogen or optionally substituted alkyl. 68. The potent TPHI inhibitor of claim 1 or 3, wherein n is 1 or 2. 69. The potent TPHI inhibitor of claim 68, wherein n is 1. 70. The potent TPHI inhibitor of the claim 1 or 3, wherein X is a bond or S. 71. The potent TPHI inhibitor of claim 1 or 3, wherein X is -C (R4) =, = C (R4) -, C (R3R4) - , -C (R4) = C (R4) - or -C = C-. 72. The potent TPHI inhibitor of claim 71, wherein each R is independently hydrogen or optionally substituted alkyl. 73. The potent TPHI inhibitor of claim 1 or 3, wherein X is -O-, -C (R3R4) 0- or OC (R3R4) -. 74. The potent TPHI inhibitor of claim 73, wherein R3 is hydrogen or optionally substituted alkyl, and R is hydrogen or optionally substituted alkyl. 75. The potent TPHI inhibitor of claim 74, wherein R3 is hydrogen and R4 is trifluoromethyl. 76. The potent TPHI inhibitor of claim 1 or 3, wherein X is -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C ( R3R4) S (02) - or -S (02) C (R3R4) -. 77. The potent TPHI inhibitor of claim 76, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl and Rs is hydrogen or optionally substituted alkyl. 78. The potent TPHI inhibitor of claim 1 or 3, wherein X is -N (R5) -, -N (R5) C (O) N (R5) -, -C (R3R4) N (R5) - or -N (R5) C (R3R4) -. 79. The potent TPHI inhibitor of claim 78, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl and each R5 is independently hydrogen or optionally substituted alkyl. 80. The potent TPHI inhibitor of claim 3, which is stereomerically pure and of the formula: 81. The potent TPHI inhibitor of claim 80, wherein R3 is trifluoromethyl. 82. The potent TPHI inhibitor of claim 3, which is stereomerically pure and of the formula: 83. The potent TPHI inhibitor of claim 82, wherein R3 is hydrogen. 84. The potent TPHI inhibitor of claim 3, which is of the formula: wherein: each of Zi, Z2, Z3 and Z4 is independently N or CR6: each R6 is independently hydrogen, cyano, halogen, OR7, NR8R9, amino, hydroxyl or alkyl, alkyl-aryl or optionally substituted alkyl-heterocycle; each R7 is independently hydrogen or alkyl-alkyl aryl or optionally substituted alkyl-heterocycle; each R8 is independently hydrogen or alkyl-alkyl aryl or optionally substituted alkyl-heterocycle; each R9 is independently hydrogen or alkyl-alkyl aryl or optionally substituted alkyl-heterocycle; and m is 1-4. 85. The potent TPHI inhibitor of claim 84, which is of the formula: 86. The potent TPHI inhibitor of claim 84, which is stereomerically pure and of the formula: 87. The potent TPHI inhibitor of claim 86, wherein R3 is trifluoromethyl. 88. The potent TPHI inhibitor of the Claim 84, which is stereomerically pure and of the formula: 89. The potent TPHI inhibitor of claim 88, wherein, R3 is hydrogen. 90. The potent TPHI inhibitor of claim 84, wherein Zi, Z2, Z3 and Z4 are N. 91. The potent TPHI inhibitor of claim 84, wherein only three of Zi, Z2, Z3 and Z4 are N 92. The potent TPHI inhibitor of claim 84, wherein only two of Zi, Z2, Z3 and Z4 are N. 93. The potent TPHI inhibitor of claim 84, wherein only one of Zi, Z2, Z3 and Z4 is N. 94. The potent TPHI inhibitor of claim 84, wherein none of the Zi, Z2, Z3 and Z is N. 95. The potent TPHI inhibitor of claim 3, which is of the formula: wherein: each of Z'i, Z'2, and Z'3 is independently N, NH, S, O, or CR6: each Re is independently amino, cyano, halogen, hydrogen, OR7, SR7, NR8Rg, or alkyl, alkyl-aryl or optionally substituted alkyl heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-3. 96. The potent TPHI inhibitor of claim 95, which is of the formula: 97. The potent TPHI inhibitor of claim 95, which is stereomerically pure and of the formula: 98. The potent TPHI inhibitor of claim 97, wherein, R3 is trifluoromethyl. 99. The potent TPHI inhibitor of claim 95, which is stereomerically pure and of the formula: 100. The potent TPHI inhibitor of claim 99, wherein R3 is hydrogen. 101. The potent TPHI inhibitor of claim 95, wherein all three Z'i, Z'2 and Z'3 are N or NH. 102. The potent TPHI inhibitor of claim 95, wherein only two of Z'i, Z'2, and Z'3 are N or NH. 103. The potent TPHI inhibitor of claim 95, wherein only one of Z'i, Z'2, and Z'3 is N or NH 104. The potent TPHI inhibitor of claim 95, wherein none of the Z'i, Z'2, and Z'3 is N or NH. 105. The potent TPHI inhibitor of claim 3, which is of the formula: each of Z '' ?, Z''2, Z''3 and Z''4 is independently N or CRio; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR? 2R? 3 or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; Y each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. 106. The potent TPHI inhibitor of claim 105, which is of the formula: 107. The potent TPHI inhibitor of claim 105, which is stereomerically pure of the formula: 108. The potent TPHI inhibitor of claim 107, wherein R3 is trifluoromethyl. 109. The potent TPHI inhibitor of claim 105, which is stereomerically pure and of the formula: 110. The potent TPHI inhibitor of claim 109, wherein R3 is hydrogen. 111. The potent TPHI inhibitor of claim 105, wherein all Z '' ?, Z''2, Z''3 and Z''4 are N. 112. The potent TPHI inhibitor of claim 105, wherein only three of Z''x, Z''2, Z''3 and Z "are N. 113. The potent TPHI inhibitor of claim 105, wherein only two of Z '' ?, Z '' 2, Z''3 and Z "are N. 114. The potent TPHI inhibitor of claim 105, wherein only one of Z '' ?, Z''2, Z''3 and Z "4 is N. 115. The potent TPHI inhibitor of claim 105, wherein none of Z '' ?, Z''2, Z''3 and Z" 4 is N. 116. The potent inhibitor of TPHl of the
  3. Claim 3, which is of the formula: wherein: each of Z '' ?, Z "2, Z''3 and Z''4 is independently N or CRio, each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR? 2R? 3 or optionally substituted alkyl, alkyl-aryl or alkyl heterocycle, each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle, each Ri2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each Ri3 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle. 117. The potent TPHI inhibitor of claim 116, which is of the formula: 118. The potent TPHI inhibitor of claim 116, which is stereomerically pure of the formula: 119. The potent TPHI inhibitor of claim 118, wherein R3 is trifluoromethyl. 120. The potent TPHI inhibitor of claim 116, which is stereomerically pure and of the formula: 121. The potent TPHI inhibitor of claim 120, wherein R3 is hydrogen. 122. The potent TPHI inhibitor of claim 116, wherein all Z '' ?, Z''2, Z''3 and Z''4 are N. 123. The potent TPHI inhibitor of claim 116, wherein only three of Z '' ?, Z''2, Z''3 and Z '' 4 are N.124. The potent TPHI inhibitor of claim 116, in where only two of Z '' ?, Z''2, Z''3 and Z "4 are N. 125. The potent TPHI inhibitor of claim 116, wherein only one of Z '' ?, Z''2, Z''3 and Z" 4 is N. 126. The potent inhibitor of TPHI of claim 116, wherein none of Z '' ?, Z''2, Z''3 and Z '' 4 is N. 127. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond -O-, -S-, -C (O) -, -C (R4) =. = C (R4) -, - C (R3R4) ", -C (R4) = C (R4) -, -C = C-, -N (R5) ~, -N (R5) C (O) N ( R5) -, - C (R3R4) N (R5) -, -N (R5) C (R3R) -, -ONC (R3) -, -C (R3) NO-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR? 2Ri3 or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3; and q is 1-2. 128. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond -0-, -S-, -C (0) -, -C (R4) =, = C (R4) -, - C (R3R4) ", -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N (R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, ORu, SRn, NR? 2Ri3 or alkyl, alkyl-aryl or optionally substituted alkyl heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3; and q is 1-2. 129. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond -O-, -S-, -C (O) -, -C (R4) =, = C (R4) -, - C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (O) N (R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R4) -, -ONC (R3) -, -C (R3) NO-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, ORu, SRn, NR? 2Ri3 or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3; and r is 1-3. 130. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond -0-, -S-, -C (0) -, -C (R4) =, = C (R4) -, - C (R3R4) ", -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N (R5) -, -C (R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NRi2Ri3 or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 2 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle; each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; n is 0-3. 131. The compound of one of claims 127-130, wherein A is optionally substituted cycloalkyl. 132. The compound of claim 131, wherein the cycloalkyl is 6 members. 133. The compound of claim 131, wherein the cycloalkyl is 5 membered. 134. The compound of one of the claims 127-130, wherein A is optionally substituted aryl. 135. The compound of claim 134, wherein the aryl is phenyl or naphthyl. 136. The compound of one of claims 127-130, wherein A is optionally substituted heterocycle. 137. The compound of claim 136, wherein the heterocycle is 6 members. 138. The compound of claim 137, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. 139. The compound of claim 136, wherein the heterocycle is 5 members. 140. The compound of claim 139, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 141. The compound of one of claims 127-130, wherein A is aromatic. 142. The compound of one of claims 127-130, wherein A is non-aromatic. 143. The compound of one of the claims 127-130, wherein A is an optionally substituted bicyclic residue. 144. The compound of claim 143, wherein the bicyclic residue is indole, isoindole, pyrrolo-pyridine or naphthylene. 145. The compound of one of claims 127-130, wherein E is optionally substituted heterocycle. 146. The compound of claim 145, wherein the heterocycle is 6 members. 147. The compound of claim 146, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine or triazine. 148. The compound of claim 145, wherein the heterocycle is 5 members. 149. The compound of claim 148, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene or furan. 150. The compound of one of the claims 127-130, where E is aromatic. 151. The compound of one of the claims 127-130, where E is non-aromatic. 152. The compound of one of claims 127-130, wherein E is an optionally substituted bicyclic residue. 153. The compound of claim 152, wherein the bicyclic residue is indole, isoindole, pyrrolo-pyridine or naphthylene. 154. The compound of one of claims 127-130, wherein Ri is hydrogen or optionally substituted alkyl. 155. The compound of one of claims 127-130, wherein R2 is hydrogen or optionally substituted alkyl. 156. The compound of one of claims 127-130, wherein n is 1 or 2. 157. The compound of claim 156, wherein n is 1. 158. The compound of one of claims 127-130, in where X is a bond or S. 159. The compound of one of the claims 127-130, wherein X is -C (R4) =, = C (R4) -, -C (R3R4) -, C (R4) = C (R4) - or -C = C-. 160. The compound of claim 159, wherein each R is independently hydrogen or optionally substituted alkyl. 161. The compound of one of claims 127-130, wherein X is -O-, -C (R3R4) 0- or -OC (R3R4) -. 162. The compound of claim 161, wherein R3 is hydrogen or optionally substituted alkyl, and R is hydrogen or optionally substituted alkyl. 163. The compound of claim 164, wherein R3 is hydrogen and R4 is trifluoromethyl. 164. The compound of one of claims 127-130, wherein X is -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4 ) S (02) - or -S (02) C (R3R4) -. 165. The compound of claim 168, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and each R5 is independently hydrogen or optionally substituted alkyl. 166. The compound of one of claims 127-130, wherein X is -N (R5) -, -N (R5) C (0) N (R5) -, C (R3R4) N (R5) - or - N (R5) C (R3R) -. 167. The compound of claim 166, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl and R5 is hydrogen or optionally substituted alkyl. 168. The compound of one of claims 127-130, wherein both A and E are optionally substituted phenyl. 169. The compound of claim 168, wherein X is -0-, -C (R3R4) 0- or -OC (R3R4) -. 170. The compound of claim 169, wherein R3 is hydrogen and R4 is trifluoromethyl. 171. The compound of claim 170, wherein n is 1. 172. The compound of claim 171, which is stereomerically pure. 173. The compound of one of claims 127-130, which has a TPH1_IC50 less than about 1 μM. 174. The compound of claim 173, which inhibits TPHI with an IC5o of less than about 500 nM. 175. The compound of claim 174, which has a TPH1_IC50 less than about 250 nM. 176. A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is: (S) -2-amino-3- (4- (4-amino-6- ((R) -1- ( naphthalen-2-yl) ethylamino) -1,3, 5-triazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (4-amino-6- ((4'-methylbiphenyl-4-yl) methylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (4-morpholino-6- (naphthalen-2-ylmethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (2- (trifluoromethyl) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1-p-tolylethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1-cyclohexyl-2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (6- (2-fluorophenoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (4- (3- (4-chlorophenyl) piperidin-1-yl) -1,3,5-triazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (4-amino-6- (2,2,2-trifluoro-1-phenylethoxy) -1,3,5-triazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (5- (4-amino-6- ((R) -l- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) pyridin-2-yl) propanoic; (S) -2-amino-3- (3- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) -lH-pyrazol-1-yl) propanoic acid; (S) -2-amino-3- (4 '(3- (cyclopentyloxy) -4-methoxybenzylamino) biphenyl-4-yl) propanoic acid; (S) -2-amino-3- (4- (6- (3- (cyclopentyloxy) -4-methoxybenzylamino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (6- (3- (cyclopentyloxy) -4-methoxybenzylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- ((4'-methyl-biphenyl-2-yl) -methylamino) -pyrazin-2-yl) -phenyl) -propanoic acid; (2S) -2-amino-3- (4- (6- (2,2,2-trifluoro-1-phenylethoxy) -pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (1- (3,4-difluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- (3- (cyclopentyloxy) -4-methoxybenzylamino) -pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- ((3- (cyclopentyloxy) -4-methoxybenzyl) - (methyl) amino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- ((1,3-dimethyl-lH-pyrazol-4-yl) methylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (4-amino-6 ((S) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yloxy) phenyl acid propanoic; (S) -2-amino-3- (4- (4-amino-6- ((R) -1- (biphenyl-2-yl) -2,2,2-trifluoroethoxy) -1,3,5 -triazin-2-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (1- (6,8-difluoronaphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (2,2,2-trifluoro-1- (3'-methyl-biphenyl-2-yl) ethoxy) -1, 3, 5 acid -triazin-2-yl) phenyl) propanoic; (S) -2-amino-3- (4- (5- (3,4-dimethoxyphenylcarbamoyl) -pyrazin-2-ylphenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (4- (2- (trifluoromethyl) phenyl) -piperidin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((R) -1-naphthalen-2-yl) ethylamino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (methyl ((R) -1- (naphthalen-2-yl) ethyl) amino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((S) -2,2,2-trifluoro-1- (6-methoxynaphthalen-2-yl) ethoxy) pyrimidin-4 acid -yl) phenyl) propanoic; (S) -2-amino-3- (4- (5- (biphenyl-4-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5-naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2- (tert-butoxycarbonylamino) -3- (4- (5- (naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-morpholinoethyl-2-amino-3- (4- (5- (naphthalen-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoate; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3'-fluorobiphenyl-4-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- (benzylthio) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (naphthalen-2-ylmethylthio) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (3, 4-difluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6 (2,2,2-trifluoro-1- (3'-methylphenyl-2-yl) ethoxy) pyrimidin-4-yl) phenyl acid propanoic; (S) -2-amino-3- (4- (5- (3- (cyclopentyloxy) -4-methoxybenzylamino) pyridin-3-yl) phenyl) propanoic acid; 2-amino-3 (3- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid; 2-amino-3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) -2-fluorophenyl acid propanoic; (2S) -2-amino-3- (4- (4-amino-6- (1-adamantyl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (4- (trifluoromethyl) -benzylamino) pyrimidin-4-yl) phenyl) propanoic acid; 2-amino-3- (5- (5-phenylthiophen-2-yl) -lH-indol-3-yl) propanoic acid; (S) -2-amino-3- (4- (4- (4-phenoxyphenyl) -1H-1,2,3-triazol-1-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (4- (4- (thiophene-2-carboxamido) phenyl) -1 H-1,2,3-triazol-1-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- (4- (thiophene-2-carboxamido) phenyl) -1 H-1,2,3-triazol-1-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (phenylethynyl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- (2-fluoro-4,5-dimethoxybenzylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (4- (2-methoxyphenyl) piperidin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (6- (3- (cyclopentyloxy) -4-methoxybenzylamino) -2- (dimethylamino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- (3,4-dimethylbenzylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- (biphenyl-2-ylmethylamino) pyrazin-2-yl) phenyl) propanoic acid; (S) -ethyl-2-amino-3- (4- (2-amino-6- (4- (trifluoromethyl) benzylamino) pyrimidin-4-yl) phenyl) propanoate; (S) -2-amino-3- (4- (5- (cyclopentylmethylamino) pyrazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (3- (2- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6 (1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((R) -1- (naphthalen-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1, 2-diphenylethylamino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((R) -l- (4- (benzo [b] thiophen-3-yl) phenyl) ethylamino) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (4-amino-6- ((R) -1- (4'-methoxybiphenyl-4-yl) ethylamino) -1,5,5-triazin-2 acid -yl) phenyl) propanoic; 2-amino-3- (1- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) piperidin-4-acid il) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (1- (4-fluoronaphthalen-1-yl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic; (S) -2-amino-3- (4- (4-amino-6- ((3'-fluorobiphenyl-4-yl) methylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid; 2-amino-3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) -2-fluorophenyl acid propanoic; (S) -2-amino-3- (4- (2-amino-6- ((R) -2,2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (2,2,2-trifluoro-1- (3'-fluorobiphenyl-2-yl) ethoxy) -1, 3, 5 acid -triazin-2-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (1- (4-tert-butylphenyl) ethylamino) -1,3,5-triazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3'-fluorobiphenyl-4-yl) ethoxy) pyrimidine-4- (2S) acid il) phenyl) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (6,7-dihydroxy-l-methyl-3,4-dihydroisoquinolin-2 (IH) -yl) -1,3 acid 5-triazin-2-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (4-amino-6- (2,2,2-trifluoro-1- (3'-methyl-biphenyl-4-yl) ethoxy) -1, 3, 5 acid -triazin-2-yl) phenyl) propanoic; (S) -2-amino-3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) pyrimidin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (benzylthio) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (4'-fluorobiphenyl-4-yl) ethoxy) pyrimidin-4-yl) acid) phenyl) propanoic; (2S) -2-amino-3- (4- (6- (3- (4-chlorophenoxy) piperidin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -3- (4- (4-amino-6- ((R) -1- (naphthalen-2-yl) ethylamino) -1,3,5-triazin-2-yl) phenyl) -2 acid - (2-aminoacetamido) propanoic; (S) -2-amino-3- (4- (6- ((R) -1- (naphthalen-2-yl) ethylamino) -2- (trifluoromethyl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (4- (3-chlorophenyl) piperazin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((R) -2,2,2-) acid trifluoro-1-phenylethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1,4-diphenylbutylamino) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (1- (3'-chlorobiphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (4-amino-6- (1- (biphenyl-4-yl) -2,2,2-trifluoroethoxy) -1,3,5-triazin-2 acid -yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 3, 3, 3-pentafluoro-1- (3-fluoro-4-methylphenyl) propoxy) pyrimidin-4 acid -yl) phenyl) propanoic; (S) -ethyl-2-amino-3- (4- (2-amino-6- ((R) -2,2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine -4-yl) phenyl) propanoate; (S) -2-amino-3- (4- (2-amino-6- ((S) -2,2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3-fluoro-3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (3 '- (dimethylamino) biphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidine-4 (2S) acid il) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3'-methoxy-5-methylbiphenyl-2-yl) ethoxy) pyrimidine- 4- il) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (4'-methoxy-5-methylbiphenyl-2-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3'-methoxy-3- (methylsulfonyl) biphenyl-4-yl) ethoxy} acid ) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (2- (cyclopropylmethoxy) -4-fluorophenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (6- (1- (2- (cyclopropylmethoxy) -4-fluorophenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (2- (isopentyloxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (5- (2, 2, 2-trifluoro-1- (3'-fluorobiphenyl-4-yl) ethoxy) pyrazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (4'-methoxybiphenyl-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (3'-carbamoylbiphenyl-2-yl) -2,2, 2-trifluoromethoxy) pyrimidin-4-yl) phenyl acid propanoic; (2S) -2-amino-3- (4- (2-amino-6- (l- (4'-) acid carbamoylbiphenyl-2-yl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (4- (2-methoxyphenoxy) phenyl) ethoxy) pyrimidin-yl) phenyl acid propanoic; (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1- (4- (2-methoxyphenoxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2, 2, 2-trifluoro-1- (2- (isopentyloxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -3- (4- (6- (1, 3'-Acetamidobiphenyl-2-yl) -2,2-trifluoroethoxy) -2-aminopyrimidin-4-yl) phenyl) -2-aminopropanoic acid; (2S) -3- (4- (6- (1- (4'-Acetamidobiphenyl-2-yl) -2,2, 2-trifluoroethoxy) -2-aminopyrimidin-4-yl) phenyl) -2-aminopropanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (4-cyanophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -ethyl-2-amino-3- (4- (2-amino-6- ((R) -2,2,2, trifluoro-1-p-tolylethoxy) pyrimidin-4-yl) phenyl) propanoate; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (1-methoxy-benzyl [2,2,2] oct-5-en-2) acid -yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (4- (cyclopentyloxy) phenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (1- (4- (cyclopentyloxy) phenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (4- (3-methoxyphenoxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (4,5-dimethoxybiphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (4,5-dimethoxy-3'-methyl-biphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidine -4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (5- (2,2,2-trifluoro-l- (2'-methylbiphenyl-2-yl) ethoxy) pyrazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1- (4- (3-methoxyphenoxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (2- (3, 5-difluorophenoxy) phenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl acid phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (4- (4-methoxyphenoxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (l- (4 '- ((S) -2-) acid amino-2-carboxyethyl) biphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (2-bromophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (5- (2, 2, 2-trifluoro-1- (3'-methyl-biphenyl-2-yl) -ethoxy) -pyrazin-2-yl) -phenyl) -propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (4-methoxybiphenyl-2-yl) ethoxy) pyrimidin-4-yl) phenyl acid propanoic; (2S) -2-amino-3- (4- (5- (2, 2, 2-trifluoro-1- (2- (4-methylthiophen-3-yl) phenyl) ethoxy) pyrazin-2-yl) acid) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (4-methoxy-3'-methyl-biphenyl-2-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3 '- (hydroxymethyl) bifeni1-2-i1) ethoxy) pyrimidin-4 acid -yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (l- (3'-cyanobiphenyl-2-yl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl acid propanoic; (2S) -2-amino-3- (4- (6- (1- (2- (3, 5-difluorophenoxy) phenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1- (4- (4-methoxyphenoxy) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (2- (4-methylthiazol-2-yl) thiophen-3-yl)) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (5- (4-methoxyphenyl) isoxazol-3-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (l-phenyl-5- (trifluoromethyl) -lH-pyrazol-4-yl) acid ) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (2- (cyclohexyloxy) -4-methylphenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (l- (2- (cyclopentyloxy) -4-methylphenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (enzo [d] thiazol-6-yl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) acid) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (l-methyl-lH-imidazol-5-yl) ethoxy) pyrimidin-4 acid -yl) phenyl) propanoic; (2S) -2-amino-3- (4- (6- (1- (2- (cyclopentyloxy) -4-methylphenyl) -2,2,2-trifluoroethoxy) pyrimidin-4- (2S) acid il) phenyl) propanoic; (2S) -2-amino-3- (4- (6- (1- (2- (cyclohexyloxy) -4-methylphenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (pyridin-3-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (1,3-dimethyl-lH-pyrazol-5-yl) -2,2,2-trifluoroethoxy) pyrimidine- 4-yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- (3-hydroxyphenyl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3'-hydroxybiphenyl-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- (3, 5-difluorophenyl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (3 ', 5'-difluorobiphenyl-2-yl) -2,2, 2-trifluoroethoxy) pyrimidin-4 (2S) acid il) phenyl) propanoic; (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1- (3'-fluorobiphenyl-3-yl) ethoxy) pyrazin-2-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (5-ethoxy-2-methyl-2,3-dihydrobenzofuran-6-yl) -2,2,2- trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (benzofuran-5-yl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (2-m-tolylfuran-3-yl) ethoxy) pyrimidin-4-yl acid phenyl) propanoic; (S) -ethyl-3- (4- (2-amino-6- ((R) -2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidin-4-yl ) phenyl) -2- (2-aminoacetamido) propanoate; (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1- (2- (4-methylthiophen-3-yl) phenyl) ethoxy) pyrazin-2-yl) acid) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (5-methyl-3-phenylisoxazol-4-yl) ethoxy) pyrimidin-4 acid -yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- (3- (methylthio) phenyl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3 '- (methylthio) biphenyl-2-yl) ethoxy) pyrimidin-4 acid -yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1 - (3 '- ((dimethylamino) methyl) biphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidine -4-yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- (3- (trifluoromethoxy) phenyl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-) acid trifluoro-1- (3 '- (trifluoromethoxy) biphenyl-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -3- (4- (2-amino-6- ((R) -2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidin-4-yl) acid) phenyl) -2- (2-aminoacetamido) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1 (l-methyl-5-phenyl-1H-pyrazol-4-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (4- (methylsulfonyl) phenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- ((R) -1- (3 '- (dimethylamino) biphenyl-2-yl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (2-chloro-4- (methylsulfonyl) phenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl acid phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (3- (furan-2-yl) thiophen-2-yl) ethoxy) acid) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (2- (cyclopentyloxy) -4-fluorophenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (2- (3-methoxyphenyl)) cyclohex-1- (2S) acid enyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (pyrimidin-5-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (5- (2,2,2-trifluoro-l- (3'-methoxybiphenyl-3-yl) ethoxy) pyrazin-2-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((S) -1- (3 '- (dimethylamino) bifeni1-2-i1) -2,2,2-trifluoroethoxy) pyrimidin- (yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (2-furan-2-carboxamido) phenyl) ethoxy) pyrimidin-4-yl acid phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (1- (4-chloro-2- (methylsulfonyl) phenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl acid phenyl) propanoic; (S) -isopropyl-2-amino-3- (4- (2-amino-6- ((R) -2,2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine -4-yl) phenyl) propanoate; (2S) -2-amino-3- (4- (6- (1- (2- (cyclopentyloxy) -4-fluorophenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (1- (2- (cyclohexyloxy) -4-fluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-) acid trifluoro-1- (1- (thiophen-2-yl) cyclohexyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2- (2, 2, 2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) thiazol-5-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (l- (2- (cyclohexyloxy) -4-fluorophenyl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (1- (4-methoxyphenyl) cyclohexyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (6- (2, 2, 2-trifluoro-1- (4-fluoro-2-methylphenyl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2, 2, 2-trifluoro-1- (4-fluoro-2-methylphenyl) ethoxy) pyrimidin-4-yl) phenyl acid propanoic; (2S) -2-amino-3- (4- (2-amino-6- (oxazol-2-yl) phenyl) methoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- (1-cyclohexyl-2,2,2-trifluoroethylidenaminooxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (2- (3- (dimethylamino) phenyl) furan-3-yl) -2,2,2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (5-phenylthiophen-2-yl) ethoxy) pyrimidin-4-acid il) phenyl) propanoic; (S) -phenyl-2-amino-3- (4- (2-amino-6- ((R) -2,2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine -4-yl) phenyl) propanoate; (S) -2-amino-3- (4- (2-amino-6- ((R) -l- (3 '- ((dimethylamino) methyl) biphenyl-4-yl) -2.2.2 acid -trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (1- (3-methoxybenzoyl) -1H-pyrazol-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (6- (2,2,2-trifluoro-1- (5-phenylfuran-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (4-chloro-2-fluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (S, E) -2-amino-3- (4- (2-amino-6- (4- (trifluoromethyl) styryl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (3,4-dichlorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1- (4-chloro-3-fluorophenyl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (S) -2-amino-3- (4- (2-amino-6- ((R) -1- (3 '• (dimethylamino) biphenyl-4-yl) -2,2, 2-trifluoroethoxy) pyrimidin-4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (l-chloro-2, 2,2-trifluoro-1- (4-methoxybiphenyl-2-yl) ethoxy) pyrimidin-4 (2S) acid -yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2, 2, 2-trifluoro-1- (5-phenylthiophen-2-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (5- (4-phenoxyphenyl) -1H-1,2,3-triazol-1-yl) phenyl) propanoic acid; (S, E) -2-amino-3- (4- (2-amino-6- (2- (biphenyl-4-yl) vinyl) pyrimidin-4-yl) phenyl) propanoic acid; (S) -2-amino-3- (4- (4-amino-6- ((R) -2,2,2-trifluoro-1- (3'-methoxybiphenyl-4-yl) ethoxy) pyrimidine- 2-yl) phenyl) propanoic; (S) -2-amino-3- (4- (4'-methoxybiphenyl-4-ylsulfonamido) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-l- (6- (3-methoxyphenyl) pyridin-3-yl) ethoxy) pyrimidine- 4-yl) phenyl) propanoic; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (6- (2-fluoro-3-methoxyphenyl) pyridin-3-yl) acid) ethoxy) pyrimidin-4-yl) phenyl) propanoic acid; 2-amino-3- (5- (4'-methyl-biphenyl-4-yl) -lH-indol-3-yl) -propanoic acid; 2-amino-3- (5-m-tolyl-lH-indol-3-yl) propanoic acid; (2S) -2-amino-3- (4- (2- (2-methoxyphenyl) furan-3-acid carboxamido) phenyl) propanoic; 2-amino-3- (5- (1-benzyl-1H-pyrazol-4-yl) -1H-indol-3-yl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (2,2,2-trifluoro-1- (6- (thiophen-2-yl) pyridin-3-yl) ethoxy) pyrimidin-4-yl) phenyl) propanoic; 2-amino-3- (6- (1-benzyl-1H-pyrazol-4-yl) -1H-indol-3-yl) propanoic acid; (S) -2-amino-3- (4- ((2- (4- (trifluoromethyl) phenyl) thiazol-4-yl) methylamino) phenyl) propanoic acid; (S) -2-amino-3- (4- ((4'-methoxybiphenyl-4-ylsulfonamido) methyl) phenyl) propanoic acid; (S) -2-amino-3- (4- (3- (2-methoxydibenzo [b, d] furan-3-yl) ureido) phenyl) propanoic acid; (S) -2-amino-3- (4- (3- (2,2-diphenylethyl) ureido) phenyl) propanoic acid; (S) -2-amino-3- (4- (phenylethynyl) phenyl) propanoic acid; (S) -2-amino-3- (4- (2-amino-6- ((5- (l-methyl-5- (trifluoromethyl) -lH-pyrazol-3-yl) thiophen-2-yl) methoxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (1,1,1-trifluoro-3- ((R) -2,2, 3-trimethyl-cyclopent-3-enyl) -propane -2-yloxy) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (3- (2-hydroxyethylcarbamoyl) pyridin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; (2S) -2-amino-3- (4- (2-amino-6- (3- (pyridin-2-yloxy) piperidin-1-yl) pyrimidin-4-yl) phenyl) propanoic acid; or (S) -2-amino-3- (4- (2-amino-6- (4-chloro-3- (piperidine-1-carbonyl) phenyl) pyrimidin-4-yl) phenyl) propanoic acid; 177. The compound of claim 176, which is stereomerically pure. 178. A stereomerically enriched composition of the potent TPHI inhibitor of claim 1 or 3. 179. A pharmaceutical formulation comprising a potent TPHI inhibitor of claim 1 or 3. 180. A unique form of unit dose comprising the pharmaceutical formulation. of the claim 179. 181. A method for inhibiting the TPHI activity comprising contacting TPHI with a compound of the formula I: I or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -0-, -S-, -C (0) -, -C (R) =, = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N (R5) -, -C ( R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, -OC (R3R) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; D is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3. 182. The method of claim 181, wherein the compound is of the formula I (A): 183. A method for inhibiting TPH1 activity, comprising contacting TPHI with a compound of formula II: II or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -O-, -S-, -C (O) -, -C (R4) =, = C (R4) -, -C (R3R) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (O) N (R5) -, - C ( R3R4) N (R5) -, -N (R5) C (R3R4) -, -ONC (R3) -, -C (R3) NO-, -C (R3R4) 0-, -OC (R3R4) -, - S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R) -; D is aryl or optionally substituted heterocycle; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3. 184. The method of claim 183, wherein the compound is of formula II (A): HA 185. A method for treating, preventing or managing a disease or disorder mediated by peripheral serotonin in a patient, comprising inhibiting the activity of TPHI in the patient. 186. The method of claim 185, wherein the inhibition is caused by administering to the patient a therapeutically or prophylactically effective amount of a potent TPHI inhibitor. 187. The method of claim 185, wherein the inhibition is caused by administering to the patient a therapeutically or prophylactically effective amount of a compound of the formula I: I or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -0-, -S-, -C (0) -, -C (R4) =, = C (R4) -, -C (R3R4) ", -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (0) N (R5) -, - C ( R3R4) N (R5) -, -N (R5) C (R3R4) -, -0NC (R3) -, -C (R3) N0-, -C (R3R4) 0-, -OC (R3R4) -, -S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) -; D is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3. 188. The method of claim 187, wherein the compound is of the formula I (A): IA 189. The method of claim 185, wherein the inhibition is caused by the administration to the patient of a therapeutically or prophylactically effective amount of a compound of the formula II: II or a pharmaceutically acceptable salt or solvate thereof, wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X is a bond, -O-, -S-, -C (O) -, -C (R) =, = C (R4) -, -C (R3R4) -, -C (R4) = C (R4) -, -C = C-, -N (R5) -, -N (R5) C (O) N (R5) -, - C ( R3R4) N (R5) -, -N (R5) C (R3R4) -, -ONC (R3) -, -C (R3) NO-, -C (R3R4) 0-, -0C (R3R4) -, - S (02) -, -S (02) N (R5) -, -N (R5) S (02) -, -C (R3R4) S (02) -, or -S (02) C (R3R4) - , * D is aryl or optionally substituted heterocycle; E is aryl or optionally substituted heterocycle; Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R2 is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or optionally substituted heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3. 190. The method of claim 189, wherein the compound is of formula II (A): HA 191. The method of claim 185, wherein the disease or disorder is carcinoid syndrome. 192. The method of claim 185, wherein the disease or disorder is a gastrointestinal disease or disorder. 193. The method of claim 185, wherein the disease or disorder is emesis. 194. A method for treating, preventing or managing a gastrointestinal disease or disorder, comprising administering to a patient in need of such treatment, prevention or management, a therapeutic or prophylactically effective amount of a potent TPHI inhibitor of claim 1 or 3. 195. The method of claim 194, wherein the disease or disorder is diarrhea, constipation, or irritable bowel syndrome. 196. A method for treating, preventing or managing emesis, comprising administering to a patient in need of such treatment, prevention or management, a therapeutically or prophylactically effective amount of a compound of a potent TPHI inhibitor of claim 1 or 3. 197 A method for preparing a compound of formula 1 (a): Ka) comprising contacting a compound of the formula 2 2 with a compound of formula 3: under conditions sufficient for the formation of the compound of the formula I (a), wherein: A is cycloalkyl, aryl or optionally substituted heterocycle; X 'is 0, S, or NR5; Yi is halogen or pseudohalogen; One of Z "?, Z''2, Z''3 and Z''4 is a carbon atom attached to the adjacent residue of optionally substituted phenyl, and the others are each independently CR? 0 or N; Pi is Ri or a protecting group, P2 is a protecting group, Ri is hydrogen or alkyl, alkyl-aryl, alkyl-heterocycle, aryl or optionally substituted heterocycle, R3 is hydrogen, cyano or optionally substituted alkyl, each Re is independently hydrogen, cyano , halogen, OR7, NR8R9, amino, hydroxyl or alkyl, alkyl-aryl or optionally substituted alkyl heterocycle, each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rg is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rio is independently hydrogen, cyano, halogen, ORn, NR? 2Ri3, amino, hydroxyl or optionally substituted alkyl, alkylaryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 2 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle; each R 3 is independently hydrogen or optionally substituted alkyl, alkyl aryl or alkyl heterocycle; and m is 1-4. 198. The method of claim 197, wherein the compound of formula 2 is prepared by contacting a compound of formula 4: 4 with a compound of formula 5: 5 under sufficient conditions for the formation of the compound of formula 2, wherein: Ai is optionally substituted cycloalkyl, aryl or heterocycle; A2 is cycloalkyl, aryl or optionally substituted heterocycle; Y2 is halogen or pseudohalogen; and each R is independently hydrogen, alkyl, alkyl-aryl, alkyl-heterocycle, aryl or optionally substituted heterocycle or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane. 199. The method of claim 197, wherein the compound of formula 3 is prepared by contacting a compound of formula 6: with a compound of the formula 7: ^ yrt 7 under sufficient conditions for the formation of the compound of the formula 3 (a): 3 (a) and deprotecting P3 to provide the compound of formula 3, wherein: Y3 is halogen or pseudohalogen; P3 is 0R2 or a protection group; R 2 is hydrogen or optionally substituted alkyl, alkyl aryl, alkyl heterocycle, aryl or heterocycle; and each R 'is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl or heterocycle or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane. 200. The method of claim 197, wherein sufficient conditions for the formation of the compound of formula 2 comprise a transition metal catalyst, a base, and a solvent or mixture of solvents with water. 201. The method of claim 199, wherein sufficient conditions for the formation of the compound of the formula 3 (a) comprise a transition metal catalyst, a base, and a solvent or solvent mixture with Water. 202. The method of claim 197, further comprising deprotecting the compound of the formula I (a) to provide a compound of the formula 1 (b): Kb)
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