MX2011012263A - Isoxazolines as inhibitors of fatty acid amide hydrolase. - Google Patents

Isoxazolines as inhibitors of fatty acid amide hydrolase.

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Publication number
MX2011012263A
MX2011012263A MX2011012263A MX2011012263A MX2011012263A MX 2011012263 A MX2011012263 A MX 2011012263A MX 2011012263 A MX2011012263 A MX 2011012263A MX 2011012263 A MX2011012263 A MX 2011012263A MX 2011012263 A MX2011012263 A MX 2011012263A
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Mexico
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alkyl
independently
aryl
alkynyl
carbocyclyl
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MX2011012263A
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Spanish (es)
Inventor
Louis Grenier
Stephane Peluso
Mark L Behnke
Alfredo C Castro
Catherine A Evans
Michael J Grogan
Daniel A Snyder
Thomas T Tibbitts
Lawrence K Chan
Yves Leblanc
Tao Liu
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Infinity Pharmaceuticals Inc
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Publication of MX2011012263A publication Critical patent/MX2011012263A/en

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Abstract

The present invention provides isoxazoline FAAH inhibitors of the formula (I): or pharmaceutically acceptable forms thereof, wherein each of G, Ra, Rb, Rc, and Rd are as defined herein. The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. The present invention also provides methods for treating an FAAH-mediated condition comprising administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable form thereof, to a subject in need thereof.

Description

ISOXAZOLINAS AS HYDROLASE INHIBITORS OF AMIDA DE FATTY ACID CROSS REFERENCE TO RELATED REQUESTS The present application claims priority to the provisional patent applications of the United States serial numbers 61 / 179,280, 61 / 179,283 and 61 / 179,285, filed on May 18, 2009, the entirety of which is hereby incorporated by reference .
BACKGROUND OF THE INVENTION Fatty acid amide hydrolase (FAAH), also referred to as oleamide hydrolase and anandamide amidohydrolase, is an integral membrane protein responsible for the hydrolysis of several important endogenous neuromodulatory fatty acid amides (FAAs), including anadamide, oleoylethanolamide and palmitoylethanol-amide, and is intimately involved in its regulation. Since these FAAs interact with cannabinoid and vanilloid receptors, they are often referred to as "endocannabinoids" or "endova n i i ioid es". Initial interest in this area focused on developing FAAH inhibitors to increase FAA actions and reduce pain. More research found that inhibitors of FAAH, through interactions of FAAs with extracellular receptors and single intracellular drugs, can be used to treat a variety of conditions including, but not limited to, inflammation, metabolic disorders (eg, conditions related to obesity and consuming conditions such as cachexia and anorexia), system disorders central nervous (for example, disorders associated with neurotoxicity and / or neurotrauma, embolism, multiple sclerosis, spinal cord damage, movement disorders such as basal ganglia disorders, amilotrophic lateral sclerosis, Alzheimer's disease, epilepsy, mental disorders such as anxiety, depression, learning disorders and schizophrenia, sleep disorders such as insomnia, nausea and / or emesis, and drug addiction), cardiac disorders (eg, hypertension, circulatory shock, reperfusion injury to the myocardium and atherosclerosis) and glaucoma (Pacher et al., "The Endocannabinoid System as an Emerging Target of Pharmacotherapy" Pharm acological Reviews (2006) 58: 389-462; Pillarisetti et al., "Pain and Beyond: Fatty Acid Amides and Fatty Acid Amide Hydrolase Inhibitors in Cardiovascular and Metabolic Diseases" Drug Discovery Today (2009) 597: 1-14).
BRIEF DESCRIPTION OF THE INVENTION The present invention provides FAAH inhibitor compounds of isoxazoline of the formula (I): or pharmaceutically acceptable forms thereof, where: (i) each of a, Rb and Rc independently is selected from H, C1-10 alkyl and perhaloalkyl, Rd is the group -L-Z, and Z is selected from the aryl of (I) each of Ra, R and Rc independently is selected from -H, alkyl of? -10 and perhaloalkyl of Ci.io, Rd is a group -L-Z, and Z is selected from heterocyclyl of 3-14 members and heteroaryl of 5-14 members; (iii) Ra and Rd come together to form a fused carbocyclic ring of C3.i0 or 3-14 membered heterocyclyl, and R and Rc independently are selected from -H, C- | 10 alkyl and perhaloalkyl C1-10; or (iv) Rc and Rd come together to form a spiro-fused ring of carbocyclyl of C3-10 or heterocyclyl of 3-14 members, and Ra and Rb independently are selected from-H, C1-10alkyl and perhaloalkyl of Ci. 0; L is a covalent bond or a divalent C1-6 hydrocarbon group, wherein one, two or three methylene units of L are optionally and independently replaced with one or more oxygen, sulfur or nitrogen atoms; G is selected from -CN, -N02, -S (= 0) Re, -S02Re, -S02NRfRe, -P02Re, -P02ORe, -P02NRfRe, - (C = 0) Re, - (C = 0) ORe , - (C = 0) NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -ONRf (C = 0) Re, -ONRfS02Re, -ONRfP02Re, -ONRfP02ORe, -SRe, -OS02Re , -NRfS02Re, -OP02Re, -OP02ORe, -NRfP02Re, -N RfP02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, -NRf (C = 0) Re, -NRf (C = 0) ORe, -0 (C = 0) NRfRe, -NRf (C = NRf) NRfRe, -0 (C = NRf) NRfRe, -NRf (C = NRf) ORe, - [N (Rf ) 2Re] + X ", where X" is a counter ion; each Re is selected from C1-10 alkyl, alkenyl C2-10. C2-io alkynyl. carbocyclyl of C3.10, aryl of C6-i4, heterocyclyl of 3-14 members and heteroaryl of 5-14 members; each Rf attached to a nitrogen atom, independently, is selected from -H, Ci.10 alkyl, or an amino protecting group; or Re and Rf are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.
The present invention also provides pharmaceutical compositions comprising a compound of the formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.
The present invention also provides methods for treating a condition mediated by FAAH in a subject comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable form thereof, to a subject in need thereof.
The details of additional embodiments of the invention are set forth in the accompanying Detailed Description and Exemplification as described below. Other aspects, objects and advantages of the invention will be apparent from this description and from the claims.
DEFINITIONS The definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Manual of Chemistry and Physics, 75th edition, interior of the cover, and specific functional groups are generally defined as described herein. Additionally, the general principles of organic chemistry, as well as specific functional portions and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.
Certain compounds of the present invention may comprise one or more asymmetric centers, and thus may exist in various isomeric forms, for example, enantiomers and / or diastereomers. The compounds provided herein may be in the form of a single enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers are provided.
In addition, certain compounds, as described herein, may have one or more double bonds that may exist as the c / 's or trans, or the E or Z isomer, unless otherwise indicated. The invention further encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers, for example, racemic mixtures of E / Z isomers or mixtures enriched in an E / Z isomer.
The terms "enantiomerically enriched", "enantiomerically pure" and "non-racemic", as used herein interchangeably, refer to compositions wherein the weight percent of an enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (eg, greater than 1: 1 by weight). For example, an enantiomerically enriched preparation of the (S) -enantiomer means a preparation of the compound having more than 50% by weight of the (S) -enantiomer relative to the (R) -enantiomer, more preferably at least 75% by weight, and even more preferably at least 80% by weight. In some embodiments, the enrichment can be much greater than 80% by weight, providing a preparation "substantially enantiomerically enriched", "substantially enantiomerically pure" or "substantially non-racemic", which refers to preparations of compositions having at least 85% by weight of one enantiomer relative to another enantiomer, more preferably at least 90% by weight, and even more preferably at least 95% by weight. In preferred embodiments, the enantiomerically enriched composition has a greater potency with respect to therapeutic utility per unit mass than the racemic mixture of that composition. Enantiomers of mixtures can be isolated by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts.; or preferred enantiomers can be prepared by asymmetric synthesis. See, for example, Jacques, 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. De Notre Dame Press, Notre Dame, IN 1972).
When a range of values is listed, it should encompass each value and sub-range within the range. For example, "Ci-6 alkyl" should encompass C-i, C2, C3, C4, C5, C6, C1.6, C1-5, C1-, C1.3, Ci-2, C2 C2-5. C2-4, C2-3, C3-6, C3.5, C3.4, C -6, C4-5 and C5-6 alkyl.
As used herein, a "direct link" or "covalent link" refers to a single link joining two groups.
As used herein, alone or as part of another group, "halo" and "halogen" refer to fluoride (fluorine, -F), chloride (chlorine, -Cl), bromide (bromine, -Br), or iodide (iodine, -I).
As used herein, alone or as part of another group, "alkyl" refers to a monoradical of a straight or branched chain saturated hydrocarbon group having from 1 to 10 carbon atoms ("C t. 0"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1.9 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C < .5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("Ci-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("Ci. 2 alkyl"). In or some embodiments, an alkyl group has 1 carbon atom ("d alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2.6 alkyl"). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4) ), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5) and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group independently is unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") is substituted with 1, 2, 3, 4 or 5 substitutes as describes in the present. In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH 3). In certain embodiments, the alkyl group is a substituted C-0 alkyl.
"Perhaloalkyl" as defined herein refers to an alkyl group having from 1 to 10 carbon atoms wherein all hydrogen atoms each independently is halogen replaced, for example, selected from fluorine, bromine, chlorine or iodine ("perhaloalkyl of C-0"). In some embodiments, the alkyl portion of 1 to 8 carbon atoms ("perhaloalkyl of Ci. 8"). In some embodiments, the alkyl portion has 1 to 6 carbon atoms ("perhaloalkyl of d.6"). In some embodiments, the alkyl portion has 1 to 3 carbon atoms ("C1-3 perhaloalkyl"). In some embodiments, the alkyl portion has 1 to 2 carbon atoms ("C1-2 perhaloalkyl"). In some embodiments, all hydrogen atoms are each replaced with fluorine. In some embodiments, all hydrogen atoms are each replaced with chlorine. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCI3 > -CFCI2, -CF2CI and the like.
As used herein, alone or as part of another group, "alkenyl" refers to a monoradical or straight or branched chain hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds ( "C2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl") - In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2.7 alkenyl"). In some modalities, an alkenyl group has 2 to 6 carbon atoms ("C2.6 alkenyl") - In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2 5 alkenyl"). Alkenyl group has 2 to 4 carbon atoms ("C2.4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group It has 2 carbon atoms ("C2 alkenyl") The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C2-4 include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C) and the like Examples of alkenyl groups of C2-6 include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6) and the like Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrien ilo (C8) and similar. Unless otherwise specified, each instance of an independently alkenyl group is unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with 1, 2, 3, 4 or 5 substitutes as described in the present. In certain embodiments, the alkenyl group is an unsubstituted C2.io alkenyl. In certain embodiments, the alkenyl group is a substituted C2-io alkenyl.
As used herein, alone or as part of another group, "alkynyl" refers to a monoradical or straight or branched chain hydrocarbon group having from 2 to 10 carbon atoms and one or more triple carbon-carbon bonds ("C2-io alkynyl") - In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2_9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("alkynyl"). C2-8") - In some embodiments, an alkynyl group has 2 to 7 carbon atoms (" C 2-7 alkynyl "). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (" C 2-6 alkynyl "). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl") In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2- alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 ato carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4) and the like. Examples of C 2-6 alkynyl groups include the aforementioned C 2-4 alkynyl groups as well as pentinyl (C5), hexynyl (C6) and the like. Additional examples of alkynyl include heptinyl (C7), octynyl (C8) and the like. Unless otherwise specified, each instance of an independently alkynyl group is unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with 1, 2, 3, 4 or 5 substitutes as described in the present. In certain embodiments, the alkynyl group is an unsubstituted C2-io alkynyl. In certain embodiments, the alkynyl group is a substituted C2-io alkynyl.
A "divalent d-6 hydrocarbon group" is a divalent C 6 -alkyl group, divalent C 1-5 alkenyl group or divalent C 1-6 alkynyl group wherein one, two or three methylene units (-CH 2 - ) of the hydrocarbon chain are optionally and independently replaced with one or more oxygen, sulfur or nitrogen atoms. In certain embodiments, the divalent Ci.6 hydrocarbon group is a divalent C1-6 alkyl group. In certain embodiments, the divalent C1-6 hydrocarbon group is a group unsubstituted divalent C 1-6 hydrocarbon (for example, an unsubstituted divalent C 1-6 alkyl group).
As used herein, alone or as part of another group, "alkoxy" refers to an alkyl group, as defined herein, substituted with an oxygen atom, wherein the point of attachment is the oxygen atom . In certain embodiments, the alkyl group has 1 to 10 carbon atoms ("C1-10 alkoxy"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 alkoxy"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("d.e. alkoxy"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C-IV alkoxy.) Example of C1- alkoxy groups include methoxy (C-,), ethoxy (C2), propoxy (C3), isopropoxy ( C3), butoxy (C4), fer-butoxy (C5) and the like Examples of alkoxy groups of d-6 include the aforementioned Ci.4 alkoxy groups as well as pentyloxy (C5), isopentyloxy (C5), neopentyloxy (C5) ), hexyloxy (C6) and the like Additional examples of alkoxy include heptyloxy (C7), octyloxy (C8) and the like, Unless otherwise specified, each instance of the alkyl portion of the alkoxy group independently is unsubstituted (a "unsubstituted alkoxy") or substituted (a "substituted alkoxy") with 1, 2, 3, 4 or 5 substitutes as described herein In certain embodiments, the alkoxy group is an unsubstituted C2-io alkoxy (per example, -OCH3.) In certain embodiments, the alkoxy group is a substituted C2-io alkoxy (e.g., perhaloalkoxy as defined herein).
"Perhaloalkoxy" refers to an alkoxy group in which all the hydrogen atoms of the alkyl portion each are independently replaced with halogen atoms selected from fluorine, chlorine, bromine and iodine. In certain embodiments, the alkyl portion has 1 to 10 carbon atoms ("C1-10 perhaloalkoxy"). In certain embodiments, the alkyl portion has 1 to 8 carbon atoms ("C1-8 perhaloalkoxy"). In certain embodiments, the alkyl portion has 1 to 6 carbon atoms ("C1-6 perhaloalkoxy"). In certain embodiments, the alkyl portion has 1 to 4 carbon atoms ("C1.4 perhaloalkoxy"). In certain embodiments, the alkyl portion has 1 to 3 carbon atoms ("C1-3 perhaloalkoxy"). In certain embodiments, the alkyl portion has 1 to 2 carbon atoms ("C, .2" perhaloalkoxy). In some embodiments, all hydrogen atoms are each replaced with fluorine. In some embodiments, all hydrogen atoms are each replaced with chlorine. Examples of perhaloalkoxy groups include, but are not limited to, -OCF3, -OCF2CF3, -OCF2CF2CF3, -OCCI3, -OCFCI2, -OCF2CI and the like.
As used herein, alone or as part of another group, "carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C2-io carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbol atoms ("C3.8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carb atoms ("C3.6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbolic atoms ("C5 carbocyclyl 10"). Examples of C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) and the like. Examples of C3-8 carbocyclyl groups include the above-mentioned C3.6 carbocyclyl groups such as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo [2.2.1] heptanil, bicyclo [ 2.2.2] octanyl and the like. Examples of C3-i0 carbocyclyl groups include the above-mentioned C3.8 carbocyclyl groups as well as octahydro-1 H-indenyl, decahydronaphthalenyl, spiro [4.5] decanyl and the like. As the above examples illustrate, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic cabling") or polycyclic (e.g., containing a fused, bridged or spiral ring system such as a bicyclic system ("bicyclic carbocyclyl") ") or tricyclic system (" tricyclic carbocyclyl ")) may be saturated or may contain one or more double or triple carbon-carbon bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the attachment points are on the carbocyclyl ring. Unless otherwise specified, each carbocyclyl group independently is substituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with 1, 2, 3, 4 or 5 substitutes as described in I presented. In certain embodiments, the carbocyclyl group is an unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3.10 carbocyclyl.
In certain embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3.10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3.8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3.6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5.6 cycloalkyl"). In some modalities, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5.0 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3.6 cycloalkyl groups include the aforementioned C5.6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3.8 cycloalkyl groups include the aforementioned C3_6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group independently is unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with 1, 2, 3, 4 or 5 substitutes as described in the present. In certain embodiments, the cycloalkyl group is an unsubstituted C3_i0 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-10 cycloalkyl.
As used herein, alone or as part of another group, "heterocyclyl" refers to a radical of a non-aromatic ring system of 3 to 14 members having ring carbon atoms and 1 to 4 ring heteroatoms, in wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, since valence allows it. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiral ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and it can be saturated or it can contain one or more double or triple carbon-carbon bonds. Polycyclic heterocyclyl ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or ring systems wherein the The heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a non-aromatic 5-10 membered ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 5-10 membered heterocyclyl "). In some embodiments, a heterocyclyl group is a non-aromatic ring system of 5-8 members having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sugar (" 5-8 membered heterocyclyl "). In some embodiments, a heterocyclyl group is a non-aromatic ring system of 5-6 members having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 5-6 membered heterocyclyl "). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 member heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1 heteroatom include, without limitation, azirinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyls containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl and thiadiazolinyl. Heterocyclyl groups of 6 exemplary members containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Heterocyclyl groups of 6 exemplary members containing 2 hereroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Heterocyclyl groups of 6 exemplary members containing 2 heteroatoms include, without limitation, triazinanil. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and tiepanyl. Heterocyclic 8-membered heterocyclic groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahidroquinilinilo, tetrahydroisoquinolinyl, decahydroquinolinyl, decahidroisoquino-linilo, octahidrocromentilo, octahidroisocromenilo, decahidronaftiri-dinilo, decahydro-1, 8-naft¡ Ridinyl, octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1,4] diazepinyl, 1, 4,5,7-tetrahydropyran [3,4-b] ] pyrrolyl, 5,6-dihydro-4H-furo [3,2-b] pyrrolyl, 6,7-dihydro-5H-furo [3,2-b] pyran, 5,7-dihydro-4H-thieno [2 , 3-c] pyranyl, 2,3-dihydro-1 H -pyrrolo [2,3-b] pyridinyl, 2,3-dihydrofuro [2,3-b] pyridinyl, 4,5,6,7-tetrahydro- 1 H -pyrrolo [2,3-b] -pyridinyl, 4,5,6,7-tetrahydrofuro [3,2-c] pyridinyl, 4,5,6,7-tetrahydro-thieno [3,2-b] pyridinyl, 1, 2,3,4-tetrahydro-1,6-naphthyridinyl and the like. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with 1, 2, 3, 4 or 5 substitutes as described herein . In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
As used herein, alone or as part of another group, "aryl" refers to a radical of a monocyclic or polycyclic aromatic ring system (e.g., bicyclic or tricyclic) (e.g., having 6, 10 or 14 p electrons shared in a cyclic distribution) having 6-14 carbon ring atoms and zero heteroatoms provided in the aromatic ring system ("C6-1 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", for example phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("Ci0 aryl", for example, naphthyl such as 1-n aftyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl", eg, anthracyl). "Arilo" also includes ring systems where the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups wherein the radical or attachment point is on the aryl ring. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with 1, 2, 3, 4 or 5 substitutes as described in the present. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.
"Aralkyl" is a subset of "alkyl" and refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein, wherein the point of attachment is on the alkyl pon .
As used herein, alone or as part of another group, "heteroaryl" refers to a 5-14 member monocyclic or polycyclic aromatic ring system (e.g., bicyclic or tricyclic) ring (e.g. 6, 10 or 14 p shared electrons in a cyclic distribution) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( "heteroaryl 5-14 members"). In heteroaryl groups containing one or more nitrogen atoms, the fixation point can be a carbon or nitrogen atom, as valence allows. Polycyclic heteroaryl ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused to one or more aryl groups wherein the point of attachment is on the aryl or on the heteroaryl ring, or where the ring of heteroaryl, as defined above, is fused to one or more carbocyclic or heterocyclic groups wherein the point of attachment is on the heteroaryl ring. For polycyclic heteroaryl groups wherein a ring does not contain a heteroatom (for example, indolyl, quinolinyl, carbazolyl and the like) the attachment point can be on any ring, ie, whether the ring carries a heteroatom (eg. -indolyl) or the ring does not contain a heteroatom (for example, 5-indolyl). In some embodiments, a heteroaryl group is an aromatic ring system of 5-10 members having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-8 member heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 member aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary 5-membered heteroaryls containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, thiadiazolyl. Exemplary 5-membered heteroaryls containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryls containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryls containing 2 heteroatoms include, without limitation, pi ridazi or lo, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryls containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing 1 heteroatom include, without limitation, azepinyl, oxepinyl and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, without limitation, indole, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. . Exemplary 6,6-bicyclic heteroaryls include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryls include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with 1, 2, 3, 4 or 5 substitutes as described in the present. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
"Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl portion .
As used herein, the term "partially unsaturated" refers to a ring portion that includes at least one double or triple bond. The term "partially unsaturated" should encompass rings having multiple sites of unsaturation, but should not include aromatic groups (e.g., aryl or heteroaryl moieties) as defined herein.
The alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups, as defined herein, are optionally substituted (eg, "substituted" or "unsubstituted" alkyl group, "substituted" or "unsubstituted" alkenyl , "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterecyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl ). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present in a group (e.g., a carbon or nitrogen atom etc.) is replaced with a permissible substitute, for example, a substitute that upon substitution results in a stable compound, for example, a compound that does not pass spontaneously by transformation such as by rearrangement, cyclization , elimination or other reaction. Unless otherwise indicated, a "substituted" group has a substitute in one or more substitutable positions in the group, and when more than one position is replaced in a given structure, the substitute is the same or different in. each position.
Exemplary carbon atom substitutes include, but are not limited to, halogen (i.e., fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I)), -CN, -N02 , -N3, -S02H, -S03H, -OH, -ORaa, -ON (Rbb) 2, -N (R) 2, -N (R) 3 + X ", -N (ORcc) R b, -SH , -SRaa, -SSRCC, - C (= 0) Raa, -C02H, -CHO, -C (ORcc) 2, -C02Raa, -OC (= 0) Raa, -OC02Raa, -C (= 0) N ( Rbb) 2, -OC (= 0) N (Rbb) 2 > -NRbbC (= 0) Raa, -NRbbC02Raa, -NRbbC (= 0) N (Rbb) 2, -C (= NRbb) Raa, -C (= NRbb) ORaa, -OC (= NRbb) Raa, -OC (= NRbb) ORaa, -C (= NRbb) N) Rbb) 2, -OC (= NRbb) N (Rbb) 2, NRbbC (= NRbb ) N (Rbb) 2, -C (= 0) NRbbS02Raa, -NRbbS02Raa, -S02N (Rbb) 2, -S02Raa, -S02ORaa, -OS02Raa, -S (= 0) Raa, -OS (= 0) Raa, -Yes (Raa) 3, -Osi (Raa) 3 > -C (= S) N (Rbb) 2, -C (= 0) SRaa, -C (= S) SRaa, -SC (S) SRaa, -P (= 0) 2Raa, -OP (= 0) 2Raa, -P (= 0) (Raa) 2 > -OP (= 0) (Raa) 2, OP (= 0) (ORcc) 2, - P (= 0) 2N (Rbb) 2, -OP (= 0) 2N (R) 2, -P (= 0) (NRb) 2 > -OP (= 0) (NRbb) 2, -NRbbP (= 0) (ORcc) 2> -NRbbP (= 0) (NRbb) 2, -P (RCC) 2 > -P (RCC) 3 > -OP (Rcc) 2, -OP (Rcc) 3 , -B (ORcc) 2, -BRaa (OR "), C, alkyl. 10, perhaloalkyl Ci-10, alkenyl of C2.10, alkynyl of C2-io. carbocyclyl of C3. , 3-14 membered heterocyclyl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rdd groups; or two gemine hydrogens in a carbon atom are replaced with the group = 0, = S, = NN (Rbb) 2, = NNR bC (= 0) Raa, = NNRb C (= 0) ORaa, = NNRbbS (= 0 ) 2Raa, = NRbb, = NORcc; each instance of Raa is, independently, selected from Ci.i0 alkyl, Ci.i0 perhaloalkyl, C2.10 alkenyl, C2-10 alkynyl, C3_10 carbocyclyl, 3-14 membered heterocyclyl, C6 aryl. -i4 and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rdd groups; each Rbb instance is independently selected from hydrogen, -OH, -ORaa, -N (RCC) 2, -CN, -C (= 0) Raa, -C (= 0) N (Rcc) 2, -C02Raa , -S02Raa, -C (= NRcc) ORaa, -C (= NRCC) N (RCC) 2, -S02N (Rcc) 2, -S02Rcc, -S02ORcc, -SORaa, -C (= S) N (RCC) 2, -C () 0) SRcc, -C (= S) SRCC, -P (= 0) 2Raa, -P (= 0) (Raa) 2, -P (= 0) 2N (Rcc) 2, - P (= 0) (NRcc) 2, C1-10 alkyl, C1-10 perhaloalkyl, C2-io alkenyl. C2-io alkynyl. carbocyclyl of C3-0, heterocyclyl of 3-14 members, aryl of C6-14 and heteroaryl of 5-14 members, or two RCC groups attached to an atom of N join to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Ráü groups; each Rcc instance is independently selected from hydrogen, Ci-10 alkyl, CM0 perhaloalkyl, C2-10 alkenyl, C2.10 alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, C6 aryl .14 and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom come together to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 Rdd groups; each instance of Rdd independently is selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORee, - ON (Rf,) 2, -N (R, f) 2 > -N (Rff) 3 + X-, -N (ORee) Rff, -SH, -SRee, -SSRee, -C (= 0) Ree, -C02H, -C02Ree, -OC (= 0) Ree, -OC02Ree , -C (= 0) N (Rff) 2, -OC (= 0) N (Rff) 2 > -NRffC (= 0) Ree, -NRffC02Ree, -NRffC (= 0) (Rff) 2, -C (= NR, f) ORee, -OC (= NR, f) Ree, -OC (= NRff) ORee, -C (= NRff) N (Rff) 2, -OC (= NRff) N (Rff) 2, -NRffC (= NRff) N (R f) 2, -NRffS02Ree, -S02N (Rff) 2, -S02Ree, -S02ORee, -OS02Ree, -S (= 0) Ree, -Yes (Ree) 3, -OSi (Ree) 3, -C (= S) N (Rff) 2, -C (= 0) SRee, -C (= S) SRee, -SC (= S) SRee, -P (= 0) 2Ree, -P (= 0) 2Ree, -P (= 0) (Ree) 2, -OP (= 0) (Ree) 2, -OP (= 0) (ORee) 2, C1-10 alkyl, C1- 0 perhaloalkyl, C2.i0 alkenyl, C2.10 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6.io aryl and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R "groups, or two Derivatives Rdd Gemmals can be put together to form = 0 or = S; each Ree instance independently is selected from C1- 0 alkyl, C1-10 perhaloalkyl, C2.i0 alkenyl, C2-0 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6 aryl 10 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R "groups; each Rff instance is independently selected from hydrogen, Ci.10 alkyl, C 1 .e. perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C6.10 aryl and 5-10 membered heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R "groups; each instance of R "is independently halogen, -CN, -N02, -N3, -S02H, -SO3H, -OH, -alkyl of OC, .6, -ON (alkyl of d-6) 2, -N (alkyl) C1-6) 2, -N (-NH alkyl (C6 alkyl) 2X, -NH2 (C1-6 alkyl) X, -NH3X, -N (Od.6 alkyl) (alkyl of C1-6), -N (OH) (C1-6 alkyl), -NH (OH), -SH, -alkyl of SC, .6l -SS (C1-6 alkyl), -C (= 0 ) NH2, -C (= 0) N (alkyl of de) 2, -OC (= 0) NH (C1-6 alkyl), -NHC (= 0) (Ci.B alkyl), -N (alkyl) of d-6) C (= 0) (C 1-6 alkyl), -NHC02 (alkyl of de), -NHC (= 0) N (C 1-6 alkyl) 2, -NHC (= 0) NH (alkyl of d-6), -NHC (= 0) NH2, -C (= NH) 0 (alkyl of d-6), -OC (= NH) (alkyl of Ci.e), -OC (= NH) alkyl of OC, .6, -C (= NH) N (alkyl of de) 2, -C (= NH) NH (alkyl of C, .6), -C (= NH) NH2, -OC ( = NH) N (alkyl of, -OC (NH) NH (at Iq of C1-6), -OC (NH) NH2, -NHC (NH) N (alkyl of of, -NHC (= NH) NH2, NHS02 (alkyl of), -S02N (alkyl of) 2, -S02NH (C1-6 alkyl), -S02NH2, -S02alkyl of, -S02alkyl of Od-e, -OS02alk C 1-6 alkyloyl, C 1-6 alkyl, -Si (to C 1 to C 6) 3, -OS 1 (C, 6 alkyl) 3, -C (= S) N ( C 1-6 alkyl) 2, C (= S) NH (alkyl of de), C (= S) NH 2, -C (= 0) S (alkyl of de), -C (= S) S-alkyl of of, -SC (= S) S-alkyl of de. -P (= 0) 2 (d-e alkyl). -P (= 0) (alkyl of d.6) 2, -OP (= 0) (Ci.6 alkyl) 2, -OP (= 0) (alkyl of Od-e, alkyl of d-6, perhaloalkyl of CT.6, C2.6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 5-10 membered heteroaryl, or two R "gemlic substitutes can join to form = 0 or = S; where X "is a counterion.
As used herein, a "counterion" is a negatively charged group associated with a positively charged quaternary amine in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F ", CI", Br, I "), N03", CI04", OH", H2P04", HS04 sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p- toluene sulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate and the like) and carboxylate ions (eg, acetate) , ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate and the like).
Nitrogen atoms can be substituted or unsubstituted as valence allows, and include primary, secondary, tertiary and quaternary nitrogen atoms. Exemplary nitrogen atom substitutes include, but are not limited to, hydrogen, -OH, -ORaa, -N (RCC) 2, -CN, -C (= 0) Raa, -C (= 0) N (Rcc ) 2, -C02Raa, -S02Raa, -C (= N Rbb) Raa, -C (= NRcc) ORaa, -C (= NR ") N (RCC) 2, -S02N (Rcc) 2, -S02Rcc, - S02ORcc, -SORaa, C (= S) N (RCC) 2, -C (= 0) SRcc, -C (= S) SRCC, -P (= 0) 2Raa, - P (= 0) (Raa) 2 , -P (= 0) 2N (Rcc) 2, -P (= 0) (NRcc) 2, C, .10 alkyl, perhaloalkyl of d.10, C2.10 alkenyl, C2_10 alkynyl, C3 carbocyclyl. 10, heterocyclic of 3-14 members, aryl of C6.14 and heteroaryl of 5-14 members, or two Rcc groups attached to an N atom is put together to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups Rdd, and where Raa, Rbb, Rcc and Rdd as defined above.
In certain embodiments, the substitute present on the nitrogen atom is an amino protecting group. Amino protecting groups include, but are not limited to, -OH, -ORaa, -N (RCC) 2, -C (= 0) Raa, -C (= 0) N (Rcc) 2, -C02Raa, -S02Raa, -C (= NRcc) Raa, -C (= NRcc) ORaa, -C (= NRCC) N (RCC) 2, -S02N (R ") 2, -SO2OR0c, -SORaa, -C (= S) N (Rcc) 2, -C (= 0) SRcc, -C (= S) SRCC, C1-10 alkyl groups (for example, aralkyl groups), C2.10 alkenyl, C2-10 carbocyclyl C2-10 alkynyl, 3-14 membered heterocyclyl, C6.1 aryl and heteroaryl of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd they are as defined above.Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley &; Sons, 1999, which is incorporated herein by reference.
For example, amino protecting groups such as amide groups (e.g., -C (= 0) Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, A / -benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (/ V'-dithiobenzyloxycarbonylamino) acetamide, 3- (p -hydroxyphenyl) propanamide, 3- (o-nitrophenyl) propanamide, 2-methyl-2- (o-nitrophenoxy) propanamide, 2-methyl-2- (o-phenylazophenoxy) propanamide, 4-chlorobutanamide, 3-methyl-3- nitrobutanamide, o-nitrocinamide, derivative of / V-acetylmethionine, o-nitrobenzamide and o- (benzoyloxymethyl) benzamide.
Amino protecting groups such as carbamate groups (eg, -C (= 0) ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), carbamate 9- (2-sulfo) f-luorenylmethyl, carbamate of 9- (2,7-dibromo) fluorenylmethyl, 2,7-d if-butyl- [9- (10,10-d -oxo-10,10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc) ), 4-methoxyphenacyl carbamate (Fenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adam) carbamate anti I) - 1 -m et i leti lo (Adpoc), carbamate, 1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-f-BOC), carbamate of 1 , 1-d-imethyl-2, 2, 2-trichloroethyl (TCBOC), 1-methyl-1- (4-biphenyl) ethyl carbamate (Bpoc), 1- (3,5-di-f-butylphenyl) carbamate -1-methylethyl (f-Bumeoc), 2- (2'- and 4'-pyridyl) ethyl carbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethyl carbamate, f-butyl carbamate ( BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate or (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, carbamate of A / -hydroxypropyl Nyl, alkyldithium carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, carbamate of 4-methylsulfinylbenzyl (Msz), 9-anthrylmethyl carbamate, d ife carbamate or methyl I, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, carbamate 2- (p-toluesulfonyl) ethanol, carbamate of [2] - (1,3-dithynyl)] methyl (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphononoethyl carbamate (Peoc), 2-triphenylphosphonisoisopropyl carbamate (Ppoc) ), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboronyl) benzyl carbamate, 5-benzisoxazolylmethyl carbamate, carbamate 2- (trifluoromethyl) -6-chromonyl-methyl (Troc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, carbamate 3,4-dimethoxy-6-nitrobenzyl, phenyl carbamate (o-nitrophenyl) methyl, f-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate , 2,2-dimethoxycarbonylvinyl carbamate, o- (N, A / -dimethylcarboxamido) benzyl carbamate, 1,1-dimethyl-3- (V, / V-dimethylcarboxamide) carbamate, propyl , 1, 1- dimethylpropynyl carbamate, di (2-pyridyl) methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, sobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p- carbamate (p '-methoxyphenylazole) benzyl, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl I-1-cyclopropyl-methyl carbamate, 1-methyl-1 - (3,5-dim) carbamate ethoxyphenyl) ethyl, 1-methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenyl) benzyl carbamate, 2,4,6-tri-f-butylphenyl carbamate, 4- carbamic acid (trimethylammonium) benzyl and 2,4,6-trimethylbenzyl carbamate.
Amino protecting groups such as sulfonamide groups (eg, -S (= 0) 2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetra-methyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), ß-trimethylsilylethanesulfonamide (Mts), DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide.
Other amino protecting groups include, but are not limited to, phenothiazinyl- (10) -carbonyl derivative,? / '-? - toluene-sulfonylaminocarbonyl derivative, A /' -phenylaminothiocarbonyl derivative, A / -benzoylphenylalanyl derivative, derivative of A / -acetylmethionine, 4,5-diphenyl-3-oxazolin-2-one, A / -phthalimide, / V-dithiasuccinimide (Dts),? / - 2.3- diphenylmaleimide, A-2,5-dimethylpyrrole, adduct of N- 1, 1, 4, 4-tetramethyl-disilazaciclopentane (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 1,3-dibencM-1, 3,5 -triazacyclohexan-2-one 5-substituted, 3,5-dinitro-4-pyridone 1 -substituted, / V-methylamine, N-allylamine, A / - [2- (trimethylsilyl) etoi] methylamine (SEM), A / -3-acetoxypropyl-amine, A / - (1-isopropyl-4-nitro-2-oxo-3-piroolin-3-yl) amine, quaternary ammonium salts, A / -benzylamine, A / -di (4- methoxyphenyl) methylamine, N-5-dibenzosuberylamine, A / -trifenylmethylamine (Tr), / V - [(4-methoxyphenyl) -diphenylmethyl] amine (MMTr), / V-9-phenylfluorenylamine (PF), N-2 , 7-dichloro-9-fluorenylmethyleneamine , / V-ferrocenylmethylamino (Fcm),? / - 2-picolylamino,? '-oxide,? / - 1, 1 -dimethylthiomethyleneamine, A / -benzylidene-amine, A / -p-methoxybenzylideneamine, / V-diphenylmethyleneamine, N - [(2-pyridyl) mesityl] methyleneamine, A / - (/ \ / ', / \ /' - dimethylaminomethylene) amine,? / ',? /' - isopropylidene diamine, A / -p-nitrobenzylideneamine, A / -salicyl -denoamine, A / -5-chlorosalicylideneamine, A / - (5-chloro-2-hydroxyphenyl) -phenylmethyleneamine, / V-cyclohexylideneamine, A / - (5,5-dimethyl-3-oxo-1-cyclohexyl) amine, derivative of / V-borane, N-diphenylborinic acid derivative, A / - [phenyl (pentacarbonylchromium- or tungsten) carbonyl] -amine, / V-copper chelate, / V-zinc chelate, / V-nitroamine, / V-nitro-soamine, A / -amine oxide, diphenylphosphinemide (Dpp), dimethylthiophosphonamide (Mpt), diphenylthiophosphonamide (Ppt), dialkyl phospho-ramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps) , 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3-nitropyridine-sulfenamide (Npys).
As used herein, a "leaving group" is a term that is understood in the art to be reiterated to a molecular fragment that moves away with a pair of electrons in heterolitic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
These and other exemplary substitutes are described in more detail in Detailed Description, the Exemplification and in the claims. The invention should not be limited in any way by the previous exemplary list of substitutes.
As used herein, a "pharmaceutically acceptable form thereof" includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, isomers and / or polymorphs of a compound of the present invention, as defined below and herein .
As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are within the scope of the physician's judgment, suitable for use in contact with tissues of humans and minor animals without undue toxicity, irritation, allergic response. and similar, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. Describe pharmaceutically acceptable salts in detail in "J. Pharmaceutical Sciences", 1977, 66, 1-19. The pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate salts , hemisulfate, heptanoate, hexanoate, iodohydrate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. The salts are derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (alkyl of 1-4) salts. Representative salts of alkali or alkaline earth metal include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and a-i-sulfonate.
In certain embodiments, the pharmaceutically acceptable form thereof is an isomer. As used herein, the term "isomer" includes any and all geometric isomer and stereoisomer. For example, "isomers" include cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof and other mixtures thereof, such as dropping within the scope of the invention.
In certain embodiments, the pharmaceutically acceptable form thereof is a tautomer. As used herein, the term "tautomer" includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond or a double bond, a triple link to a single link, or vice versa). The exact relationship of the tautomeros depends on several factors, including temperature, solvent and pH. Tautomerizations (ie, the reaction provided by a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include tautomerizations of keto-a- enol; amide-to-amide; lactam-a-lactim; enamine-to-imine; and enamine-a- (a different one) -enamine.
In certain embodiments, the pharmaceutically acceptable form thereof is a hydrate or solvate. As used herein, the term "hydrate" refers to a compound not covalently associated with one or more molecules of water. Also, "solvate" refers to a compound not covalently associated with one or more molecules of an organic solvent.
In certain embodiments, the pharmaceutically acceptable form thereof is a prodrug. As used herein, the term "prodrug" refers to a derivative of an origin compound that requires transformation within the body in order to release the parent compound. In certain cases, a prodrug has improved physical and / or administration properties on the parent compound. Prodrugs are typically designed to improve the pharmaceutically and / or pharmacokinetically based properties associated with the parent compound. The advantage of a prodrug may depend on its physical properties, such as enhanced water solubility for parenteral administration at physiological pH as compared to the parent compound, or potentiates the absorption of the digestive tract, or may enhance the stability of drugs for long-term storage. term.
In certain embodiments, the pharmaceutically acceptable form thereof is a polymorph. As used herein, "polymorph" refers to a compound having more than one crystal structure, for example, resulting from differences in molecular packaging and / or molecular conformation of the compound in the solid state.
SEQUENCE IDENTIFICATION NUMBERS SEC. ID. NO .: amino acid sequence Homo sapiens FAAH: MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRAGLENM DRAAQRFRLQNPDLDSEALLALPLPQLVQ LHSRELAPEAVLFTYVG AWEVN GTNC VTSYLADCETQLSQAPRQGLLYGVPVSL ECFTY GQDSTLGLSLNEGVPAECDSVVVH VLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPW SS SPGGSSGGEGALIGSGGSP LGLGTDIGGSIRFPSSFCGICGLI PTGNRLS SGL GCVYGQEAVRLSVGPMARDVESLA LCLRALLCEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETK QSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNF GDFVDPCLGDLVSIL -LP QWL GLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDV VLTP LAPALDLNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGY FGDIWD MLQ GMKKSVGLPVAVQCVALPWQEELCLRF REVERL TPEKQSS DETAILED DESCRIPTION /. Compounds The present invention provides FAAH inhibitor compounds of isoxazoline of the formula (I): Rd (I) or a pharmaceutically acceptable form thereof, where each of Ra, Rb and Rc independently is selected from -H, C1-10 alkyl and Ci.io perhaloalkyl, Rd is the group -L-Z, and Z is selected from C6-14 aryl; each of Ra, R and Rc independently is selected from -H, Ci.-io alkyl and Ci-10 perhaloalkyl, Rd is the -LZ gruop, and Z is selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl; Ra and Rd come together to form a fused carbocyclyl ring of C3-0 or 3-14 membered heterocyclyl, and Rb and Rc independently are selected from -H, C00 alkyl and C1- 0 perhaloalkyl; or Rc and Rd are joined to form a spiro-fused carbocyclyl ring of C3.i0 or 3-14 membered heterocyclyl, and Ra and Rb are independently selected from-H, C1-10 alkyl and Ci-10 perhaloalkyl.; L is a covalent bond or a divalent C1-6 hydrocarbon group, wherein one, two or three methylene units of L are optionally and independently replaced with one or more oxygen, sulfur or nitrogen atoms; G is selected from -CN, -N02, -S (= 0) Re, -SQ2NRfRe, -P02Re, -P02ORe, -P02NRfRe, - (C = 0) Re, - (C = 0) ORe, - ( C = 0) NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -ONRf (C = 0) Re, -ON RfS02Re, -ONRfP02Re, -ONRfP02ORe, -SRe, -OS02Re, - NRfS02R3, -OP02Re, -OP02ORe, -NRfP02Re, -NR P02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, -NRf (C = 0) Re, -NRf (C = 0) ORe, -0 (C = 0) N RfRe, -NRf (C = NRf) NRfRe, -0 (C = NRf) NRfRe, -NRf (C = NRf) ORe, - [N (Rf) 2Re] + X "where X" is a counter ion; Y each Re is selected from C1-O alkyl, alkenyl from C2-1o, C2-io alkynyl, C3.10 carbocyclyl, C6.1 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each Rf attached to a nitrogen atom independently is selected from -H, C1-10 alkyl or an amino protecting group; or Re and Rf are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.
Group G As defined above, G is selected from -CN, -N02, -S (= 0) Re, -S02NRfRe, -P02Re, -P02ORe, -P02NRfRe, - (C = 0) Re, - (C = 0) ) ORe, - (C = 0) NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -ONRf (C = 0) Re, -ONR'SOzR6, -ONRfP02Re, -ONRfP02ORe, - SRe, -OS02Re, -NRfS02R3, -OP02Re, -OP02ORe, -NRfP02Re, -NRfP02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, -NRf (C = 0) ) Re, -NRf (C = 0) ORe, -0 (C = 0) NRfRe, -NRf (C = NRf) NRfRe, -0 (C = N Rf) Rf Re, -NRf (C = NRf) ORe, - [N (Rf) 2Re] + X "where X" is a counter ion; and wherein Re is selected from C ^ or alkyl, C2.10 alkenyl, C2-io alkynyl > C3-io carbocyclyl, C6 aryl. 4, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each Rf attached to a nitrogen atom independently is selected from -H, C 1 0 alkyl or an amino protecting group; or Re and Rf are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.
In certain embodiments, G is not a leaving group, for example, G is selected from -F, -CN, -N02, -S (= 0) Re, -S02Re, -S02NRfRe, -P02Re, -P02ORe, - P02NRfRe, - (C = 0) Re, - (C = 0) ORe and - (C = 0) NRfRe.
In certain embodiments, G is selected from -CN and -N02. In certain modalities, G is -CN. In certain modalities, G is -N02.
In certain embodiments, G is selected from -S (= 0) Re, -S02Re and -S02NRfRe. In certain modalities, G is -S (= 0) Re. In certain modalities, G is -S02Re. In certain embodiments, G is -S02N RfRe.
In certain embodiments, G is selected from -P02Re, -P02ORe and -P02NRfRe. In certain modalities, G is -P02Re. In certain modalities, G is -P02ORe. In certain modalities, G is -P02NRfRe.
In certain modalities, G is selected from - (C = 0) Re, - (C = 0) ORe and - (C = 0) NRfRe. In certain modalities, G is - (C = 0) Re. In certain modalities, G is - (C = 0) ORe. In certain modalities, G is - (C = 0) NRfRe.
However, in certain embodiments, G is a leaving group, for example, G is selected from -Cl, -Br, -I, -ORe, -ONRfRe, -ONRf (C = 0) Re, -ONRfS02Re, - ONRfP02Re, -ONRfP02ORe, -SRe, -OS02Re, -NRfS02R3, -OP02Re, -OP02ORe, -NRfP02Re, -NRfP02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, -NRf (C = 0) Re, -NRf (C = 0) ORe, -0 (C = 0) NRfRe, - Rf (C = N Rf) RfRe, -0 (C = NRf) NRfRe, -NRf (C = NRf) ORe and - [N (Rf) 2Re] + X 'where X "is a counter ion.
In certain embodiments, G is a halogen, that is, selected from -F, -Cl, -Br and -I. In certain modalities, G is -F. In certain modalities, G is -Br. In certain modalities, G is -I. In certain modalities, G is -Cl. However, in certain modalities, G is not a halogen. For example, in certain modalities, G is not -Br. In certain modalities, G is not -I. In certain modalities, G is not -F. In certain modalities, G is not -Cl.
In certain embodiments, G is selected from -ORe, -ONRfRe, -ONRf (C = 0) Re, -ONR S02Re, -ONRfP02Re, -ONRfP02ORe, -SRe, -OS02Re, -OP02Re, -OP02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -0 (C = 0) NRfRe and -0 (C = NRf) NRfRe. In certain embodiments, G is selected from -ORe, -0 (C = 0) Re, -0 (C = 0) ORe, -0 (C = 0) NRfRe and -0 (C = NRf) NRfRe. In certain embodiments, G is selected from -ONRfRe, -ONRf (C = 0) Re, -ONRfS02Re, -ONRfP02Re, -ONRfP02ORe, -OP02NRfRe, -0 (C = 0) NRfRe and -0 (C = NRf) NRfRe. In certain modalities, G is -ORe. In certain modalities, G is -ONRfS02Re. In certain modalities, G is -ONRfP02Re. In certain modalities, G is -OP02Re. In certain modes, G is -OP02ORe. In certain modalities, G is -OP02NRfRe. In certain modalities, G is -0 (C = 0) Re. In certain modalities, G is -0 (C = 0) ORe. In certain modalities, G is -0 (C = 0) NRfRe. In certain modalities, G is -0 (C = NRf) NRfRe.
In certain modalities, G is selected from -ORe and -SRe. In certain modalities, G is selected from -ORe. In certain modalities, G is -SRe.
In certain embodiments, G is selected from -NRfS02Re, -NRfP02Re, -NRfP02ORe, -NRfRe, -NRf (C = 0) Re, -NRf (C = 0) ORe, -NRf (C = NRf) NRfRe, - NRf (C = NRf) ORe and - [N (Rf) 2Re] + X ~ where X "is a counterion In certain embodiments, G is selected from -NRfS02Re, -NRfP02Re, -NRfP02ORe, -NRfRe, - NRf (C = 0) Re y - NRf (C = 0) ORe. In certain modalities, G is -NRfS02Re. In certain modalities, G is -NRfP02Re. In certain modalities, G is -NRfP02ORe. In certain modalities, G is -NRfRe. In certain modalities, G is -NRf (C = 0) Re. In certain modals, G is -NRf (C = 0) ORe. In certain embodiments, G is -NRf (C = NRf) NRfRe. In certain modalities, G is -NRf (C = NRf) ORe. In certain modalities, G is - [N (Rf) 2Re] + X "where X" is a counter ion.
Additional modalities of G, included in the description of the groups Re and Rf, and exemplified more in the Tables and Examples, are provided below and in the present.
Re of Group G As generally defined before, in certain embodiments, where G is selected from -S (= 0) Re, -S02Re, -S02NRfRe, -P02Re, -P02ORe, -P02NRfRe, - (C = 0) Re , - (C = 0) ORe, - (C = 0) NRfRe, -ORe, -ONRfRe, -ONRf (C = 0) Re, -ONRfS02Re, -ONRfP02Re, ONR'P02ORe, -SRe, -OS02Re, -NRfS02R3 , -OP02Re, -OP02ORe, -NRfP02Re, -NRfP02ORe, -OP02NR (Re, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, -NRf (C = 0) Re, -NRf (C = 0) ORe, -0 (C = 0) NRfRe, NRf (C = NRf) NRfRe, -0 (C-NRf) NRfRe, - N Rf (C = N Rf) 0 Re, - [N (Rf) 2Re] + X "where X" is a counter ion, Re selects from Ci.io alkyl, C2 alkenyl. 0, C2.10 alkynyl, C3.10 carbocyclyl, C6-14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl.
In certain embodiments, Re is selected from C-10 alkyl, C2-io alkenyl, C2-io alkynyl. carbocyclyl of C3-0, aryl of C6-14, heterocyclyl of 3-14 members and heteroaryl of 5-14 members, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are substituted with 0.1. , 2, 3, 4 or 5 Rh groups, as defined below and in the present.
In certain embodiments, Re is Ci_10 alkyl. In certain embodiments, Re is C1-6 alkyl. In certain embodiments, Re is C1-6 alkyl substituted with 0. 1, 2, 3, 4 or 5 R groups. In certain embodiments, Re is a C 1-5 alkyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a C1.4 alkyl substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Re is a C1-3 alkyl substituted with 0, 1, 2 or 3 Rh groups. In certain embodiments, Re is a C 2 alkyl substituted with 0, 1, or 2 Rh groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl, wherein said groups are substituted with 0.1. , 2, 3, 4 or 5 Rh groups.
In certain embodiments, Re is a C1-6 perhaloalkyl. In certain embodiments, Re is a perhaloalkyl of C ^. In certain embodiments, Re is a perhaloalkyl of C, .4. In certain embodiments, Re is a perhaloalkyl of C ^. In certain embodiments, Re is a perhaloalkyl of C 2- Perhaloalkyl groups Re include, but are not limited to, -CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2 and -CFCI2.
In certain embodiments, Re is alkenyl of C-10. In certain embodiments, Re is C2-6 alkenyl. In certain embodiments, Re is C2-6 alkenyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a C2.5 alkenyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a C2-3 alkenyl substituted with 0, 1, 2 or 3 Rh groups. Exemplary alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl and hexenyl, wherein said groups are substituted with 0, 1, 2 , 3, 4 or 5 Rh groups.
In certain embodiments, Re is C2-io alkynyl- In certain embodiments, Re is C2.6 alkynyl. In certain embodiments, Re is C2-6 alkynyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is C2.5 alkynyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is C2- alkynyl substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Re is C2-3 alkynyl substituted with 0, 1, 2 or 3 Rh groups. Exemplary alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl and hexynyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
However, in certain embodiments, wherein G is -ORe, then Re is not C1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, aralkyl). In certain embodiments, where G is -ORe, then Re is not alkenyl of C2.6 (eg, allyl).
In certain embodiments, wherein G is -SRe, then Re is not C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, aralkyl).
In certain embodiments, wherein G is -NReRf and Rf is -H or C 1-3 alkyl (eg, methyl, ethyl, aralkyl), then Re is not Ci-6 alkyl.
In certain modalities, Re is aril of C6.14. In certain embodiments, Re is aryl of C6_10- In certain embodiments, Re is C6-io aryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is aryl of C6 (eg, phenyl) substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a Cyl aryl (for example, naphthyl) substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
In certain embodiments, Re is phenyl. In certain embodiments, Re is phenyl substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Re is phenyl substituted with 0. 1, 2 or 3 Rh groups. In certain embodiments, Re is phenyl substituted with 0, 1 or 2 Rh groups. In certain embodiments, Re is phenyl substituted with 0 or 1 Rh group. In certain embodiments, Re is a disubstituted phenyl (i.e., substituted with 2 Rh groups). In certain embodiments, Re is a monosubstituted phenyl (i.e., substituted with 1 Rh group). In certain embodiments, Re is an unsubstituted phenyl (i.e., substituted with 0 Rh groups).
In certain embodiments, Re is phenyl substituted with at least one ortho Rh group. In certain embodiments, Re is phenyl substituted with at least one Rh meta group. In certain embodiments, Re is phenyl substituted with at least one Rh group.
In certain embodiments, Re is a phenyl group of the formula (i-a) where x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and in the present. In certain modalities, x is 0, 1, 2, 3 or 4. In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1. In certain embodiments, x is 3. In certain embodiments, Re is a disubstituted phenyl group (ie, where x is 2). In certain embodiments, Re is a monosubstituted phenyl group (ie, wherein x is 1). In certain embodiments, Re is an unsubstituted phenyl group (ie, wherein x is 0).
For example, in certain embodiments, Re is a substituted or unsubstituted phenyl group of any of the formulas: where R is as defined below and in the present. In certain modalities, Re is a naphthyl. In certain embodiments, Re is a naphthyl group of any of the formulas: (i-b) or (i-c) where x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and in the present. In certain modalities, x is 0, 1, 2, 3 or 4. In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1. In certain embodiments, Re is a trisubstituted naphthyl group (ie, where x is 3). In certain embodiments, Re is a disubstituted naphthyl group (ie, where x is 2). In certain embodiments, Re is a monosubstituted naphthyl group (ie, where x is 1). In certain embodiments, Re is an unsubstituted naphthyl group (ie, where x is 0).
For example, in certain embodiments, Re is a substituted or unsubstituted 1-naphthyl group of any of the formulas: I presented.
In certain modalities, Re is a naphthyl. In certain embodiments, Re is a 2-naphthyl group of any of the formulas: where Rn is as defined below and in the present. However, in certain embodiments, where G is -ORe, then Re is not aryl of C10 (eg, 1-naphthyl, 2-naphthyl).
In certain embodiments, Re is heteroaryl of 5-14 members. In certain embodiments, Re is a 5-10 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 5-8 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 5-6 membered heteroaryl substituted with 0, 1, 2, 3 or 4 R groups. In certain embodiments, Re is a 9-10 member heteroaryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
Exemplary heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3- pyridinyl, 4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl , indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranilo, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, f ta I azine I, quinazolinyl, fenantridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
In certain embodiments, Re is a 5-membered heteroaryl. In certain embodiments, Re is a 5-membered heteroaryl substituted with 0, 1, 2 or 3 Rh groups. In certain embodiments, Re is a 5-membered heteroaryl selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, wherein said groups are substituted with 0, 1, 2 or 3 Rh groups.
For example, in certain embodiments, Re is a 5-membered heteroaryl of the formula: (i-d) where Ya, Yb, Y ° and Yd independently are selected from CH, CRh, O, S, N or NRk, with the proviso that at least one of Ya, Yb, Yc and Yd is O, S, N or NRk, and where Rh and Rk are defined later and in the present.
In certain embodiments of the above formula (id), Ya is O, S, N or NRk and Y, Yc and Yd independently are selected from CH, CRh, NRk or N. In certain modalities of the previous formula (id) , Is already O, S, N or NRk and Yb, Yc and Yd independently are selected from CH or CRh. In certain embodiments of the above formula (i-d), Ya is O, S or NRk, Yc is N and Yb and Yd independently are selected from CH or CRh.
In certain embodiments of the above formula (id), Ya is O, S or NRk e Ya, Yc and Yd independently are selected from CH, CRh or N. In certain modalities of the previous formula (id), Yb is O , S or NRk e Ya, Yc and Yd independently are selected from CH or CRh. In certain embodiments of the above formula (i-d), Yb is O, S or NRk, Yd is N e Ya and Y ° independently are selected from CH or CRh.
In certain embodiments, Re is a substituted or unsubstituted 5-membered heteroaryl of any of the formulas: wherein x is 0, 1 or 2, and Rh and Rk are as defined below and herein. In certain embodiments, Re is an unsubstituted 5-membered heteroaryl (ie, wherein x is 0). In certain embodiments, Re is a substituted 5-membered heteroaryl (e.g., where x is 1 or 2). In certain embodiments, Re is a monosubstituted 5-membered heteroaryl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted 5-membered heteroaryl (ie, wherein x is 2). In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
However, in certain embodiments, where G is -ORe, Re thiazolyl, for example, of the formula: wherein x is 0, 1 or 2, and Rh and Rk are as defined below and herein.
In certain embodiments, Re is a 6-membered heteroaryl. In certain embodiments, Re is a 6-membered heteroaryl substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Re is a 6-membered heteroaryl selected from the group consisting of pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl) , pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazinyl, wherein said groups are substituted with 0, 1, 2, 3 or 4 Rh groups.
For example, in certain embodiments, Re is a 6-membered heteroaryl group of the formula: (i-e) where Wa, Wb, Wc, Wd and We are independently selected from CH, CRh or N, with the proviso that at least one of Wa, Wb, W °, Wd and We is N and where Rh is as defined below and in the present.
In certain embodiments, Re is a pyrindinyl group. In certain embodiments, Re is a pyrindinyl group substituted with 0, 1, 2, 3 or 4 Rh groups. For example, in certain embodiments, Re is a pyrindinyl group of the formula: wherein x is 0, 1, 2, 3 or 4 and R is as defined below and in the present. In certain embodiments, Re is an unsubstituted pyrindinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted pyrindinyl (e.g., where x is 1, 2, 3 or 4). In certain embodiments, Re is a monosubstituted pyrindinyl (ie, where x is 1). In certain embodiments, Re is a disubstituted pyrindinyl (ie, where x is 2). In certain embodiments, Re is a trisubstituted pyrindinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 2-pyrindinyl group, for example, of the formula (i-e) wherein Wa is N and Wb, Wc, Wd and We independently are CH or CRh. In certain embodiments, Re is a 3-pyrindinyl group, for example, of the formula (i-e) wherein Wb is N and Wa, Wc, Wd and We independently are CH or CRh. In certain embodiments, Re is a 4-pyrindinyl group, for example, of the formula (i-e) wherein Wc is N and Wa, Wb, Wd and We independently are CH or CRh.
In certain embodiments, Re is a substituted or unsubstituted 2-pyridinyl group of any of the formulas: where Rh is as defined below and in the present. In certain embodiments, Re is a substituted or unsubstituted 3-pyridinyl group of any of the formulas: where R is as defined below and in the present. In certain embodiments, Re is a substituted or unsubstituted 4-pyridinyl group of any of the formulas: where Rh is as defined below and in the present.
In certain embodiments, Re is a pyridazinyl group. In certain embodiments, Re is a pyridazinyl group substituted with 0, 1, 2 or 3 Rh groups. For example, in certain embodiments, Re is a pyridazinyl group of the formula: where x is 0, 1, 2 or 3 and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted pyridazinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted pyridazinyl (for example, where x is 1, 2 or 3). In certain embodiments, Re is a monosubstituted pyridazinyl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted pyridazinyl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted pyridazinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 3-pyridazinyl group, for example, of the formula (i-e) wherein Wa and W are N and Wc, Wd and We independently are CH or CR. In certain embodiments, R ° is a 4-pyridazinyl group, for example, of the formula (i-e) wherein Wb and Wc are N and Wa, Wd and We independently are CH or CRh.
In certain embodiments, Re is a substituted or unsubstituted 3-pyridazinyl group of any of the formulas: 'o where Rh is as defined below and in the present. In certain embodiments, Re is a substituted or unsubstituted 4-pyridazinyl group of any of the formulas: where Rh is as defined below and in the present.
In certain embodiments, Re is a pyrimidinyl group. In certain embodiments, Re is a pyrimidinyl group with 0, 1, 2 or 3 Rh groups. For example, in certain embodiments, Re is a pyrimidinyl group of the formula: where x is 0, 1, 2 or 3, and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted pyrimidinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted pyrimidinium (for example, where x is 1, 2 or 3). In certain embodiments, Re is a monosubstituted pyrimidinium (ie, where x is 1). In certain embodiments, Re is a disubstituted pyridazinyl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted pyrimidinium (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 2-pyrimidinyl group, for example, of the formula (i-e) wherein Wa and We are N and Wb, Wc and Wd independently are CH or CRh. In certain embodiments, Re is a 4-pyrimidinyl group, for example, of the formula (i-e) wherein Wa and W ° are N and Wb, Wd and We independently are CH or CRh. In certain embodiments, Re is a 5-pyrimidinyl group, for example, of the formula (i-e) wherein Wb and Wd are N and Wa, Wc and We independently are CH or CRh.
In certain embodiments, Re is a substituted or unsubstituted 2-pyrimidinyl group of any of the formulas: where Rh is as defined below and in the present.
In certain embodiments, Re is a substituted or unsubstituted 4-pyrimidinyl group of any of the formulas: where Rh is as defined below and in the present. In certain embodiments, Re is a substituted substituted 5-pyrimidinyl group of any of the formulas: or where Rh is as defined below and in the present.
In certain embodiments, Re is a pyrazinyl group. In certain embodiments, Re is a pyrazinyl group substituted with 0, 1, 2 or 3 Rh groups. For example, in certain embodiments, Re is a pyrazinyl group of the formula: (Rh) x wherein x is 0, 1, 2 or 3, and R is as defined below and in the present. In certain embodiments, Re is an unsubstituted pyrazinyl (ie, where x is 0). In certain embodiments, Re is a substituted pyrazinyl (eg, where x is 1, 2 or 3). In certain embodiments, Re is a monosubstituted pyrazinyl (ie, where x is 1). In certain embodiments, Re is a disubstituted pyrazinyl (ie, where x is 2). In certain embodiments, Re is a trisubstituted pyrazinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a substituted or unsubstituted pyrazinyl group of any of the formulas: where Rh is as defined below and in the present. In certain embodiments, Re is a triazinyl group. In certain embodiments, Re is a triazinyl group substituted with 0, 1 or 2 Rh groups. For example, in certain embodiments, Re is a thiazinyl group of the formula: where x is 0, 1 or 2, and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted pyrazinyl (ie, where x is 0). In certain embodiments, Re is a substituted pyrazinyl (for example, where x is 1 or 2). In certain embodiments, Re is a monosubstituted pyrazinyl (that is, where x is 1). In certain embodiments, Re is a disubstituted pyrazinyl (ie, where x is 2). In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a substituted or unsubstituted triazinyl group of any of the formulas: where Rh is as defined below and in the present. In certain embodiments, Re is a tetrazinyl group. In certain embodiments, Re is a tetrazinyl group substituted with 0 or 1 Rh group. For example, in certain embodiments, Re is a tetrazinyl group of the formula: i where x is 0 or 1, and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted pyrazinyl (ie, where x is 0). In certain embodiments, Re is a substituted pyrazinyl (for example, where x is 1). In certain modalities, x is 0 or 1.
In certain embodiments, Re is a substituted or unsubstituted tetrazinyl group of any of the formulas: where R is as defined below and in the present.
In certain embodiments, Re is a 9-membered heteroaryl (e.g., a 5,6-bicyclic heteroaryl). In certain embodiments, Re is a 5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 5,6-bicyclic heteroaryl selected from indole, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl. , indolizinyl and purinyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl of the formula: where Ye, Yf, Y9, Yi, Y ', Yk and Ym independently are C, CH, CRh, O, S, N or NRk and Yn is C or N, with the proviso that at least one of Ye , Yf, Y9 is selected from O, S, N or NRk where Rh and Rk are as defined below and in the present.
In certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formula (if), wherein Ye is selected from O, S or NRk, Yn is C, and Yf, Y9, Y \ Y ', Yk and Ym independently are C, CH or CRh. For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formulas: (Rn) where x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined later and in the present. In certain embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 0). In certain embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., where x is 1, 2, 3, 4, or 5). In certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein Ye is selected from O, S or NRk; Y9 is N; Y "is C; Yf is C, CH or CRh or N, and Y \ Y¡, Yk and Ym independently are C, CH or CRh. For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl group of The formulas: (Rh) x i where x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined later and in the present. In certain embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 0). In certain embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., where x is 1, 2, 3, 4, or 5). In certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein Ye is NRk, S or O; Ym is N; Yn is C; and Yf, Y9, Y ', Y' and Yk independently are C, CH or CRh. For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formulas: where x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined later and in the present. In certain embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 0). In certain embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., where x is 1, 2, 3, 4, or 5). In certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein Y 9 is O, S or NRk; Ym is N, Yn is C; and Ye, Yf, Y, Y 'and Yk independently are C, CH or CR. For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formulas: where x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined later and in the present. In certain embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 0). In certain embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., where x is 1, 2, 3, 4, or 5). In certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein Ye is selected from N; Yn is N; and Yf, Y \ Y1, Yk and Ym independently are C, CH or CRh. For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formula: where x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined later and in the present. In certain embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 0). In certain embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., where x is 1, 2, 3, 4, or 5). In certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 10-membered heteroaryl (eg, a 6,6-bicyclic heteroaryl). In certain embodiments, Re is a 6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 6,6-bicyclic heteroaryl selected from naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl and quinazolinyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
For example, in certain embodiments, Re is a 6,6-bicyclic heteroaryl of the formula: where Wf, W9, Wh, W \ W \ Wk, Wm and Wn independently are selected from C, CH, CRh or N, with the proviso that at least one of Wf, W9, Wh, Wj, W ', Wk, Wm or Wn is N, and where Rh is as defined below and in the present.
In certain embodiments, Re is a quinolinyl group, for example, of the formula (i-e) wherein W 'is N and W9, Wh, Wf, W, Wk, Wm and Wn independently are C, CH or CRh. For example, in certain embodiments, Re is a quinolinyl group of the formulas: where x is 0, 1, 2, 3, 4 or 5 and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted quinolinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted quinolinyl (for example, where x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted quinolinyl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted quinolinyl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted quinolinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is an isoquinolinyl group; for example, of the formula (i-g) where Wh is N and Wf, W9, Wj, Wj, Wk, Wm and Wn independently are C, CH or CRh. For example, in certain embodiments, Re is an isoquinolinyl group of the formulas: where x is 0, 1, 2, 3, 4 or 5 and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted isoquinolinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted isoquinolinyl (for example, wherein x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted isoquinolinyl (ie, wherein x is 1). In certain embodiments, Re is a disubstituted isoquinolinyl (ie, x is 2). In certain embodiments, Re is a trisubstituted isoquinolinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a quinoxalinyl group; for example, from the formula (i-g) where W * and Wj are N and W9, Wh, W \ Wk, Wm and Wn independently are C, CH or CRh. For example, in certain embodiments, Re is a quinoxalinyl group of the formulas: where x is 0, 1, 2, 3, 4 or 5 and Rh is as defined below and in the present. In certain embodiments, Re is an unsubstituted quinoxalinyl (ie, where x is 0). In certain embodiments, Re is a substituted quinoxalinyl (for example, where x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted quinoxalinyl (ie, where x is 1). In certain embodiments, Re is a disubstituted quinoxalinyl (ie, where x is 2). In certain embodiments, Re is a trisubstituted quinoxalinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 3-14 membered heterocyclyl. In certain embodiments, Re is a 3-14 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 5-10 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 5-8 member heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 5-6 member heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 9-10 member heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
Exemplary heterocyclyl Re groups include, but are not limited to, azirinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, tie-tanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydro-thiophenyl, pyrrolidinyl, dihydropyrrolyl, pi rro I il-2, 5- d iona, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl, azepanyl, oxepanyl, tiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl , tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinylinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisocromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, H-benzo [e] [1,4] -diazepinyl, 1, 4,5,7-tetrahydro-pyrano [3,4-p] pyrrolyl, 5,6-dihydro-4 H-furo [3,2- b] pyrrolyl, 6,7-dihydro-5H-furo [3,2-b] pyranyl, 5,7-dihydro-4H-thieno [2,3-c] pyranyl, 2,3-dihydro-1H-pyrrolo [ 2,3-b] pyridinyl, 2,3-dihi-drofuro [2,3-b] pyridinyl, 4,5,6,7-tetrahydro-1H- pyrrolo [2,3-b] -pyridinyl, 4,5,6,7-tetrahydrofuro [3,2-c] iridinyl and 4,5,6,7-tetrahydro-thieno [3,2-b] pyridinyl , 1, 2,3,4-tetrahydro-1,6-naphthyridinyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
In certain embodiments, Re is a 6-membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl and triazinanyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
For example, in certain embodiments, Re is a 6-membered heterocyclyl of the formula: W ° - Wp \ / (i-h) where W °, Wp, Wq, Wr and Ws independently are selected from CH2, CHRh, C (Rh) 2, NRk, O or S and W 'is N, CH, CRh, with the proviso that minus one of W °, Wp, Wq, Wr and Ws is selected from N, NRk, O or S and where Rh and Rk are defined below and in the present.
In certain embodiments, Re is a piperidinyl group. In certain embodiments, Re is a piperidinyl group substituted with 0, 1, 2, 3, 4 or 5 Rh groups, for example, of the formulas: wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are as defined below and herein. In certain embodiments, Re is an unsubstituted piperidinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted piperidinyl (e.g., where x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted piperidinyl (ie, where x is 1). In certain embodiments, Re is a disubstituted piperidinyl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted piperidinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 1-piperidinyl group, for example, of the formula (ih) wherein W 'is N and W °, Wp, W \ Wr and Ws independently are selected from CH2, CHRh, C ( Rh) 2. In certain embodiments, Re is a 2-piperidinyl group, for example, of the formula (i-h) wherein W ° is NRk; Wp, Wq, Wr and Ws independently are CHRh, C (Rh) 2 or CH2; and W is CH or CRh. In certain embodiments, Re is a 3-piperidinyl group, for example, of the formula (i-h) wherein Wp is NRk; W °, Wq, Wr and Ws independently are CHRh, C (Rh) 2 or CH2; and W is CH or CRh. In certain embodiments, Re is a 4-piperidinyl group, for example, of the formula (i-h) wherein Wq is NRk; W °, W, Wr and Ws independently are CHRh, C (Rh) 2 or CH2; and Wl is CH or CRh.
In certain embodiments, Re is a piperazinyl group. In certain embodiments, Re is a piperazinyl group substituted with 0, 1, 2, 3 or 4 Rh groups, for example, of the formulas: wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are as defined below and herein. In certain embodiments, Re is an unsubstituted piperazinyl (ie, wherein x is 0). In certain embodiments, Re is a substituted piperazinyl (e.g., where x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted piperazinyl (ie, where x is 1). In certain embodiments, Re is a disubstituted piperazinyl (ie, wherein x is 2). In certain embodiments, Re is a trisubstituted piperazinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a 1-piperazinyl group, for example, of the formula (i-h) wherein W1 is N and Wq, Wp, Wr and Ws independently are selected from CH2l CHRh, C (Rh) 2. In certain embodiments, Re is a 2-piperazinyl group, for example, of the formula (i-h) wherein W ° and Wr are NRk and Wp, Wq, Wr and Ws independently are CHRh, C (Rh) 2 or CH2; and W is CH or CRh.
In certain embodiments, Re is a morpholinyl group. In certain embodiments, Re is a morpholinyl group substituted with 0, 1, 2, 3 or 4 Rh groups, for example, of the formulas: wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are as defined below and herein. In certain embodiments, Re is an unsubstituted morpholinyl (i.e., where x is 0). In certain embodiments, Re is a substituted morpholinyl (for example, where x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted morpholinyl (ie, where x is 1). In certain embodiments, Re is a disubstituted morpholinyl (ie, where x is 2). In certain embodiments, Re is a trisubstituted morpholinyl (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a morpholinyl group of the formula (i-h) wherein W is N, Wq is O and W °, Wp, W and Ws independently are selected from CH2, CHRh, C (Rh) 2.
In certain embodiments, e is a dioxanyl group. In certain embodiments, Re is a dioxanyl group substituted with 0, 1, 2, 3 or 4 Rh groups, for example, of the formulas: wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are as defined below and herein. In certain embodiments, Re is an unsubstituted dioxanyl (ie, where x is 0). In certain embodiments, Re is a substituted dioxanyl (for example, wherein x is 1, 2, 3, 4 or 5). In certain embodiments, Re is a monosubstituted dioxanil (ie, where x is 1). In certain embodiments, Re is a disubstituted dioxanyl (ie, where x is 2). In certain embodiments, Re is a trisubstituted dioxanil (ie, where x is 3). In certain modalities, x is 0, 1, 2 or 3. In certain modalities, x is 0, 1 or 2. In certain modalities, x is 0 or 1.
In certain embodiments, Re is a dioxanyl group of the formula (i-h) wherein W ° and Wr are O and Wp, Wq, Wr and Ws independently are selected from CHRh, C (Rh) 2 or CH2; and W is CH or CRh.
Other 6-membered heterocyclic groups encompassed by the formula (ih) include monosaccharide sugars, for example, pyranosides selected from ribose, arabinose, xylose, lixose, allose, altrose, glucose, mannose, gulose, iodose, galactose and slab .
In certain embodiments, Re is a carbocyclyl of C3.10. In certain embodiments, Re is a carbocyclyl of C3-10 substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a carbocyclyl of C5.8 substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a carbocyclyl of C5.6 substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Re is a C9-10 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
Re carbocyclic groups of C3.10 examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and cycloheptadienyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
Group G Rf As defined above in general, in certain embodiments, wherein G is selected from -S02NRfRe, -P02NR Re, - (C = 0) NRfRe, -ONRfRe, -ONRf (C = 0) Re, -ONRfS02Re, - ONRfP02Re, -ONRfP02ORe, -NRfS02R3, -NRfP02Re, -NRfP02ORe, -OP02NRfRe, -NRfRe, -NRf (C = 0) Re, -NRf (C = 0) ORe, -0 (C = 0) NRfRe, NRf (C = NRf) NRfRe, -0 (C = NRf) NRfRe, - N Rf (C = N Rf) 0 Re, - [N (Rf) 2Re] + X "where X" is a counter ion, each Re fixed to a nitrogen atom independently is selected from -H or Ci_10 alkyl, or Re and Rf are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.
In certain embodiments, Rf is H or an alkyl group of C-0. In certain embodiments, Rf is H.
In certain embodiments, Rf is a C1-10 alkyl group. In certain embodiments, Rf is C1-10 alkyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups. Exemplary alkyl groups Rf include, but are not limited to, methyl, ethyl, propyl, allyl and benzyl. In certain embodiments, Rf is an unsubstituted methyl, i.e., -CH3. In certain embodiments, Rf is an unsubstituted ethyl, i.e., -CH2CH3.
In certain embodiments, Rf is an amino protecting group. For example, in certain embodiments, Rf is selected from -OH, -OR, -N (Rk) 2, -C (= 0) R, -C (= 0) N (Rk) 2, -C02R ¡, -S02R¡, -C (= NRk) R¡, -C (= NRk) OR \ -C (= NRk) N (Rk) 2, -S02N (Rk) 2, -S02Ri, -S02OR¡, - SOR, -C (= S) N (Rk) 2, -C (= 0) SRi, -C (= S) SR \ C1-10 alkyl groups (eg, aralkyl groups), C2 alkenyl. 10, C2.10 alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently it is substituted with 0, 1, 2, 3, 4 or 5 Rm groups, and wherein R ', Rk and Rm are as defined below and herein.
However, in certain embodiments, G is -NReRf and Rf is -H or C 1-3 alkyl, then Re is not C 1-6 alkyl or triazolyl.
Also, in certain modalities, where G is -OC (= 0) NRfRe, then Re and Rf are not both -CH3.
Alternatively, in certain embodiments, Re and Rf join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring; for example, when G is -S02NRfRe, -P02NRfRe, - (C = 0) NRfRe, -ONRfRe, -OP02NRfRe, -NRfRe, -0 (C = 0) NRfRe, -NRf (C = NRf) NRfRe, -0 ( C = NRf) NRfRe and - [N (Rf) 2Re] + X "where X" is a counter ion. In certain embodiments, wherein Re and Rf are combined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, the heterocyclyl ring or heteroaryl ring is substituted with 0, 1, 2, 3, 4 or 5 Rh groups, as defined below and in the present.
In certain embodiments, Re and Rf come together to form a 3-14 membered heterocyclyl ring. In certain embodiments, Re and Rf are brought together to form a 3-14 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 5-10 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 5-8 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 5-6 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 9-10 member heterocyclyl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
In certain embodiments, Re and R, are combined to form a heterocyclyl group selected from azydinyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, triazolinyl, oxadi- azolinyl, thiadiazolinyl, piperidinyl, dihydropyridinyl, thianyl, piperazinyl. , morpholinyl, triazinanyl, azepanyl, oxepanyl, tiepanyl, azocanyl, indolinyl, isoindolinyl, tetrahydrobenzothienyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indolinyl and phthalethyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
For example, in certain embodiments, Re and Rf come together to form a 5-membered heterocyclyl ring selected from the group: '(Rn) x Y where x is 0, 1, 2 or 3, where Rh and Rk are as defined below and herein.
In certain embodiments, Re and Rf are brought together to form a 6-membered heterocyclyl ring selected from the group: "(n):? (Rh) x | (Rh) - (Rh) x (Rh) x -N §-N NRk -N O N- • (Rn) x (Rh) x ^ (Rh) x (Rh) x where x is 0, 1, 2 or 3, where Rh and Rk are as defined below and herein.
However, in certain embodiments, where G is -NReRf, then Re and Rf do not come together to form a pyrrolidinyl, piperidinyl or azepanyl ring.
In certain embodiments, Re and Rf come together to form a 5-14 membered heteroaryl ring. In certain embodiments, Re and Rf are brought together to form a 5-14 membered heteroaryl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 5-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 5-8 membered heteroaryl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 5-6 membered heteroaryl ring substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re and Rf join to form a 9-10 member heteroaryl ring substituted with 0, 1, 2, 3, 4 or 5 R groups.
In certain embodiments, Re and Rf are brought together to form a 5-membered heteroaryl ring selected from: l i l i l í [ U, R¾ ?? 1? * > . Ib ^ y wherein x is 0, 1 or 2 and Rh and Rk are as defined below and in the present.
However, in certain embodiments, where G is -NRfRe, Re and Rf do not come together to form a 1,2-triazolyl ring, for example, of the formula: where x is 0 or 1, and Rh is as defined below and in the present.
In certain embodiments, Re and Rf are brought together to form a 9-membered heteroaryl ring ("5,6-bicyclic heteroaryl") selected from: wherein x is 0, 1, 2 or 3 and Rh and Rk are as defined below and herein.
Substitutes for group G Modalities of Rh As used before and wherein each instance of Rh independently is selected from halogen (fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-1)), -CN, -N02 > -N3, -S02H, -S03H, -OH, -OR -ON (Rk) 2, -N (Rk) 2, -N (Rk) 3 + X ", -N (OR ') Rk, -SH, -SR \ -SSRCC, -C (= 0) R, -C02H, -CHO, -C (OR ') 2, -C02R1, -OC (= 0) R1, -OC02R \ -C (= 0) ) N (Rk) 2, -OC (= 0) N (Rk) 2, -NRkC (= 0) R ', -NR'COzR1, NRkC (= 0) N (Rk) 2 > -C (= NRk) ) R \ -C (= NRk) OR¡, -OC (= NRk) Ri, OC (= NRk) OR \ -C (= NRk) N) Rk) 2, -OC (= NRk) N (Rk) 2, -NRkC (= NRk) N (Rk) 2, -C (= 0) NRkS02Ri , -NRkS02R1, -S02N (Rk) 2, -S02R1, -S02ORi, -OS02R1, -S (= 0) R1, -OS (= 0) R1, -S1 (R1) 3, -Osi (R ') 3, -C (= S) N (Rk) 2, -C (= 0) SRi, -C (= S) SR \ -SC (S) SR¡, -P (= 0) ) 2Ri, -OP (= 0) 2Ri, -P (= 0) (R¡) 2, -OP (= 0) (Ri) 2, -OP (= 0) (ORJ) 2, -P (= 0) ) 2N (Rk) 2, -OP (= 0) 2N (Rk) 2, -P (= 0) (NRk) 2, -OP (= 0) (NRk) 2, -NRkP (= 0) (ORJ) 2, -NRkP (= 0) (NRk) 2, -P (R¡) 2, -P (Rj) 3 > -OP (Rj) 2, -OP (RJ) 3 > -B (ORj) 2, -BR'íOR '). C, alkyl. io, perhaloalquilo de Ci.i0. C2-io alkenyl. C2-io alkynyl. carbocyclyl of C3.i, heterocyclyl of 3-14 members, aryl of C6-i4 and heteroaryl of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of R 'independently is selected from Ci.i0 alkyl, Ci-10 perhaloalkyl, C2.io alkenyl. alkynyl of C2-io, carbocyclyl of C3_14, heterocyclyl of 3-14 members, aryl of C6-i4 and heteroaryl of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of Rk is independently selected from hydrogen, -OH, -OR \ -N (Rj) 2, -CN, -C (= 0) R, -C (= 0) N (R ') 2, -C02R¡, -S02R \ -C (= NRj) ORi, -C (= NRi) N (Ri) 2, -S02N (Rj) 2, -S02Rj, -S02OR \ -SOR1, -C (= S) N (Ri) 2, -C (= 0) SR¡, -C (= S) SRi, -P (= 0) 2Ri, -P (= 0) (R¡) 2, -P (= 0) 2N ( Rj) 2, -P (= 0) (NR ') 2, Ci.10 alkyl, perhaloalkyl of C ^ .| ^ o, C2-io alkenyl. at Iquiniio of C2_10, carbocyclyl of C3.14, heterocyclyl of 3-14 members, aryl of C6-i4 and heteroaryl of 5-14 members, or two R 'groups attached to an atom of N come together to form a ring of heerocyclyl 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of R 'independently is selected from hydrogen, C1-10 alkyl, C1- 0 perhaloalkyl, C2-io alkenyl, C2.10 alkynyl, C3.14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, or two R1 groups attached to an N atom come together to form a 5-14 membered heterocyclyl ring or 5-14 membered heteroaryl, wherein each alkyl, alkenyl , alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of Rm independently is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -N3, -S02H, -S03H, - OH, -OR °, -ON (Rn) 2, -N (Rn) 2, -N (Rn) 3 + X ", -N (OR °) Rn, -SH, -SR °, -SSR °, - C (= 0) R °, -C02H, -C02R °, -OC (= 0) R °, -OC02R °, - C (= 0) N (Rn) 2, -OC (= 0) N (Rn) 2, -NRnC (= 0) R °, -NRnC02R °, NRnC (= 0) N (Rn) 2, -C (= NRn) R °, -C (= NRn) OR °, -OC (= NRn) R °, OC (= NRn) OR °, -C (= NRn) N) Rn) 2, -OC (= NRn) N (Rn) 2 > NRnC (= NRn) N (Rn) 2, -NRnS02R °, -S02N (Rn) 2, -S02R °, -S02OR °, -OS02R °, -S (= 0) R °, -OS (= 0) R °, -Y (R °) 3, -OSi (R °) 3, -C (= S) N (Rn) 2l -C (= 0) SR °, -C (= S) SR °, -SC ( S) SR °, -P (= 0) 2R °, -OP (= 0) 2R °, -P (= 0) (R °) 2, -OP (= 0) (R °) 2, -OP ( = 0) (OR °) 2 > C1-6 alkyl > perhaloalkyl of C-i _6, C2.6 alkenyl, C2-6 alkynyl, carbocyclyl of C3.10. 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups, or two gem Rm substitutes can be put together to form = 0 or = S; each instance of R ° independently is selected from C1-6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl, C2-6 alkynyl, C3 carbocyclyl, 0, 3-10 membered heterocyclyl, aryl of C6-14 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups; each Rn instance is independently selected from hydrogen, C1-6alkyl, Ci-6 perhaloalkyl, C2alkenyl. 6, C2.6 alkynyl > C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-14 aryl and 5-10 membered heteroaryl, or two Rn groups attached to an N atom come together to form a 3-14 membered heterocyclyl ring or heteroaryl of 5-14 members, in wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups; Y each Rp instance independently is fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -N3, -S02H, -S03H, -OH, -alkyl of OC1-6, -ON (Ci-6 alkyl) 2. -N (C 1-6 alkyl) 2. -N (C1-6 alkyl) 3X, -NH (Ci.6 alkyl) 2X, -NH2 (C1-6 alkyl) X, -NH3X, -N (OCi.6 alkyl) (C1-6alkyl) 6), -N (OH) (C 1-6 alkyl), -NH (OH), -SH, -alkyl of SC 1-6, -SS (C 1-6 alkyl), -C (= 0) NH 2, -C (= 0) N (C1.6 alkyl) 2, -OC (= 0) NH (C1-6 alkyl), NHC (= 0) (C 1-6 alkyl), -N (C 1-6 alkyl) C (= 0) (C 1-6 alkyl), -NHC02 (C 1-6 alkyl), -NHC ( = 0) N (C 1-6 alkyl) 2, NHC (= 0) NH (Ci 6 alkyl), -NHC (= 0) NH 2, -C (= NH) 0 (Ci. 6 alkyl), -OC (= NH) (C 1-6 alkyl), -OC (= NH) alkyl of 0C1-6, -C (= NH) N (alkyl of 0, -6) 2, -C (= NH) NH (alkyl from 01-6), -C (= NH) NH2, -OC (= NH) N (C1-6 alkyl) 2, -OC (NH) NH (at Iq of 01-6), - OC (NH) NH2, -NHC (NH) N (Ci.6 alkyl) 2, -NHC (= NH) NH2, NHS02 (alkyl of d.6), -S02N (alkyl of d.6) 2, - S02NH (C1-6 alkyl), -S02NH2, -S02Ci-6alkyl, -S02alkyl of OC1-6, -OS02alkyl of 01-6, -SOalkyl of C1-6l -Si (C1-6alkyl) 3, -OSi (0 5 alkyl) 3, -C (= S) N (C 1-6 alkyl) 2, C (= S) NH (Ci 6 alkyl), C (= S) NH 2, -C (= 0) S (alkyl of 01-6), -C (= S) S-C 5 alkyl, -SC (= S) S-alkyl of d.6, -P (= 0) 2 (alkyloxy) from 01-6), -P (= 0) (C1-6 alkyl) 2. -OP (= 0) (C1.6 alkyl) 2, -OP (= 0) (OCi.6 alkyl) 2, C1-6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl, alkynyl C2.6, carbocyclyl of C3.10, heterocyclyl of 3-14 members, aryl of Ce-14 and heteroaryl of 5-14 members; or two gemimonal RP substitutes can be put together to form = 0 or = S; where X "is a counterion.
In certain embodiments, Rh is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -N3, -S02H, -S03H, - OH, -0R1, -ON (Rk) 2, -N (Rk) 2, -N (Rk) 3 + X ", -N (OR ') R \ -SH, -SR1, -SSRCC, -C ( = 0) R1, -C02H, -CHO, -C (ORj) 2, -0O2R \ -OC (= 0) R1, -OC02R1, -C (= 0) N (Rk) 2, -OC ( = 0) N (Rk) 2, -NRkC (= 0) Ri, -NRkC02R \ NRkC (= 0) N (Rk) 2, -C (= NRk) Ri, -C (= NRk) OR¡, -OC (= NRk) R¡, OC (= NRk) ORi, -C (= NRk) N) Rk) 2, -OC (= NRk) N (Rk) 2, -NRkC (= NRk) N (Rk) 2, -C (= 0) NRkS02R ¡, -NRkS02R¡, -S02N (Rk) 2, -S02R¡, -S02OR¡, -OS02R¡, -S (= 0) R¡, -OS (= 0) Ri, -Si (R¡) 3. -Os¡ (R¡) 3. -C (= S) N (Rk) 2, -C (= 0) SRi, -C (= S) SR ', -SC (S) SRi, -P (= 0) 2R \ -OP (= 0 ) 2Ri, -P (= 0) (R¡) 2, OP (= 0) (R ') 2, -OP (= 0) (OR¡) 2, -P (= 0) 2N (Rk) 2, -OP (= 0) 2N (Rk) 2, P (= 0) (NRk) 2, -OP (= 0) (NRk) 2, -NRkP (= 0) (OR¡) 2, -NRkP (= 0) (NRk) 2, -P (R ') 2, -P (RJ) 3. -OP (Rj) 2, -OP (Rj) 3, -B (ORJ) 2, -BR ^ OR '), C, alkyl. 10, perhalo C1-10 alkyl, C2-io alkenyl. C2 alkynyl. 0, C3.14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups Rm; and where X "is a counterion.
In certain embodiments, Rh is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -OH, -OR1, -SR ' , - N (Rk) 2, -N (Rk) 3 + X ", -C (= 0) R1, -C02R1, -C02H, -OC (= 0) R ', -OC02R, -C (= 0) ) N (Rk) 2, -OC (= 0) N (Rk) 2, -NRkC) (= 0) Rj, -NRkC02Ri, NRkC (= 0) N (Rk) 2, -C (= 0) NRkS02Ri , -NRkS02R1, -S02N (Rk) 2, -S02R1, C1-10 alkyl, C6 aryl and 5-6 membered heteroaryl, wherein each alkyl, aryl and heteroaryl independently is substituted with 0, 1, 2 , 3 or 4 Rm groups, and where X "is a counterion.
In certain embodiments, Rh is -OR ', for example, selected from -OCH3, -OCF3, -OCH2CH3, -OCH2CF3-OiPr and -OnBu.
In certain embodiments, Rh is -SR ', for example, selected from -SCH3.
In certain embodiments, Rh is -N (Rk) 2 or -N (Rk) 3 + X ", for example, selected from -NH2 and -NH3 + X".
In certain embodiments, Rh is -C (= 0) R ', for example, selected from -C (= 0) CH3.
In certain embodiments, Rh is -C02R ', for example, selected from -C02CH3.
In certain embodiments, Rh is -C (= 0) N (Rk) 2, for example, selected from -C (= 0) NHOH, -C (= 0) NH2. -C (= 0) NHCH 3, -C (= 0) N (CH 3) 2, -C (= 0) NHCH 2 CH 3, -C (= 0) NHCH 2 CF 3, -C (= 0) NH (CH 2) 1. 6NH3 + X ", -C (= 0) NHCH2C (= 0) OCH3, -C (= 0) NHCH2C (= 0) OH and -C (= 0) NHCH2CH2OH.
In certain embodiments, Rh is -OC (= 0) R ', for example, selected from -OC (= 0) CH3.
In certain embodiments, Rh is -OC02R ', for example, selected from -OC02CH3.
In certain embodiments, Rh is -OC (= 0) N (Rk) 2, for example, selected from -OC (= 0) NH2.
In certain embodiments, Rh is -NRkC (= 0) R ', for example, selected from -NHC (= 0) CH3.
In certain embodiments, Rh is NRkC02R ', for example, selected from -NHC (= 0) OCH3 and -NHC (= 0) OtBu.
In certain embodiments, Rh is -NRkC (= 0) N (Rk) 2, for example, selected from -NHC (= 0) NH2.
In certain embodiments, Rh is -C (= 0) NRkSO2R ', for example, selected from -C (= 0) NHS02CH3, -C (= 0) NHS02CH2CH3, -C (= 0) NHS02C5H9 and -C (= 0) NHS02iBu.
In certain embodiments, Rh is -NRkS02R ', for example, selected from -NHS02CH3.
In certain embodiments, Rh is -S02N (Rk) 2, for example, selected from -S02NH2, -S02N (CH3) 2.
In certain embodiments, Rh is -S02R ', for example, selected from -S02CH3, -S02CH2CH3, -S02C5H9 and -S02iBu.
In certain embodiments, Rh is Ci_i0 alkyl, for example, selected from -CH3, -CH2CH3, -iPr, -nBu, -CF3, CH2CH2C02Me, -CH2CH2C02H and -CH2CH2C02NH2.
In certain embodiments, Rh is selected from -C (= 0) R ', -C02H and -SC ^ R1. In certain modalities, Rh is -C (= 0) R ,. In certain embodiments, Rh is -S02R '. In certain embodiments, Rh is -C02H or -S02CH3. In certain embodiments, Rh is -C02H. In certain embodiments, Rh is -S02CH3.
In certain embodiments, each instance of Rh independently is selected from fluorine (-F), bromine (-Br), chlorine (-CI), iodine (-1), -NH2, -S02CH3, -S02CH2CH3, -S02C5H9, -S02iBu, -S02NH2, -S02N (CH3) 2, -C (= 0) NHS02CH3, C (= 0) NHS02CH2CH3, -C (= 0) NHS02C5H9 > -C (= 0) NHS02iBu, C (= 0) CH3, -C02H, -C02CH3, -OC (= 0) CH3, -OC02CH3, -C (= 0) NHOH, -C (= 0) NH2, -C (= 0) NHCH3, -C (= 0) N (CH3) 2l -C (= 0) NHCH2CH3, -C (= 0) NHCH2CF3, -C (= 0) NH (CH2) 1-6NH3 + X-, -OC (0) NH2, NHC (= 0) CH3, -NHC (= 0) OCH3, -NHC (= 0) OtBu, -NHC (= 0) NH2, -NHS02CH3, -CH3, -CH2CH3, -iPr, -nBu, -CF3) -OH , -OCH3, -SCH3, -OCF3, -OCH2CH3) -OCH2CF3, -OiPr, -OnBu, -CH2CH2C02Me, -CH2CH2C02H, -CH2CH2CO2NH2, -C (= 0) NHCH2C (= 0) OCH3, C (= 0) NHCH2C (= 0) OH, -C (= 0) NHCH2CH2OH, C6 aryl substituted with 0, 1 or 2 Rm groups and 5-6 membered heteroaryl substituted with 0, 1 or 2 Rm groups; and where X "is a contrión.
In certain embodiments, Rh is a C6aryl (for example, phenyl) substituted with 0, 1 or 2 Rm groups. In certain embodiments, Rh is an aryl of C6 (eg, phenyl) substituted with 1 group Rm, and Rm is -C02H, -C02CH3, -C02CH2CH3 and -C (= 0) NH2.
In certain embodiments, Rh is a 5-6 membered heteroaryl substituted with 0, 1 or 2 Rm groups. In certain embodiments, Rh is a 5-membered heteroaryl substituted with 0, 1 or 2 Rm groups. The 5-membered heteroaryl Rh groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, midazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, wherein said groups are substituted with 0 or 1 group Rm. In certain embodiments, the 5-membered heteroaryl Rh group is selected from pyrazolyl and oxadiazolyl, wherein said groups are substituted with 0 or 1 Rm group.
Modalities of Ri In certain embodiments, each instance of R 'independently is selected from alkyl of? · ,. 0 > perhaloalkyl of C 1-10 alkenyl of C 2 -io > C2.io alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is replaced.
In certain embodiments, R 'is C- 0.alkyl. In certain embodiments, R' is perhaloalkyl of Ci_i0. In certain embodiments, R 'is C2 alkenyl. 0. In certain embodiments, R 'is C2-io alkynyl- In certain embodiments, R' is C3_10 carbocyclyl. In certain embodiments, R 'is 3-14 membered heterocyclyl. In certain embodiments, R 'is aryl of C6-14. In certain embodiments, R 'is heteroaryl of 5-14 members.
Modalities of Rm In certain embodiments, each Rm instance is independently selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-1), -CN, -N02, -S02H, -S03H, -OH, -OR °, -ON (Rn) 2, -N (Rn) 2, -N (Rn) 3 + X ", -N (OR °) Rn, -SH, -SR °, -SSR °, -C (= 0) R °, -C02H, -C02R °, -OC (= 0) R °, -OC02R °, -C (= 0) N (Rn) 2, -OC (= 0) N (Rn ) 2, -NRnC (= 0) R °, -NRnC02R °, -NRnC (= 0) N (Rn) 2, -C (= NRr) R °, C (= NRn) OR °, -OC (= NRn ) R °, -OC (= NRn) OR °, -C (= NRn) N) Rn) 2, -OC (= NRn) N (Rn) 2, -NRnC (= NRn) N (Rn) 2, - NRnS02R °, -S02N (Rn) 2, -S02R °, -S02OR °, -OS02R °, -S (= 0) R °, -OS (= 0) R °, -Si (R °) 3, -OSi (R °) 3, -C (= S) N (Rn) 2, -C (= 0) SR °, -C (= S) SR °, -SC (S) SR °, -P (= 0) 2R °, -OP (= 0) 2R °, -P (= 0) (R °) 2, -OP (= 0) (R °) 2, -0P (= O) (OR0) 2, alkyl of d 6, perhaloalkyl of C ^, carbocyclyl of C3.10, heterocyclyl of 3-14 members, aryl of C6-14 and heteroaryl of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently replaced and with 0, 1, 2, 3, 4 or 5 Rp groups.
In certain embodiments, each Rm instance is independently selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -S02H, -S03H, -OH, -OR °, -ON (Rn) 2, -N (Rn) 2, -N (Rn) 3 + X-, -N (OR °) Rn, -SH, -SR °, -SSR °, -C (= 0) R °, -C02H, -C02R °, -OC (= 0) R °, -OC02R °, -C (= 0) N (Rn) 2, -0C (= 0) N (Rn ) 2, -NRnC (= 0) R °, -NRnC02R °, -NRnC (= 0) N (Rn) 2, -C (= NRn) R °, C (= NRn) OR °, -OC (= NRn ) R °, -OC (= N Rn) 0 R °, -C (= NRn) N) Rn) 2, OC (= NRn) N (Rn) 2, -NRnC (= NRn) N (Rn) 2, -NRnS02R °, -S02N (Rn) 2, -S02R °, -S02OR °, -OS02R °, -S (= 0) R °, -OS (= 0) R °, -Si (R °) 3, - OSi (R °) 3, -C (= S) N (Rn) 2, -C (= 0) SR °, -C (= S) SR °, -SC (S) SR °, -P (= 0 ) 2R °, -OP (= 0) 2R °, -P (= 0) (R °) 2, -OP (= 0) (R °) 2, -OP (= 0) (OR °) 2 > alkyl of d. 6 > C1-6 perhaloalkyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl.
In certain embodiments, Rm is selected from (-F), bromine (-Br), chlorine (-CI), iodine (-I), -NH2, -NH3 + X ", -CN, -N02, -S02CH3 , -S02CH2CH3, -S02C5H9, -S02¡Bu, -S02NH2, -S02N (CH3) 2, -C (= 0) NHS02CH3, -C (= 0) NHS02CH2CH3, -C (= 0) NHS02C5H9, C (= 0) NHS02iBu, -C (= 0) CH3, -C02H, -C02CH3, -OC (= 0) CH3, -OC02CH3, -C (= 0) NHOH, -C (= 0) NH2I-C ( = 0) NHCH3 > -C (= 0) N (CH3) 2, -C (= 0) NHCH2CH3, -C (= 0) NHCH2CF3, -C (= 0) NH (CH2) 1-6NH3 + X ", OC (0) NH2 > -NHC (= 0) CH 3, -NHC (= 0) OCH 3, - NHC (= 0) Ot B u, NHC (= 0) NH 2, -NHS02CH 3, -CH 3, -CH 2 CH 3, -iPr, -nBu, -CF3, -OH, -OCH3, -SCH3, -OCF3 > -OCH2CH3, -OCH2CF3, -OiPr, -OnBu, -CH2CH2C02Me, -CH2CH2C02H, -CH2CH2C02NH2, C (= 0) NHCH2C (= 0) OCH3, -C (= 0) NHCH2C (= 0) OH, C (= 0) NHCH 2 CH 2 OH.
Modalities of Rk As used before and in the present, each instance of independently is selected from -OH, -OR ', -N (Rk) C (= 0) R \ -C (= 0) N (Rk) 2, - C02R¡, -S02R \ -C (= NRk) R \ -C (= NRk) OR C (= NRk) N (Rk) 2, -S02N (Rk) 2, -S02R1, -S02OR1, -SORC -C (= S) N (Rk) 2 > -C (= 0) SR ', -C (= S) SR', C1-10 alkyl groups (eg, aralkyl), C2.10 alkenyl, C2-io alkynyl. carbocyclyl of C3. 0, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups Rm, and wherein R \ Rk and Rm are as defined below and herein.
In certain embodiments, each instance of R independently is selected from -H, -C (= 0) R ', -C (= 0) OR', -S02R 'or C 1-6 alkyl. In certain embodiments, each Rk instance is independently selected from -H or Ci_6 alkyl. In certain embodiments, each Rk instance is independently selected from -H and -CH3. In certain embodiments, each Rk instance is independently selected from -H. In certain embodiments, each Rk instance is independently selected from -CH3.
Groups Ra, Rb and Rc As generally defined above, wherein Rd is the group -L-Z, each of Ra, Rb and Rc independently is selected from -H, alkyl of d -io and perhaloalkyl of d.i0.
In certain embodiments, each of Ra, Rb and Rc independently is selected from -H, Ci-6 alkyl and C1-6 perhaloalkyl. In certain embodiments, each of Ra, Rb and Rc independently is selected from -H, C1-3 alkyl and C1-3 perhaloalkyl. In certain embodiments, each of Ra, Rb and Rc independently is selected from -H, -CH3, -CH2CH3 and -CF3. In certain embodiments, each of Ra, R and Rc independently is selected from -H, -CH3 and -CF3.
In certain embodiments, Ra and Rb are H and Rc is selected from C1-3 alkyl and C1-3 perhaloalkyl. In certain embodiments, Ra and Rb are H and Rc is selected from -CH3 and -CF3. In certain embodiments, Ra and Rb are H and Rc is -CH3. In certain embodiments, Ra and Rb are H and Rc is -CF3.
In certain embodiments, Rb and Rc are H and Ra is selected from C1-3 alkyl and C1-3 perhaloalkyl. In certain embodiments, Rb and R ° are H and Ra is selected from -CH3 and -CF3. In certain embodiments, Rb and Rc are H and Ra is -CH3. In certain embodiments, Rb and Rc are H and Ra is -CF3.
In certain embodiments, each of Ra, R and Rc independently is selected from H, -CH3 and -CF3. In certain embodiments, each of Ra, Rb and Rc independently is selected from H or -CH3. In certain embodiments, each of Ra, Rb and Rc is H.
Group Rd As it was usually defined before, in certain modalities, Rd is the group -L-Z, wherein L is a covalent bond or a divalent hydrocarbon group of C 1-6, wherein one, two or three methylene units of L are optionally and independently replaced with one or more oxygen, sulfur or nitrogen atoms, and Z is selected from aryl of C6.10, heterocyclyl of 3-14 members or heteroaryl of 5-14 members.
Group L of Rd As generally defined above, L is a covalent bond or a divalent hydrocarbon group of C 1-6, wherein one, two, three or three methylene units of L are optionally and independently replaced with one or more oxygen atoms, Sulfur or nitrogen.
In certain modalities, L is a covalent bond.
In certain embodiments, L is a divalent hydrocarbon group of C 1-6, wherein one, two or three methylene units of L are optionally and independently replaced with one or more oxygen atoms (-0-), sulfur (-S- ) or nitrogen (for example, -NR1-).
In certain embodiments, L is a divalent hydrocarbon group of C-6, wherein one, two or three methylene units of L are optionally and independently replaced with one or more oxygen atoms (-0-).
In certain embodiments, L is a divalent hydrocarbon group of C 1-6, wherein one, two or three methylene units of L are optionally and independently replaced with one or more sulfur atoms (-S-).
In certain embodiments, L is a divalent hydrocarbon group of Ci-6, wherein one, two or three methylene units of L are optionally and independently replaced with one or more nitrogen atoms (-N-). However, in certain embodiments, wherein L is a divalent hydrocarbon group of C 1-6 comprising one, two or three nitrogen atoms, then L is a divalent hydrocarbon group of C-6 unsubstituted and L is not the group -CH 2 NR 1 - wherein R1 is H, C1-6 alkyl or an amino protecting group.
In certain embodiments, L is a divalent hydrocarbon group of C 1-6, wherein a methylene unit of L is optionally and independently replaced with an oxygen, sulfur or nitrogen atom. In certain embodiments, L is a divalent hydrocarbon group of Ci_6, wherein a methylene unit of L is optionally and independently replaced with an oxygen atom. In certain embodiments, L is a divalent hydrocarbon group of C, ^, wherein a methylene unit of L is optionally and independently replaced with a sulfur atom. In certain embodiments, L is a divalent hydrocarbon group of Ci-6, wherein a methylene unit of L is optionally and independently replaced with a nitrogen atom.
In certain embodiments of L, the divalent hydrocarbon group of C-6 is a non-substituted divalent C 1-6 hydrocarbon group. In certain embodiments of L, the divalent hydrocarbon group of C1-6 contains an oxygen, sulfur or nitrogen atom. In certain embodiments, the divalent hydrocarbon group of C 1-6 is an unsubstituted divalent hydrocarbon group of Ci-6 (for example, a non-substituted divalent group of C 1-6 alkyl).
For example, in certain embodiments, L is an alkyl group of C -6 unsubstituted divalent, where one methylene unit of L is replaced with an oxygen, sulfur or nitrogen atom. In certain embodiments, L is an unsubstituted divalent C 1-6 alkyl group, wherein a methylene unit of L is replaced with an oxygen atom. In certain embodiments, L is an unsubstituted divalent C-6 alkyl group, wherein a methylene unit of L is replaced with a sulfur atom. In certain embodiments, L is an unsubstituted divalent C 5 alkyl group, wherein a methylene unit of L is replaced with a nitrogen atom. However, in certain embodiments, wherein L is an unsubstituted divalent C-6 alkyl group, then L is not a group -CH 2 NR 1 - wherein R 1 is H, C 1-6 alkyl or an amino protecting group.
In certain embodiments, L is a divalent Ci hydrocarbon group, wherein a methylene unit of L is replaced with an oxygen, sulfur or nitrogen atom, for example, L is selected from oxygen (-0-), sulfur (-S) or nitrogen (for example, -NR1-). In certain embodiments, L is oxygen (-O-). In certain embodiments, L is sulfur (-S-). In certain embodiments, L is nitrogen (e.g., -NR1-).
In certain embodiments, L is selected from the group consisting of - (C (R10) 2) m-, - (C (R11) 2) m-0- (C (R 2) 2) n-, - ( C (R11) 2) mS- (C (R12) 2) n-, or - (C (R11) 2) m-NR - (C (R12) 2) n-, where m and n are, independently, 0, 1, 2, 3, 4, 5 or 6, and each instance of R 0, R 11 and R 12 independently are selected from H, halogen or C 1-6 alkyl. In certain embodiments, each of R10, R1 and R12 are -H.
In certain embodiments, L is - (C (R 10) 2) m-- In certain embodiments, L is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 - , -CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2-; In certain embodiments, L is - (CÍR11) 2) m-0- (C (R1) 2) n-. In certain embodiments, L is selected from -O-, -CH20-, -OCH2- -OCH2CH2-, -OCH2CH2-, -OCH2CH2CH2-, -CH2CH2CH20-, CH2OCH2CH2- and -CH2CH2OCH2-.
In certain embodiments, L is - (C (R1) 2) m-S- (C (R1) 2) n-. In certain embodiments, L is selected from -S-, -CH2S-, -SCH2-, -SCH2CH2-, -CH2CH2S-, -SCH2CH2CH2-, -CH2CH2CH2S-, CH2SCH2CH2- and -CH2CH2SCH2-.
In certain embodiments, L is - (C (R11) 2) m-NR, - (C (R12) 2) n-. In certain embodiments, L is selected from -NR1-, -CH2NR1-, -NR1CH2-, -NR CH2CH2-, -CH2CH2NR1-, -NR1 CH2CH2CH2-, CH2CH2CH2NR1-, CH2NR1CH2CH2- and -CH2CH2N R CH2-, wherein R1 is selected from H, a C1-6 alkyl group or amino protector.
In certain embodiments, R1 is selected from H or Ci_6 alkyl. In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is -CH3.
Modalities where the Z Group of Rd is aryl As it was usually defined before, in certain embodiments, Z is aryl of C6-14.
In certain embodiments, Z is aryl of C6.14. In certain embodiments, Z is C6.14 aryl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is C6 aryl (e.g., phenyl) substituted with 0, 1, 2, 3, 4 or 5 R 5 groups. In certain embodiments, Z is C10 aryl (e.g., naphthyl) substituted with 0 , 1, 2, 3, 4 0 5 groups R15.
In certain embodiments, Z is phenyl. In certain embodiments, Z is phenyl substituted with 0, 1, 2, 3 or 4 R15 groups. In certain embodiments, Z is phenyl substituted with 0, 1, 2 or 3 R15 groups. In certain embodiments, Z is phenyl substituted with 0, 1 or 2 R15 groups. In certain embodiments, Z is phenyl substituted with 0 or 1 group R15.
In certain embodiments, Z is a disubstituted phenyl (i.e., substituted with 2 R15 groups). In certain embodiments, Z is a monosubstituted phenyl (ie, substituted with 1 group R15). In certain embodiments, Z is an unsubstituted phenyl (ie, substituted with 0 R15 groups).
In certain embodiments, Z is phenyl substituted with at least one ortho group R 5. In certain embodiments, Z is a phenyl substituted with at least one target group R15. In certain embodiments, Z is phenyl substituted with at least one group for R15.
In certain embodiments, Z is a monosubstituted phenyl substituted with an ortho R 5 group. In certain embodiments, Z is a monosubstituted phenyl substituted with a target group R 15. In certain embodiments, Z is a monosubstituted phenyl with a group for R15.
In certain embodiments, Z is a disubstituted phenyl substituted with an ortho group R15 and a meta group R15. In certain embodiments, Z is a disubstituted phenyl substituted with an ortho R15 group and a group for R15. In certain embodiments, Z is a disubstituted phenyl substituted with a target group R15 and a group for R15. In certain embodiments, Z is a disubstituted phenyl substituted with two target groups R15.
In certain embodiments, Z is a phenyl group of the formula: (ii-a) wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and in the present. In certain modes, z is 0, 1, 2, 3 or 4. In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1. In certain embodiments, x is 3. In certain embodiments, Z is a disubstituted phenyl group (ie, wherein z is 2). In certain embodiments, Z is a monosubstituted phenyl group (ie, wherein z is 1). In certain embodiments, Z is an unsubstituted phenyl group (ie, where z is 0).
For example, in certain embodiments, Z is a substituted or unsubstituted phenyl group of any of the formulas: wherein R15 is as defined below and in the present. In certain embodiments, Z is a naphthyl. In certain embodiments, Z is a naphthyl group of any of the formulas: wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and in the present. In certain modes, z is 0, 1, 2, 3 or 4. In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1. In certain embodiments, Z is a trisubstituted naphthyl group (ie, where z is 3). In certain embodiments, Z is a disubstituted naphthyl group (ie, where z is 2). In certain embodiments, Z is a monosubstituted naphthyl group (ie, where z is 1). In certain embodiments, Z is an unsubstituted naphthyl group (ie, where z is 0).
For example, in certain embodiments, Z is a substituted or unsubstituted 1-naphthyl group of any of the formulas: wherein 5 is as defined below and in the present. In certain embodiments, Z is a substituted or unsubstituted 2-naphthyl group of any of the formulas: R15 or 'wherein R15 is as defined below and in the present.
Modalities where the Z Group of Rd is heterocyclyl or heteroaryl As generally defined above, in certain embodiments, Z is selected from heterocyclyl of 3-14 members and heteroaryl of 5-14 members.
In certain embodiments, Z is heteroaryl of 5-14 members. In certain embodiments, Z is a 5-10 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 5-8 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 5-6 membered heteroaryl substituted with 0, 1, 2, 3 or 4 R 5 groups. In certain embodiments, Z is a 9-10 membered heteroaryl substituted with 0, 1, 2, 3 , 4 or 5 groups R15.
Exemplary heteroaryl Z groups include, but are not limited to, pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl , thiepinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, uranyl benzoisof, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, wherein said groups e replaced with 0, 1, 2, 3, 4 or 5 groups 15.
In certain embodiments, Z is a 5-membered heteroaryl substituted with 0, 1, 2 or 3 R15 groups. In certain embodiments, Z is a 5-membered heteroaryl selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, wherein said groups are substituted with 0, 1, 2 or 3 groups R15.
For example, in certain embodiments, Z is a 5-membered heteroaryl of the formula: (ii-d) wherein Y1, Y2, Y3 and Y4 independently are selected from CH, CR 5, O, S, N or NR18, with the proviso that at least one of Y1, Y2, Y3 and Y4 is O, S, N or NR18, and wherein R15 and R18 are defined below and in the present.
In certain embodiments of the above formula (ii-d), Y1 is O, S or NR18 and Y2, Y3 and Y4 independently are selected from CH, CR15 or N. In certain embodiments of the above formula (ii-d) , Y1 is O, S or NR18, Y3 is N and Y2 and Y4 are independently selected from CH or CR15. In certain embodiments of the above formula (ii-d), Y1 is S, Y3 is N, and Y2 and Y4 are independently selected from CH or CR15. In certain embodiments of the above formula (ii-d), Y1 is S, Y3 is N, Y2 is CR15 and Y4 is CH. In certain embodiments of the above formula (ii-d), Y1 is S and Y2, Y3 and Y4 is CH or CR15.
In certain embodiments of the above formula (ii-d), Y2 is O, S or NR18 and Y1, Y3 and Y4 are independently selected from CH, CR15 or N. In certain embodiments of the above formula (ii-d) , Y2 is O, S or NR18 and Y1, Y3 and Y4 are independently selected from CH or CR15. In certain embodiments of the above formula (ü-d), Y2 is O, S or NR18, Y4 is N and Y1 and Y3 are independently selected from CH or CR15.
In certain embodiments, Z is a substituted or unsubstituted 5-membered heteroaryl of any of the formulas: wherein R15 and R18 are as defined below and herein, and z is 0, 1 or 2. wherein z is 0, 1 or 2, and R 5 and R 18 are as defined below and herein. In certain embodiments, Z is an unsubstituted 5-membered heteroaryl (ie, wherein z is 0).
In certain embodiments, Z is a substituted 5-membered heteroaryl (e.g., where z is 1 or 2). In certain embodiments, Z is a monosubstituted 5-membered heteroaryl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted 5-membered heteroaryl (ie, wherein z is 2). In certain modalities, z is 0, 1 or 2. In certain modalities, z is 0 or 1.
In certain embodiments, Z is a 6-membered heteroaryl substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Z is a 6-membered heteroaryl selected from the group consisting of pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4- pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazinyl, wherein said groups are substituted with 0, 1, 2, 3 or 4 R15 groups.
For example, in certain embodiments, Re is a 6-membered heteroaryl group of the formula: W1-W2 w3 w5 = w4 ("-and) wherein W1, W2, W3, W4 and W5 independently are selected from CH, CR15 or N, with the proviso that at least one of W1, W2, W3, W4 and W5 is N, and where R15 is as defined below and in the present.
In certain embodiments, Z is a pyrindinyl group. In certain embodiments, Z is a pyrindinyl group substituted with 0, 1, 2, 3 or 4 R15 groups. For example, in certain embodiments, Z is a pyrindinyl group of the formula: wherein z is 0, 1, 2, 3 or 4 and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted pyrindinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted pyrindinyl (e.g., where z is 1, 2, 3 or 4). In certain embodiments, Z is a monosubstituted pyrindinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted pyrindinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted pyrindinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 2-pyrindinyl group, for example, of the formula (ii-e) wherein W1 is N and W2, W3, W4 and W5 independently are CH or CR15. In certain embodiments, Z is a 3-pyrindinyl group, for example, of the formula (ii-e) wherein W2 is N and W1, W3, W4 and W5 independently are CH or CR15. In certain embodiments, Z is a 4-pyrindinyl group, for example, of the formula (ii-e) wherein W3 is N and W, W2, W4 and W5 independently are CH or CR15.
In certain embodiments, Z is a substituted or unsubstituted 2-pyridinyl group of any of the formulas: wherein R15 is defined below and in the present.
In certain embodiments, Z is a substituted or unsubstituted 3-pyridinyl group of any of the formulas: or wherein R15 is as defined below and in the present. In certain embodiments, Z is a substituted or unsubstituted 4-pyridinyl group of the formulas: wherein R15 is as defined below and in the present.
In certain embodiments, Z is a pyridazinyl group. In certain embodiments, Z is a pyridazinyl group substituted with 0, 1, 2 or 3 R15 groups. For example, in certain embodiments, Z is a pyridazinyl group of the formula: wherein z is 0, 1, 2 or 3 and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted pyridazinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted pyridazinyl (for example, where z is 1, 2 or 3). In certain embodiments, Z is a monosubstituted pyridazinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted pyridazinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted pyridazinyl (ie, wherein z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 3-pyridazinyl group, for example, of the formula (ii-e) wherein W1 and W2 are N and W3, W4 and W5 independently are CH or CR15. In certain embodiments, Z is a 4-pi ridazi nyl group, for example, of the formula (ii-e) wherein W2 and W3 are N and W, W4 and W5 independently are CH or CRh.
In certain embodiments, Z is a substituted or unsubstituted 3-pyridazinyl group of any of the formulas: wherein R15 is as defined below and in the present. In certain embodiments, Z is a substituted or unsubstituted 4-pyridazinyl groups of any of the formulas: wherein R15 is as defined below and in the present.
In certain embodiments, Z is a pyrimidinyl group. In certain embodiments, Z is a pyrimidinyl group substituted with 0, 1, 2 or 3 R15 groups. For example, in certain embodiments, Z is a pyrimidinyl group of the formula: wherein z is 0, 1, 2 or 3, and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted pyrimidinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted pyrimidinyl (e.g., where z is 1, 2 or 3). In certain embodiments, Z is a monosubstituted pyrimidinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted pyridazinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted pyrimidinyl (ie, wherein z is 3). In certain modalities, z is 0, 1, 2 or 3. In certain modalities, z is 0, 1 or 2. In certain modalities, z is 0 or.
In certain embodiments, Z is a 2-pyrimidinyl group, for example, of the formula (ii-e) wherein W1 and W5 are N and W2, W3 and W4 independently are CH or CR15. In certain embodiments, Z is a 4-pyrimidinyl group, for example, of the formula (ii-e) wherein W1 and W3 are N and W2, W4 and W5 independently are CH or CR] 5. In certain embodiments, Z is a 5-pyrimidinyl group, for example, of the formula (ii-e) wherein W2 and W4 are N and W1, W3 and W5 independently are CH or CR15.
In certain embodiments, Z is a substituted or unsubstituted 2-pyrimidinyl group of any of the formulas: wherein R15 is as defined below and in the present. In certain embodiments, Re is a 4-pyrimidinyl group of any of the formulas: wherein R15 is as defined below and in the present. In certain embodiments, Z is a 5-pyrimidinyl group of any of the formulas: wherein R15 is as defined below and in the present.
In certain embodiments, Z is a pyrazinyl group. In certain embodiments, Z is a pyrazinyl group substituted with 0, 1, 2 or 3 R 5 groups. For example, in certain embodiments, Z is a pyrazinyl group of the formula: wherein z is 0, 1, 2 or 3, and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted pyrazinyl (ie, where z is 0). In certain embodiments, Z is a substituted pyrazinyl (for example, where z is 1, 2 or 3). In certain embodiments, Z is a monosubstituted pyrazinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted pyrazinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted pyrazinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a pyrazinyl group of any of the formulas: wherein R15 is as defined below and in the present.
In certain embodiments, Z is a triazinyl group. In certain embodiments, Z is a triazinyl group substituted with 0, 1 or 2 R15 groups. For example, in certain embodiments, Z is a triazinyl group of the formula: wherein z is 0, 1 or 2, and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted pyrazinyl (ie, where z is 0). In certain embodiments, Z is a substituted pyrazinyl (for example, where z is 1 or 2). In certain embodiments, Z is a monosubstituted pyrazinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted pyrazinyl (ie, wherein z is 2). In certain modalities, z is 0, 1 or 2. In certain modalities, z is 0 or 1.
In certain embodiments, Z is a substituted or unsubstituted triazinyl group of any of the formulas: OR wherein R15 is as defined below and in the present.
In certain embodiments, Z is a tetrazinyl group. In certain embodiments, Z is a tetrazinyl group substituted with 0 or 1 group R15. For example, in certain embodiments, Z is a tetrazinyl group of the formula: N ^ N wherein z is 0 or 1, and R15 is as defined below and herein. In certain embodiments, Z is an unsubstituted pyrazinyl (ie, where z is 0). In certain embodiments, Z is a substituted pyrazinyl (for example, where z is 1). In certain modalities, z is 0 or 1.
In certain embodiments, Z is a tetrazinyl group of any of the formulas: I N .N R15 or wherein R15 is as defined below and in the present. In certain embodiments, Z is a 9-membered heteroaryl (e.g., a 5,6-bicyclic heteroaryl). In certain embodiments, Z is a 5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 5,6-bicyclic heteroaryl selected from indolyl, isoindolyl, indazoyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl. , indolizinyl and purinyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 R 5 groups.
For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl of the formula: (íí-f) where Y5, Y6, Y7, Y9, Y10, Y11 and Y12 independently are C, CH, CR15, O, S, N or NR18 and Y13 is C or N, with the proviso that at least one of Y5, Y6 , Y7 is selected from O, S, N or NR18 where R15 and R18 are as defined below and herein.
In certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula (ii-f), wherein Y 5 is selected from O, S or NR 18, Y 13 is C, and Y 6, Y 7, Y 9, Y 10, Y11 and Y12 independently are C, CH or CR15. For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R8 are defined later and in the present. In certain embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y 5 is selected from O, S or NR 18; Y7 is N; Y13 is C; Y6 is C, CH or CR15 or N, and Y9, Y10, Y11 and Y12 independently are C, CH or CR15. For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are defined below and in the present. In certain embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y 5 is NRk, S or O; Y12 is N; Y13 is C; and Y6, Y7, Y9, Y10 and Y11 independently are C, CH or CR15. For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R 5 and R 8 are defined below and in the present. In certain embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 3).
In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y 7 is O, S or NRk; Y12 is N, Y13 is C; and Y5, Y6, Y9, Y10 and Y11 independently are C, CH or CR15. For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are defined below and in the present. In certain embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y 5 is selected from O, S or NR 18; Yn is N; and Y6, Y7, Y8, Y9 and Y10 independently are C, CH or CR15. For example in certain embodiments, Z is a 5,6-bicyclic heteroaryl group formula: wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are defined below and in the present. In certain embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, wherein z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 10-membered heteroaryl (eg, a 6,6-bicyclic heteroaryl). In certain embodiments, Z is a 6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 6,6-bicyclic heteroaryl selected from naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cyano I ini, quinoxalinyl, phthazinyl, and quina zolini lo, wherein said groups are replace with 0, 1, 2, 3, 4 or 5 groups R15.
For example, in certain embodiments, Z is a 6,6-bicyclic heteroaryl of the formula: W3 W12 ^ W7 II II I I w0 w9 (ii-g) where W6, W7, W8, W9, W10, W11, W12 and W13 are independently selected from C, CH, CR15 or N, with the proviso that at least one of W6, W7, W8, W9, W10 , W11, W2 or W13 is N, and where R15 is as defined below and in the present.
In certain embodiments, Z is a quinolinyl group, for example, of the formula (ii-g) wherein W9 is N and W6, W7, W8, W10, W11, W2 and W3 independently are C, CH or CR15. For example, in certain embodiments, Z is a quinolinyl group of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 is as defined below and in the present. In certain modalities, Z is an unsubstituted quinolinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted quinolinyl (e.g., where z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted quinolinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted quinolinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted quinolinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is an isoquinolinyl group; for example, of the formula (ii-g) wherein W8 is N and W6, W7, W9, W0, W11, W12 and W13 independently are C, CH or CR15. For example, in certain embodiments, Z is an isoquinolinyl group of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted isoquinolinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted isoquinolinyl (for example, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted isoquinolinyl (ie, wherein z is 1). In certain embodiments, Z is a di-substituted isoquinolinyl (ie, z is 2). In certain embodiments, Z is a trisubstituted isoquinolinyl (ie, wherein z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a quinoxalinyl group; for example, of the formula (ii-g) where W6 and W9 are N and W7, W8, W10, W11, W12 and W13 independently are C, CH or CR 5. For example, in certain embodiments, Z is a group quinoxalinyl of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 is as defined below and in the present. In certain embodiments, Z is an unsubstituted quinoxalinyl (ie, where z is 0). In certain embodiments, Z is a substituted quinoxalinyl (for example, where z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted quinoxalinyl (ie, where z is 1). In certain embodiments, Z is a disubstituted quinoxalinyl (ie, where z is 2). In certain embodiments, Z is a trisubstituted quinoxalinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 3-14 membered heterocyclyl. In certain embodiments, Z is a 3-14 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 5-10 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 5-8 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a 9-10 member heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups.
Exemplary heterocyclyl Z groups include, but are not limited to, azirinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, tie-tanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydro-thiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrole I-I, -d -one, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thienyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl, azepanyl, oxepanyl, tiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl , isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydrobenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinylinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisocromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1 H-be nzo [e] [1,4] -diazepinyl, 1,4,5,7-tetrahydro-pyrano [3,4-p] pyrrolyl, 5,6-dihydro-4H-furo [3,2-b] pyrrolyl, 6,7-dihydro-5H-furo [3,2-b] pyranyl, 5,7-dihydro-4H-thieno [2,3-c] pyranyl, 2,3-dihydro-1H-pyrrolo [2,3- b) pyridinyl, 2,3-dihydro-drofuro [2,3-b] pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo [2,3-b] -pyridinyl, 4,5,6 , 7-tetrahydrofuro [3,2-c] pyridinyl and 4,5,6,7-tetrahydro-thieno [3,2-b] pyridinyl, 1, 2, 3, 4-tetra h id ro- 1, 6-nafti ri dini lo, where said groups are substituted with 0, 1, 2, 3, 4 or 5 R 5 groups.
In certain embodiments, Z is a 6-membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R 5 groups. In certain embodiments, Z is a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl , piperazinyl, morpholinyl, dithianyl, dioxanyl and triazinanyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 R15 groups.
For example, in certain embodiments, Z is a 6-membered heterocyclyl of the formula: W14_ w15 W / 19 \ W16 \ / w8- w17 (ii-h) wherein W14, W15, W16, W17 and W18 independently are selected from CH2, CHR15, C (Rh) 2, NR18, O or S and W19 is N, CH, CR15, with the proviso that at least one of W14, W15, W16, W17 and W18 is selected from N, NR18, O or S and wherein R15 and R18 are defined below and herein.
In certain embodiments, Z is a piperidinyl group. In certain embodiments, Z is a piperidinyl group substituted with 0, 1, 2, 3, 4 or 5 R15 groups, for example, of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R 5 and R 18 are as defined below and herein. In certain embodiments, Z is an unsubstituted piperidinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted piperidinyl (e.g., where z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted piperidinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted piperidinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted piperidinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a 1-piperidinyl group, for example, of the formula (ii-h) wherein W19 is N and W14, W15, W16, W17 and W18 are independently selected from CH2, CHR 5, C (R15) 2. In certain embodiments, Z is a 2-piperidinyl group, for example, of the formula (ii-h) wherein W 4 is NR 18; W15, W16, W7 and W8 independently are CHR15, C (R15) 2 or CH2; and W 9 is CH or CR15. In certain embodiments, Z is a 3-piperidinyl group, for example, of the formula (ii-h) wherein W 5 is NR 18; W 4, W16, W17 and W18 independently are CHR15, C (R15) 2 or CH2; and W19 is CH or CR15. In certain embodiments, Z is a 4-piperidinyl group, for example, of the formula (ii-h) wherein W16 is NR18; W14, W15, W17 and W18 independently are CHR15, C (R15) 2 or CH2; and W19 is CH or CR15.
In certain embodiments, Z is a piperazinyl group. In certain embodiments, Z is a piperazinyl group substituted with 0, 1, 2, 3 or 4 R15 groups, for example, of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are as defined below and herein. In certain embodiments, Z is an unsubstituted piperazinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted piperazinyl (for example, where z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted piperazinyl (ie, wherein z is 1). In certain embodiments, Z is a disubstituted piperazinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted piperazinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a piperazinyl group, for example, of the formula (ii-h) wherein W19 is N, W16 is NR18 and W4, W15, W16, W17 and W18 are independently selected from CHR15, C (R15) 2, or CH2. In certain embodiments, Z is a piperazinyl group wherein W19 is CH or CR15, W14 and W17 independently they are NR18, and W15, W16 and W18 independently are CHRh, C (R15) 2 or CH2.
In certain embodiments, Z is a morpholinyl group substituted with 0, 1, 2, 3 or 4 R 5 groups, for example, of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are as defined below and herein. In certain embodiments, Z is an unsubstituted morpholinyl (ie, wherein z is 0). In certain embodiments, Z is a substituted morpholinyl (for example, where z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted morpholinyl (ie, where z is 1). In certain embodiments, Z is a disubstituted morpholinyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted morpholinyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a morpholinyl group; for example, of the formula (ii-h) wherein W19 is N, W16 is O and W14, W15, W16 and W17 are independently selected from CH2l CHR15, C (R15) 2. In certain embodiments, Z is a morpholinyl group wherein W19 is CH or CR15, W14 and W17 independently are selected from O and NR18, and W15, W6 and W18 independently are CHR15, C (R15) 2 or CH2.
In certain embodiments, Z is a dioxanyl group. In certain embodiments, Z is a dioxanyl group substituted with 0, 1, 2, 3 or 4 R15 groups, for example, of the formulas: wherein z is 0, 1, 2, 3, 4 or 5 and R 5 is as defined below and in the present. In certain embodiments, Z is an unsubstituted dioxanyl (ie, wherein x is 0). In certain embodiments, Z is a substituted dioxanyl (for example, wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted dioxanil (ie, wherein z is 1). In certain embodiments, Z is a disubstituted dioxanyl (ie, wherein z is 2). In certain embodiments, Z is a trisubstituted dioxanyl (ie, where z is 3). In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 0 or 1.
In certain embodiments, Z is a dioxanyl group, for example, of the formula (ii-h) wherein W 14 and W 17 are O and W 15, W 6 and W 18 independently are selected from CHR 15, C (R 15) 2 or CH2; and W19 is CH or CR15. In certain embodiments, Z is a dioxanyl group wherein W19 is CH or CR15, W14 or W16 independently they are selected from O, and W 5, W 7 and W 8 independently are CHR15, C (R15) 2 or CH2. In certain embodiments, Z is a dioxanyl group in which W19 is CH or CR15, W15 and W17 independently are selected from O, and W14, W16 and W18 independently are CHR15, C (R5) 2 or CH2.
In certain embodiments, Z is a carbocyclyl of C3.10. In certain embodiments, Z is a C3-10 carbocycly substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a C5-8 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain embodiments, Z is a carbocyclyl of C5.6 substituted with 0, 1, 2, 3 or 4 R15 groups. In certain embodiments, Z is a C9-10 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R 5 groups.
Modalities where Ra and Rd come together (merge) As generally defined above, in certain embodiments, Ra and Rd come together to form a fused ring of carbocyclyl of C3.10 or heterocyclyl of 3-14 members, and Rb and Rc independently are selected from -H, alkyl of C1-10 and perhaloalkyl of Ci. 10 In certain embodiments, each of Rb and Rc independently is selected from -H, Ci.6 alkyl and C1-6 perhaloalkyl. In certain embodiments, each of Rb and R ° independently is selected from -H, C1-3 alkyl and C3-perhaloalkyl. In certain embodiments, each of Rb and R ° independently is selected from -H, C1 alkyl and C- perhaloalkyl. In certain embodiments, each of Rb and Rc independently is selected from -H, -CH3 and -CF3. In certain embodiments, each of Rb and Rc independently is selected from -H and -CH3. In certain embodiments, each of Rb and Rc independently is selected from -H and -CF3. In certain modalities, R and Rc are both -H.
In certain embodiments, Ra and Rd come together to form a fused ring of carbocyclyl of C5.7 or heterocyclyl of 5-7 members. In certain embodiments, Ra and Rd come together to form a fused carbocyclic ring of C5_7 or 5-7 membered heterocyclyl of the formula: OH) where W20, W21, W22 and W23 independently are CH2, CHR15, C (R15) 2 or NR18, R15 and R18 are as defined below and in the present, s is 0, 1 or 2, and the dotted line indicates ring fusion.
In certain embodiments, Ra and Rd come together to form a carbocyclic fused ring of C5-7. For example, in certain modalities of the formula (ii-j), W20, W21, W22 and W23 independently they are CH2, CHR15 or C (R15) 2. Carbocyclic groups of C5.7 exemplary wherein Ra and Rd can be brought together to form include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 groups R15.
In certain embodiments, Ra and Rd come together to form a 5-7 membered heterocyclyl ring. For example, in certain embodiments of the formula (ii-j), W20 is NR18, and W21, W22 and W23 independently are CH2, CHR15 or C (R15) 2. In certain embodiments of the formula (ii-j), W21 is NR18, and W20, W22 and W23 independently are CH2, CHR15 or C (R15) 2. In certain embodiments of the formula (ii-j), W22 is NR18, and W20, W21 and W23 independently are CH2, CHR15 and C (R15) 2. Heterocyclyl groups of 5-7 exemplary members that Ra and Rd can join to form include, but are not limited to, pyrrolidinium, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and azepanyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 groups R15.
In certain embodiments, where s is 0, Ra and Rd come together to form a fused carbocyclyl ring of C5 or 5-membered heterocyclyl of the formula: W2 / w22 (ii-k) wherein W20, W21 and W22 independently are CH2, CHR15, C (R15) 2 or NR18, R15 and R18 are as defined below and the dashed line indicates ring fusion.
In certain embodiments of the formula (ii-k), Ra and Rd come together to form a carbocyclic fused ring of C5 (ie, cyclopentyl), for example, wherein W20, W21 and W22 independently are CH2, CHR15, C (R15) 2.
In certain embodiments of the formula (ii-k), Ra and Rd come together to form a 5-membered heterocyclic fused ring (eg, pyrrolidinyl), for example, wherein W21 is NR18, and W20, W22 and W23 independently are CH2, CHR15 or C (R 5) 2. In certain embodiments of the formula (ii-k), Ra and Rd come together to form a 5-membered heterocyclic fused ring (e.g., pyrrolidinyl), e.g., where W20 is NR18, and W21, W22 and W23 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, where s is 1, Ra and Rd come together to form a fused carbocyclyl ring of C6 or 6-membered heterocyclyl of the formula: (ii-m) wherein W20, W2, W22 and W23 independently are CH2, CHR15, C (R5) 2 or NR18, R5 and R18 are as defined below and herein, and the dotted line indicates ring fusion.
In certain embodiments of the formula (ii-m), Ra and Rd come together to form a carbocyclic fused ring of C6 (ie, cyclohexyl), for example, wherein W20, W2, W22 and W23 independently are CH2, CHR15 , C (R 5) 2.
In certain embodiments of the formula (ii-m), Ra and Rd come together to form a fused ring of 6-membered heterocyclic (eg, piperidinyl), for example, wherein W21 is NR18, and W20, W22 and W23 independently they are CH2, CHR15 or C (R15) 2. In certain embodiments of the formula (ii-m), Ra and Rd come together to form a fused ring of 6-membered heterocyclic (eg, piperidinyl), for example, wherein W20 is NR18, and W21, W22 and W23 independently they are CH2, CHR15 or C (R 5) 2.
In certain embodiments, where s is 2, Ra and Rd come together to form a fused carbocyclic ring of C7 or 7-membered heterocyclyl of the formula: (a) wherein W20, W21, W22 and W23 independently are CH2, CHR15, C (R15) 2 or NR18, R15 and R18 are as defined below and herein, and the dashed line indicates ring fusion.
In certain embodiments of the formula (ii-n), Ra and Rd come together to form a fused carbocyclic ring of C7 (ie, cycloheptyl), for example, wherein W20, W21, W22 and W23 independently are CH2, CHR15 , C (R15) 2.
In certain embodiments of the formula (ii-n), Ra and Rd come together to form a 7-membered heterocyclic fused ring (e.g., azepanyl), for example, wherein W21 is NR18, and W20, W22 and W23 independently are CH2, CHR15 or C (R15) 2. In certain embodiments of the formula (ii-n), Ra and Rd come together to form a 7-membered heterocyclic fused ring (e.g., azepanyl), e.g., wherein W20 is NR18, and W21, W22 and W23 independently are CH2, CHR15 or C (R15) 2.
Modalities where Rc and Rd come together (spiro-fusion) As generally defined above, in certain embodiments, Rc and Rd come together to form a fused ring of carbocyclyl of C3-10 or heterocyclyl of 3-14 members, and Ra and Rb independently are selected from -H, alkyl of C1-10 and perhaloalkyl of d_ 1 or · In certain embodiments, each of R a and R b independently is selected from -H, C-6 alkyl and Ci-6 perhaloalkyl. In certain embodiments, each of Ra and Rb independently is selected from -H, alkyl and perhaloalkyl of C -3. In certain embodiments, each of Ra and Rb independently is selected from -H, alkyl and perhaloalkyl of Ci. In certain embodiments, each of Ra and Rb independently is selected from -H, -CH3 and -CF3. In certain embodiments, each of Ra and R independently is selected from -H and -CH3. In certain embodiments, each of Ra and Rb independently is selected from -H and -CF3. In certain modalities, Ra and Rb are both -H.
In certain embodiments, Rc and Rd come together to form a spiro-fused carbocyclyl ring of C5.7, a 5-7 membered heterocyclyl, a 5,6-bicyclic carbocyclyl, a 6,6-bicyclic carbocyclyl, a heterocyclyl 5,6-bicyclic or a 6,6-bicyclic heterocyclyl.
For example, in certain embodiments, Rc and Rd come together to form a fused carbocyclic spiro ring of C5.7, a 5-7 membered heterocyclyl, a 5,6-bicyclic carbocyclyl or 5,6-bicyclic heterocyclyl of the formula : (i i-a) wherein W24, W25, W26, W27, W28 and W29 independently are CH2I CHR15, C (R15) 2 or NR18, optionally wherein W25 and W26 are substituted with a fused C6 aryl ring or fused 6-membered heteroaryl ring; t and v independently are 0 or 1; and R15 and R18 are as defined below and herein. In certain modalities, t is 0 and v is 0. In certain modalities, t is 0 and v is 1. In certain modalities, t is 1 and v is 0. In certain modalities, t is 1 and v is 1.
In certain embodiments, Rc and Rd come together to form a spiro-fused carbocyclyl ring of C5.7. For example, in certain embodiments of the formula (iii-a), W24, W25, W26, W27, W28 and W29 independently are CH2, CHR15 or C (R15) 2. Carbocyclic groups of C5.7 exemplary which Rc and Rd can be combined to form include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, wherein said groups are substituted with 0, 1, 2, 3, 4 or 5 groups R15.
In certain embodiments, Rc and Rd come together to form a spiro-fused 5-7 membered heterocyclyl ring. For example, in certain embodiments of the formula (ii-a), W25 is NR18 and W26, W27, W28 and W29 independently are CH2, CHR15, C (R15) 2. In certain embodiments of the formula (iii-a), W26 is NR18 and W24, W25, W27, W28 and W29 independently are CH2, CHR15, C (R15) 2. In certain embodiments of the formula (iii-a), W27 is NR18 and W24, W25, W26, W28 and W29 independently are CH2, CHR15, C (R15) 2. Heterocyclyl groups of 5-7 exemplary members that Rc and Rd can be coupled to form include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and azepanyl, wherein said groups are substituted with 0,1, 2, 3, 4 or 5 R 15 groups.
In certain embodiments, where t is 0 and v is 0, Rc and Rd come together to form a spiro-fused ring of carbocyclyl of C5 or heterocyclyl of 5 members of the formula: iiii-b) where W ", \ N¿b, \ N¿ / and W28 independently are CH2, CHR 5, C (R15) 2 or NR18, and R15 and R18 are as defined below and herein.
In certain embodiments, R ° and Rd come together to form a spiro-fused carbocyclyl ring of C5 (eg, cyclopentyl); for example, of the formula (iii-b) wherein W25 is NR18 and W26, W27 and W28 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, Rc and Rd come together to form a spiro-fused 5-membered heterocyclyl ring; for example, of the formula (iii-b) wherein W26 is NR18 and W25, W27 and W28 are independently CH2, CHR15 or C (R15) 2.
In certain embodiments, where t is 0 and v is 1, Rc and Rd come together to form a spiro-fused ring of C6 carbocyclyl or 6-membered heterocyclyl of the formula: (iii-c) wherein W ", W2b, W27, W28 and W 9 independently are CH2, CHR15, C (R15) 2 or NR18, and R15 and R18 are as defined below and herein.
In certain embodiments, R ° and Rd come together to form a spiro-fused carbocyclyl ring of C6 (eg, cyclohexyl); for example, of the formula (iii-c) wherein W25 is NR18 and W26, W27, W28 and W29 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, Rc and Rd come together to form a spiro-fused 5-membered heterocyclyl ring; for example, of the formula (iii-c) wherein W26 is NR18 and W25, W27, W28 and W29 are independently CH2, CHR15 or C (R15) 2. In certain embodiments, Rc and Rd come together to form a spiro-fused 5-membered heterocyclyl ring of the formula (iii-c) wherein W27 is NR18 and W25, W26, W28 and W29 independently are CH2, CHR15 or C ( R15) 2.
In certain embodiments, where t is 1 and v is 1, Rc and Rd come together to form a spiro-fused ring of C7 carbocyclyl or 7-membered heterocyclyl of the formula: (iii-d) where V \ r \ V \ T5, V \ rb, \ ?? 7, W¿8 and V \ r9 independently are CH2, CHR15, C (R15) 2 or NR18, and R15 and R8 are as defined more forward and in the present.
In certain embodiments, Rc and Rd come together to form a spiro-fused carbocyclyl ring of C7 (eg, cycloheptyl); for example, of the formula (iii-d) wherein W24, W25, W26, W27, W28 and W29 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, Rc and Rd come together to form a spiro-fused 7-membered heterocyclyl ring; for example, of the formula (iii-d) wherein W25 is NR18 and W24, W26, W27, W28 and W29 are independently CH2, CHR15 or C (R15) 2. In certain embodiments, Rc and Rd come together to form a spiro-fused 7-membered heterocyclyl ring of the formula (iii-d) wherein W26 is NR18 and W24, W25, W27, W28 and W29 independently are CH2, CHR15 or C (R1) 2. In certain embodiments, Rc and Rd come together to form a spiro-fused 7-membered heterocyclyl ring of the formula (iii-d) wherein W27 is NR18 and W24, W25, W26, W28 and W29 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, Rc and Rd come together to form a spiro-fused ring of 5,6-bicyclic carbocyclyl or a 5,6-bicyclic heterocyclyl spiro-fused ring. For example, in certain embodiments of the formula (iii-a), tyv are both 0, W25 and W26 are substituted with a fused C6 aryl ring or fused 6-membered heteroaryl ring, and W27 is CH2, CHR15, C (R15) 2, and NR18, and W28 is CH2, CHR15 or C (R 5) 2. In certain embodiments of the formula (iii-a), Rc and Rd join to form a 5,6-bicyclic carbocyclyl spiro-fused ring, for example, where tyv both are 0, W25 and W26 are substituted with a ring of fused C6 aryl or fused 6-membered heteroaryl ring, and W27 and W28 independently are CH2, CHR15 or C (R15) 2. In certain embodiments, W25 and W26 are substituted with a fused C6 aryl ring.
For example, in certain embodiments, where t and v are both 0 and W25 and W26 are substituted with a fused C6 aryl ring, Rc and Rd come together to form a spiro-fused ring of 5,6-bicyclic carbocyclyl of the formula: (iii-d) wherein W27 and W28 independently are CH2, CHR15 and C (R15) 2, z is 0, 1, 2, 3 or 4; R15 is as defined below and in the present. In certain embodiments, W27 and W28 are both CH2 groups. In certain modes, z is 0, 1, 2, 3 or 4. In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 2. In certain modalities, z is 1. In certain modalities, z is 0.
In certain embodiments, R ° and Rd come together to form a spiro-fused carbocyclic ring., 6-bicyclic or a 6,6-bicyclic heterocyclyl spiro-fused ring. For example, in certain embodiments of the formula (iii-a), t is 0 and v is 1, W25 and W26 are substituted with a fused C6 arc ring or 6-membered heteroaryl ring fused, and W27 and W28 independently are CH2, CHR15, C (R15) 2 and NR18, and W29 is CH2, CHR15, C (R15) 2. In certain embodiments of the formula (iii-a), Rc and Rd come together to form a 6,6-bicyclic carbocyclyl spiro-fused ring, for example, where t is 0 and v is 1, W25 and W26 are substituted with a fused C6 aryl ring or ring 6-membered heteroaryl fused, and W27, W28 and W29 independently are CH2, CHR 5 or C (R15) 2. In certain embodiments, W25 and W2S are replaced with a fused C6 aryl ring.
For example, in certain modalities, where t is 0 and v is 1 and W25 and W26 are substituted with an aryl ring of fused CB, Rc and Rd are joined to form a 6,6-bicyclic carbocyclyl spiro-fused ring of the formula: (iii-e) wherein W27, W28 and W29 independently are CH2, CHR15 and C (R15) 2, z is 0, 1, 2, 3 or 4; R15 is as defined below and in the present. In certain embodiments, W27, W28 and W29 are each CH2 groups. In certain modes, z is 0, 1, 2, 3 or 4. In certain modes, z is 0, 1, 2 or 3. In certain modes, z is 0, 1 or 2. In certain modes, z is 2. In certain modalities, z is 1. In certain modalities, z is 0.
In another aspect, Rc and Rd come together to form a spiro-fused bridged carbocyclic ring or bridged heterocyclic ring of the formula: (iii-f) wherein W, W, W32, W33 and W34 independently are CH2) CHR15, C (R15) 2 or NR 8; and W34 and W35 independently are CH or CR15, and R15 and R8 are as defined below and herein.
In certain embodiments of the formula (iii-f), W30, W31, W32, W33 independently are CH2, CHR15 or C (R15) 2; W3S is NR18; and W34 and W35 independently are CH or CR15. In certain embodiments of the formula (iii-f), W30, W3, W32, W33 and W36 independently are CH2 > CHR15 or C (R15) 2; and W34 and W35 independently are CH or CR15. In certain embodiments of the formula (iii-f), W34 and W35 are CH.
Groups R15 As used herein, each instance of R15 independently is selected from halogen (ie, fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I)), -CN, -N02, -N3, -S02H, -S03H, -OH, -OR16, -ON (R18) 2, -N (R18) 2l -N (R18) 3 + X-, -N (OR17) R18, -SH , -SR16, -SSR17, -C (= 0) R16, -C02H, -CHO, -C (OR17) 2, -C02R16, -OC (= 0) R16, -OC02R16, -C (= 0) N ( R18) 2, -OC (= 0) N (R18) 2, -NR18C (= 0) R16, -NR18C02R16, -NR18C (= 0) N (R18) 2, -C (= NR18) R16, -C ( = NR18) OR16, -OC (= NR18) R16, -OC (= NR18) OR16, -C (= NR18) N) R18) 2, -OC (= NR18) N (R18) 2, -NR18C (= NR18 ) N (R18) 2, -C (= 0) NR18S02R16, NR18S02R16, -S02N (R18) 2, -S02R16, -S02OR16, -OS02R16, -S (= 0) R16, -OS (= 0) R16, - Si (R16) 3, -Osi (R 5) 3, -C (= S) N (R18) 2, -C (= 0) SR16, -C (= S) SR16, -SC (S) SR16, - P (= 0) 2R16, -OP (= 0) 2R16, -P (= 0) (R16) 2, -OP (= 0) (R16) 2, -OP (= 0) (OR17) 2, -P (= 0) 2N (R18) 2, -OP (= 0) 2N (R18) 2, -P (= 0) (NR18) 2, -OP (= 0) (NR18) 2, -NR18P (= 0) (OR17) 2, NR18P (= 0) (NR18) 2, -P (R17) 2, -P (R17) 3, -OP (R17) 2, -OP (R17) 3, -B (OR17) 2, -BR16 (OR17) , C 1-10 alkyl, C 1 .10 perhaloalkyl, C2.10 alkenyl, C2.10 alkynyl, C3.1 carbocyclyl, 3-14 membered heterocyclyl, C6.14 aryl, and 6-14 heteroaryl. members wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R 9 groups; or two vicinal groups R15 are replaced with the group -0 (C (R2) 2) i 20- where each R2 is independently H, Ci_6 alkyl or halogen; each instance of R16 independently is selected from Ci_io alkyl, Ci_10 perhaloalkyl, C2 alkenyl. 0, C2.10 alkynyl, C3.14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R 8 independently is selected from hydrogen, hydrogen, -OH, -OR16, -N (R17) 2, -CN, -C (= 0) R16, -C (= 0) N (R17) 2 , -C02R16, -S02R16, -C (= NRl7) OR16, -C (= NR17) N (R17) 2 > -S02N (R17) 2, -S02R17, -S02OR17, -SOR16, -C (= S) N (R7) 2, -C () 0) SR17, -C (= S) SR17, -P (= 0 ) 2R16, -P (= 0) (R16) 2, -P (= 0) 2N (R17) 2, -P (= 0) (NR17) 2, C1.10 alkyl, perhaloalkyl of Ci.10, alkenyl of C2-0, C2-io alkynyl. carbocyclyl of C3.10, heterocyclyl of 3-14 members, aryl of C6-14 and heteroaryl of 5-14 members, or two groups R17 attached to an atom of N join to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R17 is independently selected from hydrogen, C to C alkyl, Ci-10 perhaloalkyl, C2.10 alkenyl. C2.10 alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two R17 groups attached to an N atom come together to form a heterocyclyl ring 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R19 is independently selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR20, - ON (R21) 2) -N (R2) 2, -N (R21) 3 + X-, -N (OR20) R21, -SH, -SR20, -SSR20, -C (= 0) R20, -C02H, -C02R20, -OC (= 0) R20, -OC02R2 °, -C (= 0) N (R21) 2, -OC (= 0) N (R21) 2, -NR2 C (= 0) R20, -NR21C02Ree , -NR21C (= 0) (R 1) 2, -C (= NR 1) OR20, -OC (= NR2) R20, -OC (= NR21) OR20, -C (= NR21) N (R2) 2, -OC (= NR 1) N (R21) 2, -NR 1C (= NR21) N (R2) 2, -NR21S02R2 °, -S02N (R1) 2, -S02R20, -S02OR20, -OS02R20, -S ( = 0) R2 °, -Si (R20) 3, -OSi (R20) 3, -C (= S) N (R21) 2, -C (= 0) SR20, -C (= S) SR20, -SC (= S) SR20, -P (= 0) 2R2 °, -P (= 0) 2R20, -P (= O) (R20) 2, -OP (= O) (R20) 2, -OP (= O) ) (OR20) 2 > C1-6alkyl, C1-6alkalkyl > C2.6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl independently are substituted with 0, 1, 2, 3, 4 or 5 R22 groups, or two gem R19 substitutes can be put together to form = 0 or = S; each instance of R21 independently is selected from Ci-6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6 aryl -10 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R22 is independently halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -alkyl of OCi-6, -ON (C 6 alkyl) 2, -N ( C1.6) 2, -N (C 6 alkyl) 3X, -NH (alkyl from 01-6) 2 ?, -NH 2 (Ci-6 alkyl) X, -NH 3X, -N (OC alkyl) , -6) (to Iq ui lo of C1-6), - N (OH) (C1-6 alkyl), -NH (OH), -SH, -alkyl of SC, .6l -SS (C1 alkyl) -6), -C (= 0) NH2l -C (= 0) N (alkyl of d-6) 2, -OC (= 0) NH (C 1-6 alkyl), -NHC (= 0) (alkyl of de), -N (Ci.6 alkyl) C (= 0) (C1-6 alkyl), -NHC02 (de alkyl), -NHC (= 0) N (C1-6 alkyl) 6) 2, -NHC (= 0) NH (d-β alkyl). -NHC (= 0) NH2, -C (= NH) 0 (alkyl of d-6), -OC (= NH) (C1-6 alkyl), -OC (= NH) alkyl of OC1-6, - C (= NH) N (C 1-6 alkyl) 2, -C (= NH) NH (C 1-6 alkyl), -C (= NH) NH 2, -OC (= NH) N (0 alkyl, -6) 2, -OC (NH) NH (alkyl of de), -OC (NH) NH 2, -NHC (NH) N (C 6, alkyl) 2, -NHC (= NH) NH 2 > -NHS02 (C1-6 alkyl), -S02N (C1.6 alkyl) 2, -S02NH (C1-6 alkyl), -S02NH2, -S02 C1-6 alkyl > -S02alkyl of OC1-6, -OS02alkyl of from, -SOalkyl of C1-6-S i (to I qui I of C1-6) 3, -OSi (alkyl of C, .6) 3, -C (= S) N (d-6 alkyl) 2, C (= S) NH (d-β alkyl). C (= S) NH2, -C (= O) S (alkyl of de), -C (= S) S-alkyl of d.6, -SC (= S) S-C1-6 alkyl, -P (= 0) 2 (alkyl of), -P (= 0) (Ci_6 alkyl) 2, -OP (= 0) (alkyl of d.6) 2, -OP (= 0) (OC alkyl, 6) 2, C1-6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6-yl aryl, and heteroaryl 5 -10 members; or two gem-like R22 substitutes can be put together to form = 0 or = S; where X "is a counterion.
In certain embodiments, each instance of R15 independently is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -OR16, -C (= 0) N (R18 2, -S02N (R18) 2, d-10 alkyl, d-io perhaloalkyl > C2-io alkenyl, C2-io alkynyl > C6_i4 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups.
In certain embodiments, each instance of R15 independently is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine -OR16 and perhaloalkyl of C1- 0. In certain embodiments, R15 is independently selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I) and -OR16. In certain embodiments, R15 is independently selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I) and perhaloalkyl of Ci-i0.
In certain embodiments, R15 is selected from -OR16 and C1-10 perhaloalkyl.
In certain modalities, R15 is -OR16. In certain embodiments, R 16 is selected from C 1-10 alkyl, C 1 0 perhaloalkyl, C 2 -io C2-io-alkynyl alkenyl, C 6-10 aryl, and 5-6 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups.
In certain embodiments, R15 is -OR16, and R16 is selected from alkyl of d.i0. In certain embodiments, R 5 is -OR 16, and R 16 is selected from C 1-6 alkyl- In certain embodiments, R 15 is -OR 16, and R 16 is selected from Cu 4 alkyl. In certain embodiments, R 5 is -OR 16, and R 16 is selected from C 1 -2 alkyl. In certain embodiments, R 15 is -OR 16, and R 16 is -CH 3, -Et, -iPr, -nBu, -n-pentyl. In certain embodiments, R15 is -OR16 and R16 is -CH3.
In certain embodiments, R15 is -OR16, and R16 is selected from perhaloalkyl of Ci-10. In certain embodiments, R15 is -OR16, and R6 is selected from C1-6 perhaloalkyl. In certain embodiments, R15 is -OR16, and R16 is selected from perhaloalkyl of C ^. In certain embodiments, R15 is -OR16, and R16 is selected from perhaloalkyl of Ci-2. In certain embodiments, R15 is -OR16 and R16 is -CF3, -CF2CF3 > -CF2CF2CF3, -CCI3, -CFCI2 or -CFzCl. In certain embodiments, R15 is -OR16 and R16 is -CF3.
In certain embodiments, R15 is -OR16, and R16 is selected from C2.10 alkenyl. In certain embodiments, R15 is -OR16, and R16 is selected from C2.6 alkenyl. In certain embodiments, R15 is -OR16, and R16 is selected from C2-4 alkenyl. In certain embodiments, R 5 is -OR 16, and R 16 is selected from -CH 2 CHCH 2 (i.e., a i i to).
In certain embodiments, R 5 is -OR16, and R16 is selected from C2_10 alkynyl- In certain embodiments, R15 is -OR16, and R16 is selected from C2.6 alkynyl. In certain embodiments, R15 is -OR16, and R16 is selected from C2-4 alkynyl. In certain embodiments, R15 is -OR16, and R16 is selected from -CH2CCH (ie, propargyl).
In certain embodiments, R15 is -OR16, and R16 is selected from C6 aryl (e.g., phenyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is -OR16, and R16 is phenyl substituted with 0, 1, or 2 R19 groups. In certain embodiments, R 5 is -OR 16, and R 16 is phenyl substituted with 1 group R 19. In certain embodiments, R15 is -OR16, and R16 is phenyl substituted with 0 R19 groups (ie, -C6H5).
In certain embodiments, R15 is -OR16, and R16 is selected from 5-6 membered heteroaryl substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is -OR16, and R16 is 6-membered heteroaryl substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is -OR16, and R16 is selected from pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is -OR16, and R16 is selected from pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2 or 3 R19 groups.
In certain embodiments, R15 is -C (= 0) N (R 8) 2.
In certain embodiments, R15 is -S02N (R18) 2.
In certain embodiments, R15 is perhaloalkyl of io- In certain embodiments, R5 is perhaloalkyl of Ci-6. In certain embodiments, R15 is perhaloalkyl of C4 - In certain embodiments, R15 is perhaloalkyl of C1-2. In certain embodiments, R15 is selected from -CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2 and -CF2CI. In certain embodiments, R15 is selected from -CF3.
In certain embodiments, R15 is C ^ alkyl or substituted with 0, 1, 2, 3, 4 or 5 R19 groups. In certain embodiments, R15 is C1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5 R19 groups. R15 is C1-4 alkyl substituted with 0, 1, 2, 3, 4 or 5 R19 groups. In certain embodiments, the alkyl group R15 is unsubstituted (0 groups R19). In certain embodiments, R15 is -CH3, -Et, -iPr, -nBu, n-pentyl.
In certain embodiments, R15 is C2-io alkenyl substituted with 0, 1, 2, 3, 4 or 5 groups R19. In certain embodiments, R15 is C2-6 alkenyl substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is C2-4 alkenyl substituted with 0, 1, 2 or 3 R19 groups. In certain embodiments, the alkenyl group R 5 is unsubstituted (0 groups R 19). In certain embodiments, R15 is -CH2CHCH2 (ie, allyl).
In certain embodiments, R15 is C2.10 alkynyl substituted with 0, 1, 2, 3, 4 or 5 R19 groups. In certain embodiments, R15 is C2.6 alkynyl substituted with 0, 1, 2 or 3 R19 groups. In certain embodiments, R15 is a C2-4 alkynyl substituted with 0, 1 or 2 R19 groups. In certain embodiments, the alkynyl group R15 is unsubstituted (0 R9 groups). In certain embodiments, R15 is -CH2CCH (ie, propargyl).
In certain embodiments, R15 is aryl of C6-i4. In certain embodiments, R15 is selected from C6 aryl (e.g., phenyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is an unsubstituted phenyl. In certain embodiments, R15 is a monosubstituted phenyl (ie, substituted with 1 group R19).
In certain embodiments, R15 is a 5-14 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R19 groups. In certain embodiments, R15 is a 5-6 member heteroaryl substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is a 6-membered heteroaryl substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is pyridinyl (eg, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2 or 3 R19 groups. In certain embodiments, the heteroaryl group R15 is unsubstituted (0 R9 groups).
Groups R18 In certain embodiments, each instance of R18 independently is selected from -H, -OH, -OR16, -N (R17) 2, -C (= 0) R16, -C (= 0) N (R7) 2 , -C02R16, -S02R16, -C (= NR17) OR16, -C (= NR17) OR16, -C (= NR17) N (R17) 2, -S02N (R7) 2 > -S02R16, -S02OR16, -SOR16, -C (= S) N (R7) 2, -C () 0) SR16, -C (= S) SR16, C1-10 alkylole (eg, aralkyl), alkenyl of C2.10, C2-cyclocyclyl alkynyl of C3.10, 3-14 membered heterocyclyl, C6 aryl. 4 and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups R19, and wherein R6, R17 , R 9 and Rdd are as defined above and in the present.
In certain modalities, each instance of R 7 independently is selected from -H, -C (= 0) R16, - C (= 0) OR 16, -S02R 16 or C 1-6 alkyl. In certain embodiments, each instance of R17 independently is selected from -H or C1-6 alkyl. In certain embodiments, each R17 instance is independently selected from -H or alkyl of -CH3. In certain embodiments, each instance of R17 is independently selected from -H. In certain embodiments, each instance of R17 is independently selected from -CH3.
Additional moieties of the compounds of the formula (1) As generally defined above, the present invention provides compounds of the formula (I): or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, Rc and Rd are as defined herein.
In one aspect, where Ra, Rb, Rc are each H, and Rd is the group Z, the present invention provides compounds of the formula (II): z or pharmaceutically acceptable form thereof, wherein G and Z are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
For example, in certain embodiments, wherein L is a covalent bond, Ra, Rb, Rc are each H, and G is the group -ORe, the present invention provides compounds of the formula (ll-a): Re (Jl-a) or a pharmaceutically acceptable form thereof, wherein Re and Z are as defined herein.
In certain embodiments, wherein Z is a phenyl ring, the present invention provides compounds of the formula (ll-b): (11-b) or a pharmaceutically acceptable form thereof, wherein G, L, Ra, Rb, R °, R15 and z are as defined herein. For example, in certain modes, z is 1 and R 5 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain modalities, z is 2 and R15 is in the meta and para position. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -C, -I). In certain embodiments, R15 is selected from -OR16 and perhaloalkyl from CM0.
For example, in certain embodiments, z is 1 and R15 is para to provide compounds of the formula (ll-c): G Ra (H-b) or a pharmaceutically acceptable form thereof, wherein G, L, Ra, Rb, Rc, R15 and z are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (for example, -Br, - C I, -I). In certain embodiments, R 15 is selected from -OR 6 and perhaloalkyl from C-10.
For example, in certain embodiments, z is 2 and an R15 is meta and an R15 is for to provide compounds of the formula (ll-c): R15 (ll-c) or a pharmaceutically acceptable form thereof, wherein G, L, Ra, Rb, Rc, R15 and z are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, R15 is selected from -OR16 and C14- perhaloalkyl- For example, in certain embodiments, wherein z is a phenyl ring, and G is the group -ORe, the present invention provides compounds of the Formula (Md): or a pharmaceutically acceptable thereof, wherein L, Ra, Rb, R °, R15, Re and z are as defined herein. For example, in certain modalities, z is 1 and R15 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain modalities, L is a covalent bond. In certain embodiments, R15 is selected from -OR16 and perhaloalkyl from C i. i o.
In certain embodiments, wherein z is a phenyl ring, and G is the group -ORe, and Re is a phenyl ring, the present invention provides compounds of the formula (ll-e): (Il-e) or a pharmaceutically acceptable form thereof, wherein L, Ra, Rb, R °, R15, Rh, x and z are as defined herein. For example, in certain modalities, z is 1 and R15 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain modalities, L is a covalent bond. In certain embodiments, R 5 is selected from -OR 16 and perhaloalkyl from C 1 - 10| In certain embodiments, wherein z is a phenyl ring, G is the group -ORe, and Re is a 5-membered heteroaryl ring, the present invention provides compounds of the formula (ll-f): ("-OR or a pharmaceutically acceptable form thereof, wherein Ya, Yb, Yc, Yd, L, Ra, Rb, Rc, R15 and z are as defined herein. For example, in certain modes, z is 1 and R 5 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain modalities, L is a covalent bond. In certain embodiments, R15 is selected from -OR16 and C1-10 perhaloalkyl.
In certain embodiments, wherein z is a phenyl ring, G is the group -ORe, and Re is a 6-membered heteroaryl ring, the present invention provides compounds of the formula (M-g): (M-g) or a pharmaceutically acceptable form thereof, wherein Wa, W, Wc, Wd, L, Ra, Rb, Rc, R15 and z are as defined herein. For example, in certain modes, z is 1 and R 5 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain modalities, L is a covalent bond. In certain embodiments, R15 is selected from -OR16 and perhaloalkyl from C1.10. In certain modalities, Wb is N and Wa, W °, Wd and We are selected from CH or CRh. In certain modalities, Wb and Wd are N and Wa, W °, Wd and We are selected from CH or CRh.
In certain embodiments, wherein z is a phenyl ring, G is the group -ORe, and Re is a 9-membered heteroaryl ring, the present invention provides compounds of the formula (ll-h): (ll-h) or a pharmaceutically acceptable form thereof, wherein Ye, Yf, Y9, Y1, Yk, Ym, Yn, L, Ra, Rb, Rc, R15 and z are as defined herein. For example, in certain modalities, z is 1 and R15 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain embodiments, R 15 is selected from -OR 6 and perhaloalkyl from C-0. In certain embodiments, L is a covalent bond.
In certain embodiments, wherein z is a phenyl ring, G is the group -ORe, and Re is a 10-membered heteroaryl ring, the present invention provides compounds of the formula (ll-i): (II-O or a pharmaceutically acceptable form thereof, wherein Wf, W9, Wh, W \ Wj, Wk, Wm, Wn, L, Ra, Rb, Rc, R15 and z are as defined herein. For example, in certain modalities, z is 1 and R15 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain embodiments, R15 is selected from -OR16 and C1-10 perhaloalkyl. In certain modalities, L is a covalent bond.
In certain embodiments, wherein z is a phenyl ring, G is the group -NReRf, the present invention provides compounds of the formula (ll-j): (? -j) or a pharmaceutically acceptable form thereof, L, Ra, Rb, Rc, Re, Rf, R15 and z are as defined herein. For example, in certain modalities, z is 1 and R15 is in the ortho position. In certain modalities, z is 1 and R15 is in the meta position. In certain modalities, z is 1 and R15 is in the para position. In certain modalities, L is a covalent bond. In certain embodiments, Re and Rf come together to form a 3-10 membered heterocyclic ring. In certain embodiments, Re and Rf come together to form a 5-14 membered heteroaryl ring.
In certain embodiments of the formula (II), wherein Z is a 5-membered heteroaryl ring, the present invention provides compounds of the formula (III-a): or a pharmaceutically acceptable form thereof, wherein Y 1, Y 2, Y 3, Y 4, G, L, Ra, R b and R c are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, Y1 is S, Y2 is CR15, Y3 is N, and Y4 is CH or CR15, where R15 is as defined above and in the present. In certain modalities, Y4 is CH. In certain embodiments, the substitute present in Y2 is C6 aryl (e.g., phenyl).
In certain embodiments, wherein Z is a 6-membered heteroaryl ring, the present invention provides a compound of the formula (III-b): or a pharmaceutically acceptable form thereof, wherein W1, W2, W3, W4, G, L, Ra, R and Rc are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, the 6-membered heteroaryl ring is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) or pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl).
In certain embodiments, wherein Z is a 9-membered heteroaryl ring, the present invention provides compounds of the formula (I I 1-c): (??? - d) or a pharmaceutically acceptable form thereof, wherein Y5, Y6, Y7, Y9, Y10, Y11, Y12, Y13, G, L, Ra, Rb and Rc are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, wherein Z is a 10-membered heteroaryl ring, the present invention provides compounds of the formula (III-e): (II l-e) or a pharmaceutically acceptable form thereof, wherein W6, W7, W8, W9, W10, W1, W12, W13, G, L, Ra, Rb and R ° are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, wherein Z is a 6-membered heterocyclic ring, the present invention provides compounds of the formula (III-f): (iii-f) or a pharmaceutically acceptable form thereof, wherein W 4, W 15, W 16, W 17, W 18, W 19, G, L, Ra, R b and R c are as defined herein. In certain modalities, L is a covalent bond. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, wherein Ra and Rd come together to form a C3-10 carbocyclyl or 3-14 membered heterocyclyl, the present invention provides compounds of the formula (IV): G (IV) or a pharmaceutically acceptable form thereof, wherein s is 0, 1 or 2 and W20, W21, W22, W23, G, Rc, Rd, R15 and R18 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where s is 0, the present invention provides compounds of the formula (IV-a): Rc or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc, W20, W2 and W22 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where s is 0, W21 is NR18, and W20, W22 and W23 are independently CH2, CHR15 or C (R15) 2, the present invention provides compounds of the formula (IV-b): (IV-b) or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc, R 8 and R 15 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, wherein s is 1, the present invention provides compounds of the formula (IV-c): G (IV-c) or a pharmaceutically acceptable form thereof, wherein G, R, Rc, W20, W21, W22 and W23 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where s is 1, W21 is NR18, and W20, W22 and W23 are independently CH2, CHR15 or C (R, 5) 2, the present invention provides compounds of the formula (IV-d): .W? ° N (IV-d) or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc, R 8 and R 15 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where s is 1, W21 is NR18, and W20, W21 and W23 independently are CH2, CHR15 or C (R15) 2, the present invention provides compounds of the formula (IV-e): (IV-e) or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc, R18 and R5 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, wherein s is 2, the present invention provides compounds of the formula (IV-f): or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc, W20, W2, W22 and W23 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where s is 2, W22 is NR18, and W20, W21 and W23 independently are CH2, CHR15 or C (R5) 2, the present invention provides compounds of the formula (IV-g): Rc (IV-g) or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc, R18 and R15 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
Still in another aspect, where Rc and Rd come together to form a carbocyclic ring of C3. 0 or 3-14 membered heterocyclyl, the present invention provides compounds of the formula (V): (V) or a pharmaceutically acceptable form thereof, wherein W24, W26, W27, W28 and W30 independently are CH2, CR15, C (R15) 2 or NR18, optionally wherein W25 and W26 are substituted with a fused C6 aryl ring or fused 6-membered heteroaryl ring; t and v independently are 0 or 1; wherein G, Ra, Rb, R15 and R18 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain modalities, t is 0 and v is 0. In certain modalities, t is 0 and v is 1. In cierts modalities, t is 1 and v is 0. In certain modalities, t is 1 and v is 1.
In certain embodiments, where t is 0 and v is 0, the present invention provides compounds of the formula (V-a): (Goes) or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, W25, W26, W27 and W28 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, W27 is NR18, and W25, W2G and W28 independently are CH2, CHR15 or C (R15) 2. In certain embodiments, W25, W26, W27 and W28 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, where t is 0, W27 is NR1 \ and W25, W26 and W28 independently are CH2, CHR15 or C (R1fi) 2, the present invention provides compounds of the formula (V-b): (V-b) or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, R15 and R18 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where t is 0 and v is 1, the present invention provides compounds of the formula (V-c): (V-c) or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, W25, W26, W27, W28 and W29 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, W26 is NR18, and W25, W27, W28 and W29 independently are CH2, CHR15 or C (R15) 2. In certain embodiments, W27 is NR18, and W25, W26, W28 and W29 independently are CH2, CHR15 or C (R15) 2. In certain embodiments, W25, W26, W27, W28 and W29 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, where t is 0, v is 1, W27 is NR18, and W25, W26, W28 and W29 independently are CH2, CHR15 or C (R15) 2, the present invention provides compounds of the formula (V-d): (You) or a pharmaceutically acceptable form thereof, and wherein G, Ra, Rb, R15 and R18 are as defined herein. In certain modalities, G is -ORe. In certain embodiments, G is -B. However, in certain embodiments, G is not halogen (eg, -Br, -Cl, -I).
In certain embodiments, where t is 1 and v is 1, the present invention provides compounds of the formula (V-e): (Go) or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, W24, W25, W26, W27, W28 and W29 are as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, W25 is NR18, and W2 \ W26, W27, W28 and W29 independently are CH2, CHR15 or C (R1) 2. In certain embodiments, W26 is NR18, and W24, W25, W27, W28 and W29 independently are CH2, CHR15 or C (R5) 2. In certain embodiments, W27 is NR18, and W24, W25, W26, W28 and W29 independently are CH2, CHR15 or C (R15) 2. In certain embodiments, W24, W25, W26, W27, W28 and W29 independently are CH2, CHR15 or C (R15) 2.
In certain embodiments, where t is 1, v is 1, W27 is NR18, and W24, W25, W26, W28 and W29 independently are CH2. CHR15 or C (R15) 2, the present invention provides compounds of the formula (V-f): (V-f) or a pharmaceutically acceptable form thereof, wherein G, a, Rb, R15 and R18 are. as defined herein. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
In certain embodiments, where t is 0, v is 0, W27 and W28 are independently CH2, CHR 5 or C (R15) 2, and W25 and W26 are substituted with a fused C6 aryl ring, R ° and Rd are put together to form a 5,6-bicyclic carbocyclyl spiro-fused ring of the formula (Vg): (V-g) or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, R15 and R18 are as defined herein. In certain modalities, Ra and Rb are -H. In certain modalities, z is 1. In certain modalities, G is -ORe. In certain modalities, G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain embodiments, R 5 is selected from -OR 16 and perhaloalkyl from C 1 -io- Exemplary compounds of the present invention Exemplary compounds of formulas (I) and (II), and subgenres thereof, are set forth in Tables 1a-1m below, and are also described in more detail in Examples 1-253, provided herein . The compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351.
In certain embodiments, the compound is any of the compounds provided in Table 1a, or a pharmaceutically acceptable form thereof.
Table 1 ..
Compound * G or R * Rc I-10 -Br -H -H 1-17 -Cl -H -H 1-23 -H -H 1-24 -H -H 1-25 -H -H 1-26 -H -H 1-27 -H -H 1-28 -H CN 1-29 -H -H 1-30 -H -II 1-31 -H -M 1-32 -H -H H Table 1a. 1-33 -H -11 1-34 6? -H H 1-35 -H -H 1-36 -H -H 1-37 -H -H 1-39 -H -H Me02C ^ -0A 1-40 e. -N -H H 1-41 -H -H 1-42 -H 1-43 N -H -II FAjL0 1-44 Me -H- 1-45 |OMe -H -H 1-47 -H -H 0 1-56 F3C ^ N -H -II 1-57 -H -II H Table 1a .. 1-58 CN -H -11 1-59 -H -H? F? 0 1-60 CF3 -H -H 1-61 C02 e -H -H 1-62 -II -II 1-63 Me -H- o = s = o 1-64 NH2 -H -H o = s = o 1-65 N -H -II MeC ^^ O '^' 1-66 MeO. ,? -H H 1-67 e02C- / N -H -II 1-68 -H -II 1-69 -H -H 1-90 H2N / -H -H Table 1a. 1-92 -11 -II 1-93 -H -11 1-94 H M -H -H 1-98 I W 0 -. 0 -H -H 1-99 -H -H 1-100 -H -H 1-110 H02C. .N. -H H 1-111 -11 -H I k ^ ko ^ 1-146 C02H -H 1-147 H02C ^^ -H -11 1-155 Me -H- 1-1 9 Me -H -II Table 1a. , 1-160 Me -11-11 1-197 -H -H 1-243 -H -11 H 1-244 -H -H O Me 1-245 -11-11 OH 1-256 -H 1-257 & I -H -11 1-260 0 -H -H Me 0 1-78 -Br -CU, -H (cis) 1-82 -Br -CH, -H (trans) 1-91 -CU, -II (t ans) 1-76 ¿-Br * -H -CH, 1-89 -H -CH, 1-130 cx -Br -HCF, 1-131 -H -CF, 1-95 -Br -H-CH2CH, In certain embodiments, the compound is any of the compounds provided in Table 1b, or a pharmaceutically acceptable form thereof.
Table 1b.
Ra Compound G R ", 1-14 -Br -H -H 1-46 -H -H 1-53 M -H -H 0 1-54 N -H -II 0 1-55 -H -II H02C - ^^ O 1-70 -H -H 1-71 X N »-H -H 1-72 N -H -H 1-73 NH2 ^ | -H -II 1-83 -H -II 0 ??? ^ Table 1b. 1-84-11-11 1-85 -H -H 1-86 -H -H 1-96 -H -H 1-97 -H -H M05 -11 -U 1-106 -H -H HOr «¾ L0 1-107 0 -H -H H 1-108 -11 -11 Me ^ Í Q 1-109 -H -H 1-112 -H -H ^ JL0A 1-1 18 -H -H Table 1b. 1-128 -11-11 1-132 -H -H 1-133 -H 1-134 -H -H ? 0? 1-135 -H 1-1.36 MeCk ^ N -H -H 1-151 -H - H 1-152 -H 1-157 Me -11 IT 1-161 ¾ »-H -H 1-162 j f -11 -II 1-163 -H -II 1-165 -H -H Table 1.
I-173 -H-11 1-174 = N -H -H N 'NH 1-175 N-NH -H -H 1-176 C02H -H 1-177 A -H -H 1-178 NC N -H -H k ^ 0A 1-182 0 -H -H 1-183 -H -H or L l > -H H 1-186 -11 -1! 1-187 -H 1-188 -H H02C- 01 Y * N ^ Table 1b. 1-189 -11 -1 1-190 Me -H- Me ^ JLQA 1-191 F3C -11 -11 e ^^ Jl ^ A J-192 -H -M 1-193 -H -H H02C- _jl N 1-194 -H -H Oj. N 1-195 A) -11 -1 1-199 I Me -H -11 1-200 i N = -H -II 1-201! f ~ 0 -H -H Table 1b. 1-218 Me -11-11 1-220"• / XA -H -H 1-221 N-N -H -11 V 1-223 Me -H- > = N, 1-224 Me -H -11 ) = N, 1-225 1 I / = N -n -II CyN 1-226! 1 / = N * -H -II j CX ^ N 1-230 -H Table 1b. 1-236 -11 -11 1-246 -H -H i H OH 1-248 -H -II 1-249 |H -H w 0 1-250 -H -H 1-251 -H -H 1-253 -H -H 1-255 -H Me 1-258 / = N. -H -II 1-75 -Br -11 1 ... ..: £ '"·' -. -88 * -Cl 1, 1-113 H02C N -H -CH, A0A 1-114 i 0 -H -CH, ¡H U ^ Table 1b. 1-115 O -M -CHj 1-116 -H -CH.
FSC ^ ¾ L0A 1-117 0 -H -CHj 1-129 H -H -CHj 1-154 -H-CHi 1-156 Me -H -CH » 1-158 Me -II -CU;, 1-164 -H -CU to 1-167 -H -CH. » Me-S // 0 N 1-171 -H -CH, H02C- ^ N ^ N '^ 1-172 -H ("V -CH, ^ N TO Table 1b. 1-185 -11 -Cllj 1-196 -? -CH, 1-198 -? -Cllj 1-222 Me -? -CHS Cx0 1-227 / = N > -? -CHj 1-228 T -? -CH, ¾? 0? 1-229 i Me -? -CH3 i) = N ! 1-231 1 0 -? -CHj : Table 1b. 1-232 -11 -Cl 1-233 Me. ,, Me -H -CHj 0 = S = 0 1-234 -H -CHj 1-235 Me -H -CH, 1-240 Me -H -CHj 1-241 -11 -C1I.3 M¿ kA0A 1-242 ??? -H -CHj N H 1 \ 1-261 eS ^ -H -CH, kA0x In certain embodiments, the compound is any of the compounds provided in Table 1c, or a pharmaceutically acceptable form thereof.
Table 1c.
Compound G 1-168 -H 1-169? ß? -H H 1-170 H02C_N -H -H 1-216 -H 1-217 -H -H 1-218 Me -H- N-. 1-238 MeS. ,? -H H 1-259 Me -H- In certain embodiments, the compound is any of the compounds provided in Table 1d, or a pharmaceutically acceptable form thereof.
Table 1d.
R15 -OCF3 Compound G Ra Rc | ¾ '^ = halogen 1-120 -Br -H -H -F Table 1d. 1-121 -u -H -F 1-122 Me02C ^ N. -H -H -1? 1-123 -H -H -F 1-124 -Br -11 -H -Cl 1-125 -H -H -Cl In certain embodiments, the compound is any of the compounds provided in Table 1e, or a pharmaceutically acceptable form thereof.
Table 1e.
Ra Compound G Ra Rc R1 * = unsubstituted alkyl, alkynyl 1-142 -Br -H -H 1-143 -H Ti% 1-144 -H -11 1-145 H02C XV -H -H 1-140 HO2C. .N. -H -H Me XV V-Me * 1-1.41 -H -H Me V-Me NVl \ ·. 1-15 -Br -II -II Me - Me - Table 1e. 1-137 -II -11 n-buti | o 1-138 H02C X NV -11 -H n-butyl 1-139 -II -H -butyl 1-6 -Br -II -H -CH, [-38 v -H -H -CH, [-77 -Br -CH., -H -CH., (Trans) In certain embodiments, the compound is any of the compounds provided in Table 1f, or a pharmaceutically acceptable form thereof.
Table 1f.
R8 Compound G R "Rc R = alkyl, aryl 1-20 -Br -H -H n-butyl 1-180 -11 -H n-butyl 1-181 O -II-11 n-butyl 1-179 -Br -H -H n-pentyl 1-102 -Br -H -CH, -C «H5 1-104 -H -CH, -C6H5 1-9 -Br -H -H -C (iH5 1-101 -H -H 1-103 -H. -II -C «H5 In certain embodiments, the compound is any of the compounds provided in Table 1g, or a pharmaceutically acceptable form thereof.
Table 1g.
Ra ™ Compound G = halogen I-3 -Br -Cl .1-153 -CI 1-148 -Br -Br 1-149 MeQ2CL, N -Br 1-150 H02C, N -Br 1-237 -Br 1-2 -Br -f In certain embodiments, the compound is any of the compounds provided in Table 1h, or a pharmaceutically acceptable form thereof.
Table 1h.
Ra < ^ N Compound G R " 1-12 -Br -11 -H 1-87 -H -H In certain embodiments, the compound is any of the compounds provided in Table 1, or a pharmaceutically acceptable form thereof.
Table 1!.
N- ° / = \ Ra Compound G Ra Rc 1-1 -Br -H -H .1-166 -H -H In certain embodiments, the compound is any of the compounds provided in Table 1j, or a pharmaceutically acceptable form thereof.
Table 1j.
R2 Compound G ir Rc R ~ H «halogen I-I26 -Br -H -II -F, -F 1-127 -H -H -F, -F 1-16 -Br -H -II -H In certain embodiments, the compound is any of the compounds provided in Table 1k, or a pharmaceutically acceptable form thereof.
Table 1k. 0 Ra R18 Compound G R " Table 1k. 1-22 -Br -11 -11 H, -CHzPh 1-214 O -11 -H H, -CH2Ph 1-215 -II -II H. -CH2Ph 1-203 -Br -II -H -CH ,, -CH, 1-212 -H -H -CH ,, -CH, 1-202 -Br -H -H 1-204 -Br -11 -H -II. - H, 1-208 -Br 1-209 -Br -H -H In certain embodiments, the compound is any of the compounds provided in Table 11, or a pharmaceutically acceptable form thereof.
Table 11 Compound G R "Rl R1 * 1-205 -Br -H -H 1-207 -Br -H -H -?, - CHj 1-206 -Br -H -H -CH ^ 5 -C.HU 1-210 -Br -H -H 1-211 -Br -H -H Table 11 1-213 -11 -11 -C¾ -Cih ° L] L? In certain embodiments, the compound is any of the compounds provided in Table 1m, or a pharmaceutically acceptable form thereof.
Table 1 m.
Cl Cl 1-4 1-5 O e MeO 1-7 1-8 BIAK V N M y 1-11 1-13 F F N 1-119 Me 1-18 1-19 1-21 O - ° ', 1-49 1-48 Br 1-51 1-50 Table 1m. jj ^ - < ~ V-C02Me 1-52 1-74 More exemplified compounds of the formulas (I), (II), (III), and subgenres thereof, are illustrated in Tables 2a to 2e, provided below, and are also described in more detail in Examples 254-284, provided herein. The compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351.
In certain embodiments, the compound is any of the compounds provided in Table 2a, or a pharmaceutically acceptable form thereof.
Table 2a.
N- ° \ / T ~ Compound G Ra Rl R, S R19 11-6 -Br -H -H -H 11-21 -H -H -H 11-28 -H -II -H -H 11-18 ° w -Br -II CH, -H -H 11-22 -11 -CH3 -H | -.II .11-23 -11 -CH, -II -11 l0A 11-29 -H -CH, -H -H 11-19 -Br - U, -H -II -H (cls) 11-20 -Br -CU to -H -II «1 (trans) 11-17 -Br -11 -H -H -Cl In certain embodiments, the compound is any of the compounds provided in Table 2b, or a pharmaceutically acceptable form thereof.
Table 2b.
N '_ ^ ¡] Ra i i 1 NT Compound G Ra Rc 11-25 -Br -H -H ÍI-26 -H -H 11-27 H02C_ > -H H In certain embodiments, the compound is any of the compounds provided in Table 2c, or a pharmaceutically acceptable form thereof.
Table 2c.
G ' Compound G Ra Rl II 8 -Br -lí -II 11-31 c -H -H 11-30 V OH c -II -II • ?? H OH In certain embodiments, the compound is any of the compounds provided in Table 2d, or a pharmaceutically acceptable form thereof.
Table 2d.
I A N_R18 Compound G R1 'Ra 11-15 -Br -H -H 11-16 Br -II -11 or- In certain embodiments, the compound is any of the compounds provided in Table 2e, or a pharmaceutically acceptable form thereof.
Table 2e. 11-1 11-2 N'0 N = \ N '° v / * N Bf ^^ 1J-3 11-4 O 11-5 11-7 Br - \ - / 11-10 11-9 Br / Br ^ ~ - x 11-11 Me 11-12 i) - ~ ^ N ° \ N H 11-13 Br \ - N O ^ 11-14 Table 2e.
Me - ° v 11-17 11-24 ^ ¾ The further exemplified compounds of formulas (I), (IV) and (V) and subgenres thereof are illustrated in tables 3a to 3d, provided below, and are also described in more detail in examples 285-350. , provided in this. The compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351.
In certain embodiments, the compound is any of the compounds provided in Table 3a, or a pharmaceutically acceptable form thereof.
Table 3a.
G Compound G Ili-27 -Br 111-48 -Cl ~ b- ° 111-51 11. 1 -52 1I1 1 - ?? 111-46 Table 3a. iII-59 111-60 Me ·, m-16 -Br > 111-58 ° o II 1-49 -Br) 111-50 m-9 -Br or- 111-47 -Cl o- 111-53 ° o- II 1-14 -Br -H 111-1 -Br K ° Me Table 3a. ili-17 -Br H o-O- ' 111-19 -Br III-20 ¾ -Br to 111-21 -Br OMe 111-22 -Br 111-23 -Br 111-24 -Br Me 111-25 -Br Cl 111-26 l ~~ \ -Br CF3 lil-28 -Br 111-29 -Br 111-30 -Br Table 3a. 111-31 -Br 111-32 -Br 111-33 -Br 111-34 -Br 111-35 -Br% OMe ?? - 36 -Br K ° ° - \ Me 111-37 -Br 111-38 -Br 111-39 i -Br -i Q OMe 111-40 -Br Cl 111- 1 i- Me -Br Table 3a. 111-54 111-55 Cl 111-56, or ex * H / = \ 111-57 or ! ^ _ and-CF3 In certain embodiments, the compound is any of the compounds provided in Table 3b, or a pharmaceutically acceptable form thereof.
Table 3b.
JL / (fusion of cis ring) Compound G 111-43 -Br ox x 111-44 -Br 0 111-45 -Br In certain embodiments, the compound is any of the compounds provided in Table 3c, or a pharmaceutically acceptable form thereof.
Table 3c.
N-0 ¡T Compound G IÜ-63 -Br 111-64 111-66 -Br -OCF, 111-67 -OCFj lfl-68 -OCFj Table 3c. 111-70 Me, I -OCI II 1-7.1 v! -OCF, 111-73 -OCF, ? ^? 0? 111-74 0 1 -OCF3 HCT% j l0A 1 In certain embodiments, the compound is any of the compounds provided in Table 3d, or a pharmaceutically acceptable form thereof. 3d table.
Br 111-2 J0O0 ?? - 3 111-4 II X) - 'N- Br III-8 111-10 0 '0 111-11 111-12 3d table.
N '° v 111-13 111-42 (fusion of cis ring) DO 111-62 However, in certain embodiments of the formulas (I) and (II), or subgenres thereof, any of the following compounds is specifically excluded: 224 In certain embodiments of the formulas (I), (II) and (III), or subgenres thereof, any of the following compounds, wherein R 8 is as defined herein, is specifically excluded: In certain embodiments of formulas (I), (IV) and (V), or subgenres thereof, any of the following compounds, wherein R18 is as defined herein, and R15 is -OCH3, -CN, -C02H, -CO2CH3, -CO2CH2CH3, is specifically excluded: //. Pharmaceutical compositions In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.
The pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid carriers, dispersion or suspension aids, surfactants, sotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate to the form of particular dosage desired. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams &Wilkins, 2005).
The pharmaceutical compositions described herein can be prepared by any method known in the pharmacology art. In general, said preparatory methods include the steps of carrying the active ingredient in association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, setting up and / or packaging the product in a unit. of one or multi-dose desired.
Pharmaceutical compositions can be prepared, packaged and / or sold by volume as a single unit dose and / or as a plurality of unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of said dosage such as, for example, one-half or one-third of said dosage.
Relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and / or any additional ingredient in a pharmaceutical composition of the invention will vary, depending on the identity, size and / or condition of the subject being treated and which further depends on the route by which you must administer the composition. By way of example, the composition may comprise between 0.1% and 100% (w / w) of active ingredient.
The pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions provided include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifiers, disintegrating agents, binding agents, preservatives, regulating agents, lubricating agents and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring and perfume agents may also be present in the composition.
Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol , sodium chloride, dry starch, corn starch, powdered sugar, etc., and combinations thereof.
Exemplary granulation and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, sponge natural, cation exchange resins, calcium carbonate, silicates, sodium carbonate, poly (vinyl-pyrrolidone) (crospovidone) interlaced, sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, interlaced sodium carboxymethylcellulose, methylcellulose , pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
Exemplary surfactants and / or emulsifiers include natural emulsifiers (eg, acacia, agar, alginic acid, sodium alginate, tragacanth, condrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, alcohol oleyl, triacetin mono stearate, ethylene glycol distearate, glyceryl monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (eg, carboxy polymethylene, polyacrylic acid, acrylic acid polymer and carboxyvinyl polymer), carrageenan, cellulose derivatives (for example, sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), is teres of sorbitan fatty acid [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan mono-oleate [Tween 80], sorbitan sorbate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80] , polyoxyethylene esters (eg, polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (eg example, Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij 30]), poly (vinyl pyrrolidone), diethylene glycol monolaurate, tri-ethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate , oleic acid, ethyl laurate, laurel, sodium sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, sodium docusate, etc. and / or combinations thereof.
Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, efe), natural and synthetic gums ( for example, acacia, sodium alginate, Irish mold extract, panwar gum, ghatti gum, isapol shell mucilage, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, efe, and / or combinations thereof.
Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, anti-fungal preservatives, alcohol preservatives, acid preservatives and other preservatives.
Exemplary antioxidants include alpha tocopherol, ascorbic acid, buffalo palmitate, butylated hydroxyanisole, butylated hydroxy-toluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. .
Exemplary chelating agents include ethylene diamine tetraacetic acid (EDTA) and its salts and hydrates thereof (eg, sodium edetate, disodium edetate, trisodium edetate, disodium calcium edetate, dipotassium edetate and the like), citric acid and salts and hydrates thereof (eg, monohydrate of citric acid), fumaric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, Phenyl mercuric nitrate, propylene glycol and thimerosal.
Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, biphenol, chlorobutanol, hydroxybenzoate and phenylethyl alcohol.
Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid and phytic acid.
Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparebene, Germall 115, Germaben II, Neolone, Kathon and Euxyl. In certain modalities, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.
Exemplary regulatory agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D acid -gluconic, calcium glycerophosphate, calcium lae, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, gluconate potassium, mixtures of potassium, dibasic potassium phosphate, potassium phosphate monobasic, mixtures of potassium phosphate, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lae, dibasic sodium phosphate, sodium phosphate monobasic, mixtures of sodium phosphate, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, solution isotonic saline, Ringer's solution, ethyl alcohol, ere, and combinations thereof.
Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, lauryl sulfate, magnesium, the u ri I its sodium ato, efe, and combinations thereof.
Exemplary oils include almond oils, apricot kernel, avocado, babassu, bergamot, currant seed, borage, each, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geranium, pumpkin, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, bleach, lavender, lime, litsea cubeba, macadamia, mauve, mango seed, prairie grass, mink, nutmeg, olive, orange, orange peel, palm, seed palm tree, sandalwood, sasquana, salty flavor, sea buckthorn, sesame, shea butter, silicone, soy, sunflower, tea tree, thistle, tsubaki, vetiver, walnut and wheat germ.
Liquid dosage forms for oral and parenteral administration include emulsions, pharmaceutically acceptable microemulsions, solutions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art as such, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (for example, cottonseed, peanut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. Apart from the inert diluents, the oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfume agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and combinations thereof.
Injectable preparations, for example, sterile injectable aqueous or oleoginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any soft fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. .
In order to prolong the effect of a drug, it is often desirable to reduce the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on the size of crystal and crystal form. Alternatively, the delayed absorption of a drug form parenterally administered upon dissolving or suspending the drug in an oil vehicle.
Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid. at body temperature and therefore they melt in the rectum or vaginal cavity and release the active ingredient.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms, the active ingredient is mixed with at least one inert excipient or carrier, pharmaceutically acceptable such as sodium citrate or dicalcium phosphate and / or to) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and salicylic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, ethyl alcohol and glycerol monostearate, h) absorbers such as caolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycols, solid two, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise regulatory agents.
Solid compositions of a similar type can be used as fillers in hard and soft fill gelatin capsules using such excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric layers and other coatings well known in the pharmaceutical formulating art. Optionally they may comprise opacifying agents and may be of a composition that they release the active ingredient (s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as fillings in gelatin capsules with hard and soft filler using such excipients as lactose or milk sugar such as high molecular weight polyethylene glycols and the like.
The active ingredients may be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, Pills and granules can be prepared with coatings and shells such as enteric layers, release control coating and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, for example, tablet-forming lubricants and other tablet-forming aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise regulatory agents. Optionally they can comprise opacifying agents and can be of a composition that they can release the active ingredient (s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical and / or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers and / or patches. In general, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and / or any necessary preservative and / or regulator as may be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled administration of an active ingredient to the body. Said dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the speed can be controlled by providing a speed controlling membrane and / or by dispersing the active ingredient in a polymer and / or gel matrix.
Devices for use in administering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. The intradermal compositions can be administered by devices that limit the effective penetration length of a needle in the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices that administer liquid vaccines to the dermis are suitable a liquid jet injector and / or via a needle that pierces the stratum of cornea and produces a jet that reaches the dermis. Jet injection devices are described, for example, in the U.S.A. Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; Y PCT publications WO 97/37705 and WO 97/13537. Suitable are powder / ballistic particle delivery devices that use compressed gas to accelerate the vaccine in powder form through the outer layers of the skin to the dermis. Alternatively or additionally, conventional syringes may be used in the Mantoux method of intradermal administration.
Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may comprise, for example, from about 1% to about 10% (w / w) of active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described below.
A pharmaceutical composition of the invention can be prepared, packaged and / or sold in a formulation suitable for pulmonary administration via the oral cavity. Said formulation may comprise dry particles comprising the active ingredient and having a diameter in the range of about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers. Said compositions are conveniently in the form of dry powders for administration using a device comprising a reservoir of dry powder to which a jet of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispenser container. such as a device comprising the active ingredient dissolved and / or suspended in a low boiling propellant in a sealed container. Said powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles per number have a diameter of less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter of less than 6 nanometers. The dry powder compositions can include a diluent of solid fine powder such as sugar and are conveniently provided in a unit dosage form.
The pharmaceutical compositions of the invention formulated for pulmonary administration can provide the active ingredient in the form of drops of a solution and / or suspension. The formulations can be prepared, packaged and / or sold as alcoholic solutions and / or suspensions and / or diluted, optionally sterile, comprising the active ingredient, and can be conveniently administered using any nebulizer and / or atomizer device. Said formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as sodium saccharin, a volatile oil, a regulating agent, a surfactant and / or a preservative such as methylhydroxybenzoate. The drops provided by this route of administration may have an average diameter in the range of about 0.1 to about 200 nanometers.
The formulations described herein as being useful for pulmonary administration are useful for intranasal administration of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a rough powder comprising the active ingredient and having an average particle of about 0.2 to 500 microns. Said formulation is administered, by rapid inhalation through the nasal passage from a powder container maintained near the nostrils.
Formulations suitable for nasal administration, for example, may comprise as little as 0.1% (w / w) and as much as 100% (w / w) of the active ingredient, and may comprise one or more additional ingredients described in I presented. A pharmaceutical composition of the invention can be prepared, packaged and / or sold in a formulation suitable for buccal administration. Said formulations, for example, may be in the form of tablets and / or tablets made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) of active ingredient, the balance comprising a composition that can be dissolving and / or degrading orally and, optionally, one or more of the additional ingredients described herein. Alternatively, formulations suitable for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Said powder and / or aerosol formulations, when dispersed, can have an average particle size and / or droplet in the range of about 0.1 to 200 nanometers, and may further comprise one or more additional ingredients described herein.
A pharmaceutical composition of the invention can be prepared, pack and / or sell in a formulation suitable for ophthalmic administration. Such formulations, for example, may be in the form of eye drops including, for example, a solution and / or suspension of 0.1 / 1.0% (w / w) of the active ingredient in an aqueous or oily liquid carrier. Said droplets may further comprise regulatory agents, salts and / or one or more of the additional ingredients described herein. Other formulations that can be administered ophthalmically that are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are contemplated as being within the scope of this invention.
Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions that are suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all classes. The modification of pharmaceutical compositions suitable for administration to humans in order to make the compositions suitable for administration to various animals is well understood, and the veterinary pharmacologist skilled in the art can design and / or perform said modification with ordinary experience. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, 2005.
Still more encompassed by the invention are the packaging and / or pharmaceutical kits. The packages and / or pharmaceutical kits provided may comprise a composition provided and a container (e.g., a flask, ampoule, bottle, syringe and / or dispenser package, or other suitable container). In some embodiments, the kits provided may optionally comprise a second container comprising an aqueous carrier suitable for dilution and suspension of the composition provided for administration preparation to a subject. In some embodiments, the contents of the provided formulation container and solvent container are combined to form at least one unit dosage form.
In some embodiments, a composition provided with the invention may be useful in conjunction with subject-controlled analgesic devices (PCA), wherein a subject may administer, for example, opioid analgesia as required for pain management.
Optionally, a single container may comprise one or more compartments for containing a composition provided, and / or aqueous carrier suitable for suspension or dilution. In some embodiments, a single container may be appropriate for modification so that the container may receive a physical modification to allow combination of compartments and / or components of individual compartments. For example, an aluminum sheet or plastic bag may comprise two or more compartments separated by a perforated seal that can be broken to allow combination of the contents of two individual compartments once the signal to break the seal is generated. A package or pharmaceutical kit in this manner can comprise said multi-compartment containers including a provided composition and appropriate solvent and / or aqueous carrier suitable for suspension.
Optionally, the instructions for use are additionally provided in said games of the invention. These instructions can provide, for example, instructions for dosing and administration. In other embodiments, the instructions may provide additional detail that refers to specialized instructions for particular containers and / or systems for administration. Furthermore, the instructions may provide specialized instructions for use in conjunction and / or in combination with additional therapy. In a non-limiting example, the formulations of the invention may be used in conjunction with administration of opioid analgesia, which, optionally, may comprise use of a subject controlled analgesic device (PCA). In this manner, instructions for use of formulations provided may comprise instructions for use in conjunction with PCA delivery devices.
//. Methods of use and treatment The present invention provides methods for treating a condition mediated by FAAH comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable form thereof.
The present invention also provides methods for inhibiting FAAH in a subject which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable form thereof.
The present invention also provides a method of inhibiting activation of the FAAH pathway in vivo or ex vivo, which comprises contacting an FAAH protein with a compound of the formula (I) in an amount sufficient to reduce activation of the FAAH pathway. .
The present invention also provides use of a compound of the formula (I) for the treatment of a condition mediated by FAAH in a subject.
The present invention also provides use of a compound of the formula (I) in the manufacture of a medicament. In certain modalities, the drug is useful for treating a condition mediated by FAAH.
A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or subject adult (eg, young adult, middle-aged adult, or older adult)) and / or other primates (eg, cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese and / or turkeys.
As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or reduces the progression of the disease, disorder or condition.
As used herein, and unless otherwise specified, the terms "prevent", "preventing" and "prevention" contemplate an action that occurs before a subject begins to suffer from the specified disease, disorder or condition, which inhibits or reduces the severity of the disease, disorder or condition.
As used herein, and unless otherwise specified, the terms "control", "controlling" and "control" encompass preventing the recurrence of the disease, disorder or specified condition in a subject who has already suffered from the disease , disorder or condition and / or lengthen the time a subject who has suffered from the disease, disorder or condition remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease, disorder or condition, or changing the manner in which a subject responds to the disease, disorder or condition.
As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment and control of a disease, disorder or condition, or to delay or Minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or control of the disease, disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition , or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically effective amount" may encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
As used herein, "inhibition", "inhibiting", "inhibiting" and "inhibitor" and the like, refer to the ability of a compound to reduce, decrease, stop or prevent activity of a particular biological process (e.g. , activity of FAAH) in a cell relative to vehicle.
"Condition mediated by FAAH" as used herein, refers to a disease, disorder or condition that is treatable by inhibition of FAAH activity. "Disease", "disorder" or "condition" are terms used interchangeably herein. Conditions mediated with FAAH include, but are not limited to, painful conditions, inflammatory conditions, immune disorders, central nervous system disorders, metabolic disorders, cardiac disorders and glaucoma.
In certain modalities, the condition mediated by FAAH is a painful condition. As used herein, a "pain condition" includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, pain from deafferentation, chronic pain (e.g., chronic nociceptive pain, and others). forms of chronic pain such as post-operative pain, eg, pain arising from surgery for hip, knee or other replacement), pre-operative pain, stimulation of nociceptive receptors (nociceptive pain), acute pain (eg, pain acute phantom and transient), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, post-operative pain, pain associated with medical procedures, pain resulting from itching, painful bladder syndrome, pain associated with chronic fatigue syndrome, pain associated with preterm labor, pain associated with withdrawal symptoms of drug addiction, joint pain, arthritic pain (eg, lor associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gout arthritis, reactive arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral pain, muscle-skeleton pain, headache, migraine, muscle pain, back pain, neck pain, tooth pain, dental / maxillofacial pain, visceral pain and the like.
One or more of the painful conditions contemplated herein may comprise mixtures of various types of pain provided before and in the present (eg, nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some modalities, a particular pain may dominate. In other modalities, the painful condition comprises two or more types of pain without one dominating. A skilled physician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.
In certain modalities, the painful condition is neuropathic pain. In term "neuropathic pain" refers to pain that results from damage to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is pain caused by damage to acute tissue that involves small cutaneous nerves or small nerves in muscle or connective tissue. Neuropathic pain is typically long-lasting or chronic and often develops within days or months after initial acute tissue damage. Neuropathic pain can involve persistent, spontaneous pain as well as allodynia, which is a painful response to a stimulus that is usually not painful. Neuropathic pain can also be characterized by hyperalgesia, where there is a marked response to a painful stimulus that is usually trivial, such as a pin prick. Neuropathic pain conditions may develop after neuronal damage and the resulting pain may persist for months or years, even after the original damage has healed. Neural damage can occur in the peripheral nerves, dorsal roots, spine or certain regions in the brain. Neuropathic pain conditions include, but are not limited to, diabetic neuropathy (eg, diabetic peripheral neuropathy); sciatica; non-specific low back pain; pain due to multiple sclerosis; carpal tunnel syndrome, fibromyalgia; neuropathy related to HIV; neuralgia (for example, post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma (eg, amputation, surgery, invasive medical procedures, toxins, burns, infection), pain resulting from cancer or chemotherapy (eg, pain induced by chemotherapy such as peripheral neuropathy induced by chemotherapy), and pain that results from an inflammatory condition (for example, a chronic inflammatory condition). Neuropathic pain can result from a peripheral nerve disorder such as neuroma; nerve compression; nerve crush, nerve stretch or incomplete nerve transection; mono-neuropathy or polyneuropathy. Neuropathic pain can also result from a disorder such as dorsal root ganglion compression; inflammation of the spine; contusion, tumor or hemi-section of the spine; tumors of the brain stem, thalamus or cortex; or trauma to the brain stem, thalamus or cortex.
Symptoms of neuropathic pain are heterogeneous and are often described as throbbing and lancinating pain, or constant, burning pain. In addition, there is pain associated with normally painless sensations such as "pins and needles" (paraesthesia and d isaesthesia), increased sensitivity to touch (hyperesthesia), painful sensation after innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimulation (thermal, cold, mechanical hyperalgesia), continuous pain sensation after removing stimulation (hyperpathy) or an absence of or deficit in selective sensory pathways (hypoalgesia).
In certain modalities, the painful condition is non-inflammatory pain. Types of noninflammatory pain include, without limitation, peripheral neuropathic pain (eg, pain caused by injury or dysfunction in the peripheral nervous system), central pain (eg, pain caused by injury or dysfunction of the central nervous system) , pain of deadening (eg, pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (eg, pain felt in response to tissue damage or damage to imminent tissue), phantom pain (eg, pain) sense in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (for example, pain where there can be no physical cause), and wandering pain (for example, where the pain repeatedly changes the location in the body).
In certain modalities, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) is associated with an inflammatory condition and / or an immune disorder.
In certain modalities, the condition mediated with FAAH is an inflammatory condition. The term "inflammatory condition" refers to those diseases, disorders or conditions that are characterized by signs of pain (pain, generation of harmful substances and stimulation of nerves), heat (heat, vasodilation), flushing (flushing, of vasodilatation and increased blood flow), swelling (tumor, excessive influx or outflow of restricted flow of fluid), and / or loss of function (functio laesa, which can be spatial or complete, temporary or permanent). Inflammation takes many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrous, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic inflammation , obliterative, parenchymal, plastic, productive, proliferating, pseudomembranous, purulent, sclerant, seroplastic, serosa, simple, specific, subacute, suppurative, toxic, traumatic and / or ulcerative.
Exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu arteritis), arthritis (xerj, crystalline arthritis, osteoarthritis, psoriatic arthritis, gout arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergy or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (for example, diabetes mellitus type I, diabetes mellitus type 2), a skin condition (for example, psoriasis, eczema, burns, dermatitis, pruritus (itching)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (eg, pains of migraine, tension pains), ileus (for example, postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (for example, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, gastrointestinal and respiratory syndromes) (eg, eisinophilic esophagitis, eosophilic gastritis, eisonophilic gastroenteritis, eisonophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (eg, Crohn's disease, colitis) ulcerative, collagenous colitis, lymphocytic colitis, ischemic colitis, fun colitis, Behcet syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigoid vulgar, pernicious anemia, peptic ulcers, polymyositis, cirrhosis bili primary disease, neuroinflammation associated with brain disorders (for example, Parkinson's disease, Huntington's disease and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation damage, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sclerodoma, sarcoidosis, spondyloartopathies, Sjogren, thyroiditis, rejection of transplant, tendonitis, trauma or damage (for example, freezing, chemical irritants, toxins, scarring, burns, physical damage), vasculitis, vitiligo and Wegener's granulomatosis. In certain embodiments, the inflammatory disorder is selected from (e.g., rheumatoid arthritis), inflammatory bowel disease, asthma, psoriasis, endometriosis, interstitial cystitis, and prostatistis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (eg, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis, and inflammatory bowel disease). The compounds may also be useful for treating inflammation associated with trauma and non-inflammatory myalgia. The compounds may also be useful in treating inflammation associated with cancer.
In certain modalities, the condition mediated by FAAH is an immune disorder. Immune disorders, such as autoimmune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloartopathies, gout arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylosis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma , atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (eg, psoriasis, eczema, burns, pruritus (itching)), enuresis, eisinophilic disease, gastrointestinal disorder (eg, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (eg, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (for example, Crohn's disease, ulcerative colitis tea, collagenous colitis, lymphocytic colitis, ischemic colitis, fun colitis, Behcet syndrome, indeterminate colitis), and inflammatory bowel syndrome (IBS)), and disorders improved by a gastroprokinetic agent (eg, ileus, post-operative ileus) vo and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and allergies to food and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).
In certain embodiments, the inflammatory disorder and / or the immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from gastrointestinal disorder (eg, selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding), gastrointestinal eosinophilic disorders (e.g., eosinophilic esophagitis, gastritis eosinof Mica, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (for example, Crohn's disease, ulcerative colitis, collagen colitis, lymphocytic colitis, ischemic colitis, fun colitis, Behcet syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)). In certain modalities, the gastrointestinal disorder is inflammatory bowel disease (IBD).
In certain embodiments, the inflammatory condition and / or immune disorder is a condition of the skin. In some modalities, the condition of the skin is pruritis (itching), psoriasis, eczema, burns or dermatitis. In certain modalities, the condition of the skin is psoriasis. In certain modalities, the condition of the skin is pruritis.
In certain modalities, the condition mediated with FAAH is a central nervous system (CNS) disorder ("CNS disorder"). Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, embolism, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and / or emesis. , amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction.
In certain embodiments, the CNS disorder is neurotoxicity and / or neurotrauma, for example, as a result of acute neuronal damage (e.g., traumatic brain injury (TBI), embolism, epilepsy), or a chronic neurodegenerative disorder (e.g. multiple sclerosis, Parkinson's disease, Huntington's disease, anotrophic lateral sclerosis, Alzheimer's disease). In certain embodiments, the compound of the present invention provides a neuroprotective effect, for example, against acute neuronal damage or a chronic neurodegenerative disorder.
In certain embodiments, the CNS disorder is embolism (eg, ischemic embolism).
In certain modalities, the CNS disorder is multiple sclerosis.
In certain modalities, the CNS disorder is damage to the spine.
In certain modalities, the CNS disorder is epilepsy.
In certain embodiments, the CNS disorder is a mental disorder, for example, depression, anxiety or conditions related to anxiety, a learning disability or schizophrenia.
In certain modalities, the CNS disorder is depression. "Depression", as used herein, includes, but is not limited to, disorders or depressive conditions, such as, for example, major depressive disorders (e.g., unipolar depression), dysthymic disorders (e.g., chronic depression, moderate), bipolar disorders (eg, manic-depression), temporary affective disorder, and / or depression associated with drug addiction (eg, abstinence). Depression can be clinical or subclinical depression. Depression may be associated with either premenstrual syndrome and / or premenstrual dysphoric disorder.
In certain modalities, the CNS disorder is anxiety. "Anxiety", as used herein, includes, but is not limited to, anxiety and conditions related to anxiety, such as, for example, clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorders with anxious aspects, anxiety disorder associated with depression, anxiety disorder due to general medical conditions, and substance-induced anxiety disorders , anxiety associated with drug addiction (for example, abstinence, dependence, rehabilitation) and anxiety associated with nausea and / or emesis. This treatment may also be to induce or promote sleep in a subject (e.g., a subject with anxiety).
In certain modalities, the CNS disorder is a learning disorder (for example, attention deficit disorder (ADD)).
In certain modalities, the CNS disorder is schizophrenia.
In certain modalities, the CNS disorder is a sleep condition. "Sleep conditions" include, but are not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, fast eye movement behavior disorder (RBD), work shift sleep condition (SWSD), and sleep problems (eg, parasomnias) such as nightmares, night terrors, sleeping talk, head banging , snoring and squeezing jaw and / or teeth grinding (bruxism).
In certain embodiments, the CNS disorder is a movement disorder, for example, basal ganglia disorders, such as, for example, Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia. and dystonia.
In certain modalities, the CNS disorder is Alzheimer's disease.
In certain modalities, the CNS disorder is amyotrophic lateral sclerosis (ALS).
In certain modalities, the CNS disorder is nausea and / or emesis.
In certain modalities, the CNS disorder is drug addiction (for example, addiction to opiates, nicotine, cocaine, psychostimulants or alcohol).
In still other embodiments, the condition mediated with FAAH is a cardiac disorder, for example, selected from hypertension, circulatory shock, reperfusion injury to the myocardium, and atherosclerosis.
In certain modalities, the condition mediated with FAAH is a metabolic disorder (eg, a debilitating condition, a condition related to obesity or complication thereof).
In certain modalities, the metabolic disorder is a debilitating condition. A "debilitating condition" as used herein, includes, but is not limited to, anorexia and cachexia of various natures (e.g., weight loss associated with cancer, weight loss associated with other general medical conditions, weight loss associated with knowledge delay, and the like).
In certain modalities, the metabolic disorder is a condition related to obesity or a complication of it. An "obesity-related condition" as used herein, includes, but is not limited to, obesity, unwanted weight gain (eg, weight gain induced by medication, by quitting smoking), and a disorder over eating (for example, overeating, bulimia, compulsive eating, or a lack of appetite control, each of which can optionally lead to unwanted weight gain or obesity). "Obesity" and "obese" as used herein, refer to class I obesity, class II obesity, class III obesity, and pre-obesity (eg, being "overweight") as defined by the World Health Organization.
The reduction of fat storage is expected to provide several primary and / or secondary benefits in a subject (e.g., in a subject diagnosed with a complication associated with obesity) such as xje, an increased insulin response (e.g. a subject diagnosed with diabetes mellitus type II); a reduction in elevated blood pressure; a reduction in high cholesterol levels; and / or a reduction (or reduced risk or progression) of ischemic heart disease, arterial vascular disease, angina, myocardial infarction, embolism, migraines, congestive heart failure, deep vein thrombosis, pulmonary embolism, gall bladder stones, gastroesophageal reflux disease, obstructive sleep apnea, hypoventilation syndrome due to obesity, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver damage (for example, fatty liver disease, cirrhosis of the liver, cirrhosis alcoholic, liver damage mediated with endotoxin) or chronic kidney damage. In this way, the method of this invention is applicable to obese subjects, diabetic subjects and alcoholic subjects.
In some embodiments, the treatment of a condition related to obesity or complication thereof involves the reduction of body weight in the subject. In some modalities, the treatment of a condition related to obesity or complication thereof involves control of appetite in the subject.
In other modalities, the condition mediated with FAAH is glaucoma.
IV. Administration Compounds provided can be administered using any amount and any effective route of administration for treatment. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular composition, its mode of administration, its mode of activity and the like.
The compounds provided herein are typically formulated in unit dosage form for ease of administration and uniformity of dosage. However, it should be understood that the total daily use of the compositions of the present invention will be decided by the physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors including the disease, disorder or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coinciding with the specific active ingredient used; and similar factors well known in the medical art.
The compounds and compositions provided herein may be administered by any route, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intra ventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powder , ointments, creams and / or drops), mucous, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation and / or inhalation; and / or as an oral sprayer, nasal spray and / or spray. The routes specifically contemplated are systemic intravenous injection, regional administration via blood and / or lymphatic supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend on a variety of factors including the nature of the agent (e.g., its stability in the gastrointestinal tract environment), the condition of the subject (e.g., whether the subject is able to tolerate). oral administration) etc.
The exact amount of a compound required to achieve a therapeutically effective amount will vary from subject to subject, depending, for example, on the species, age and general condition of a subject, severity of side effects or disorder, identity of the compound (s) particular, mode of administration, and the like. The desired dosage can be delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks or every four weeks In certain embodiments, the desired dosage can be administered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more administrations).
In certain embodiments, a therapeutically effective amount of a compound for administration one or more times per day to a 70 kg adult human may comprise from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, around from 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, around from 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg, of an active compound per unit dosage form. It will be appreciated that dose ranges as described herein will provide guidance for the administration of providing pharmaceutical compositions to an adult. The amount to be administered, for example, to a child or adolescent may be determined by a physician or expert in the art and may be less than or equal to that administered to an adult.
It will also be appreciated that a compound or composition, as described herein, may be administered in combination with one or more additional therapeutically active agents. The compound or composition can be administered concurrently with, before, or after, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and / or at a specific time for that agent. It will further be appreciated that the additional therapeutically active agent used in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination for use in a regimen will consider the compatibility of the inventive compound with the additional therapeutically active agent and / or the desired therapeutic effect to be achieved. In general, it is expected that the additional therapeutically active agents used in combination will be used at levels that do not exceed the levels where they are used individually. In some modalities, the levels used in combination will be lower than those used individually.
The compounds or compositions can be administered in combination with agents that improve their biodiesis, reduce and / or modify their metabolism, inhibit their excretion and / or modify their distribution within the body. It will also be appreciated that the therapy employed can achieve a desired effect for the same disorder (for example, a compound can be administered in combination with an anti-inflammatory, anti-anxiety and / or anti-depression agent, etc.), and / or can achieve different effects (for example, control of adverse side effects).
Exemplary active agents include, but are not limited to, anti-cancer agents, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroid agents, anti-inflammatory agents steroids or non-steroids, antihistamine, agents immunosuppressants, anti-neoplastic agents, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain-releasing agents, analgesics, anti-pyretics, hormones, prostaglandins, progestational agents, anti-glaucoma agents, ophthalmic agents, anti-cholinergic, anti -depressants, anti-psychotics, hypnotics, tranquilizers, anti-convulsants / anti-epileptics (for example, Neurontin, Lyrica, valproatos (for example, Depacon), and other neuro-stabilizing agents), muscle relaxants, anti-spasms, muscle contractors, channel blockers, miotic agents, anti-secretory agents, anti-thrombotic agents, anti-coagulants, anti-cholinergic agents, blocked agents ß-adrenergic receptors, diuretics, cardiovascular active agents, vasoactive agents, vasodilating agents, anti-hypertensive agents, angiogenic agents, modulators of cellular interactions-extracellular matrix (for example, inhibitors of cell growth and anti-adhesion molecules), or inhibitors / intercalators of RNA, RNA, protein-protein interactions, protein receptor interactions, ere. Active agents include small organic molecules such as compounds of drug (for example, compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins , small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
In certain embodiments, the additional therapeutically active agent is a pain relieving agent. Exemplary pain relieving agents include, but are not limited to, analgesics such as non-narcotic analgesics [e.g., salicylates such as aspirin, ibuprofen (MOTRIN®, ADVIL®), ketoprofen (ORUDIS®), naproxen (NAPROSYN®) , acetaminophen, indomethacin] or narcotic analgesics [eg, opioid analgesics such as tramadol, phentenyl, sufentanil, morphine, h id romorphone, codeine, oxycodone and buprenorphine]; non-steroidal anti-inflammatory agents (NSAIDs) [eg, aspirin, acetaminophen, COX-2 inhibitors]; steroids or anti-rheumatic agents; migraine preparations such as beta-adrenergic blocking agents, ergot derivatives; tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine); anti-epileptics (eg, clonaxepam, valproic acid, phenobarbital, phenytoin, thiagaine, gabapentin, carbamazepine, topiramate, valproate sodium); a2 agonists; selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine absorption inhibitors; benzodiazepines; mexiletine (MEXITIL); flecainide (TAMBOCOR); NMDA receptor antagonists [e.g., ketamine, detromethorphan, methadone]; and topical agents [eg, capsaicin (Zostrix), EMLA cream, lidocaine, prilocaine].
In other embodiments, the additional therapeutically active agent is an anti-inflammatory agent. Exemplary anti-inflammatory agents include, but are not limited to, aspirin; ibuprofen; ketoprofen; naproxen; etodolac (LODINE®); COX-2 inhibitors such as celecoxib (CELEBREX®), rofecoxib (VIOXX®), valdecoxib (BEXTRA®), parecoxib, etoricoxib (MK663), deracoxib, 2- (4-ethoxy-phenyl) -3- (4-methanesulfonyl- phenol) -pyrazolo [1,5-b] pyridazine, 4- (2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl) benzenesulfonamide, darbu-felone, flosulide, 4- (4-cyclohexyl) -2-methyl-5-oxazolyl) -2-fluoro-benzenesulfonamide), meloxicam, nimesulide, 1-methyl-sulfonyl-4- (1,1-dimethyl-4- (4-fluorophenyl) cyclopenta-2,4-dien -3-yl) benzene, 4- (1,5-dihydro-6-fluoro-7-methoxy-3- (trifluoromethyl) - (2) -benzothiopyran (4,3-c) pyrazol-1-yl) benzenesulfonamide , 4,4-dimethyl-2-phenyl-3- (4-methylsulfonyl) phenyl) -cyclobutenone, 4-amino-N- (4- (2-fluoro-5-trifluoromethyl) -thiazol-2-yl) -benzenesulfonamide, 1- (7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl) -4-cyclopropyl-butan-1 -one, or its physiologically acceptable salts, esters or solvates; sulindac (CLINORIL®); diclofenac (VOLTAREN®); piroxicam (FELDENE®); diflunisal (DOLOBID®), nabumetone (RELAFEN®), oxaprozin (DAYPRO®), indomethacin (INDOCIN®); or spheroids such as oral prednisolone sodium phosphate solution PEDIAPED®, sodium-prednisolone sodium succinate SOLU-MEDROL® for injection, PRELONE® brand prednisolone syrup.
Other examples of anti-inflammatory agents include naproxen, which is commercially available in the form of EC-N APROS YN® delayed release tablets, NAPROSYN® tablets, ANAPROX® and ANAPROX® DS and N APROS YN® suspension from Roche Labs, trademark CELEBREX® of celecoxib tablets, VIOXX® brand of rofecoxib, CELESTONE® brand of betamethasone, penicillamine capsules of the CU PRAM INE® brand, brand-name DEPEN® brand penicillamine tablets, DEPO-MEDROL brand of injectable suspension of methylprednisolone acetate, tablets of leflunomide ARAVA ™, brand AZULFIDINE EN-tabs® of delayed release tablets of sulfasalazine, piroxicam capsules of brand FELDENE®, potassium tablets of diclofenac CATAFLAM®, tablets of delayed release of diclofenac VOLTAREN®, tablets of release extended sodium diclofenac VOLTAREN®-XR, or ENBREL® ethanorecept products.
V. Methods of determining biological activity Methods for determining the activity of the compounds provided herein for various therapeutic uses are known in the art. These include, but are not limited to, high production selection to identify compounds that bind and / or modulate isolated FAAH activity, as well as models of in vitro and in vivo therapies.
Useful assays for selecting the compounds provided herein can detect the binding of the inhibitor to FAAH or the release of a reaction product (eg, fatty acid amide or ethanolamine) produced by the hydrolysis of a substrate such as oleylethanolamide or ananadamide. . The substrate can be labeled to facilitate detection of the released reaction products. The patent of E.U.A. No. 5,559,410 discloses high throughput screening methods for proteins and the U.S.A. Nos. 5,576,220 and 5,541,061 describe high throughput screening methods for ligand / antibody binding.
Methods for selecting FAAH inhibitors for an antinociceptive effect are known in the art. For example, compounds can be tested in the mouse hot plate test and the mouse formalin test, and the nociceptive reactions to thermal or chemical tissue damage measures (for example, see US Patent No. 6,326,156 for a description of methods of selection for antinociceptive activity, see also Cravatt et al Proc. Nati, Acad. Sci. USA (2001) 98: 9371-9376).
Two models of pharmacologically validated animal anxiety are the elevated zero maze test, and the ultrasonic emission test induced by isolation. The zero maze consists of an elevated annular platform with two open and closed quadrants and is based on the conflict between an animal instinct to explore its environment and its fear for open spaces (see, for example, Bickerdike, MJ et al., Eur. J. Pharmacol ., (994) 271, 403-411; Shepherd, JK, et al., Psychopharmacology, (1994) 116, 56-64). Clinically used anxiolytic drugs, such as benzodiazepines, increase the proportion of time spent in, and the number of entries made in, open compartments.
A second test for an anti-anxiety compound is the ultrasonic vocalization emission model, which measures the number of stress induced vocalizations emitted by rat pups removed from their nest (see, for example, Insel, TR, et al., Pharmacol Biochem. Behav., 24, 1263-1267 (1986); Miczek, KA, et al., Psychopharmacology, 121, 38-56 (1995); Winslow, JT, et al., Biol. Psychiatry, 15, 745-757 ( 1991).
The effect of the compounds provided herein in the treatment of depression can be tested in the model of anhedonia induced by chronic moderate stress in rats. This model is based on the observation that moderate chronic stress causes a gradual reduction in sensitivity to rewards, for example, consumption of sucrose, and that this reduction is dependent on a reversed dose for chronic treatment with antidepressants. See, for example, Wilner, Paul, Psychopharmacology, 1997, 134, 319-329.
Another test for antidepressant activity is the forced swimming test (Nature 266, 730-732, 1977). In this test, the animals are administered an agent 30 or 60 minutes before being placed in a water container, and the time during which they remain immobile is recorded. A reduction in the immobility time of the mice is indicative of antidepressant activity.
A similar test for antidepressant activity is the mouse caudal suspension test (Psychopharmacology, 85, 367, 377, 1985). In this test, the animals are administered an agent 30 or 60 seconds before being suspended by the tail, and their immobility time is recorded. A reduction in the immobility time of the mice is indicative of antidepressant activity.
Animal models are available to evaluate anticonvulsant activity of test compounds (see, for example, U.S. Patent Nos. 6,309,406 and 6,326,156).
Inhibition of FAAH has been recorded by inducing sleep in test animals (see, for example, U.S. Patent No. 6,096,784). Methods for studying compounds that induce sleep are known in the art (see, for example, U.S. Patent Nos. 6,096,784 and 6,271,015). Compounds can be administered to a test animal (e.g., rat or mouse) or a human and the subsequent time (e.g., onset, duration) spent sleeping can be monitored (e.g., closed eyes, motor quiescence). See also WO 98/24396.
Methods for selecting FAAH inhibitors that induce catalepsy are also well known in the art (see, for example, Quistand et al., In Toxicology and Applied Pharmacology 173: 48-55 (2001); Cravatt et al., Proc. Nati. Acad. Sci. USA 98: 9371-9376 (2001)).
Methods of evaluating appetitive behavior are known in the art (see, for example, U.S. Patent No. 6,344,474). One method of evaluating the effect on appetite behavior is to administer an FAAH inhibitor to a rat and evaluate its effect on the absorption of a sucrose solution (see, for example, WC Lynch et al., Physiol. Behav., 1993, 54 , 877-880).
Two pharmacologically validated animal models of neuropathic pain are the spinal nerve ligation model (Chung model) and a rat model of neuropathic pain induced by chemotherapy. After establishing neuropathy in these models, as a measure of mechanical allodynia, abstinence thresholds were measured by stimulation with von Frey filaments (see, for example, Kim SH and Chung JM, Pain (1992) 50, 355-63; Nozaki- Taguchi N, et al., Pain (2001) 93, 69-76). The clinically used neuropathic pain drugs, such as Gabapentin (Neurontina), increase the threshold of abstinence from stimulation with von Frey films.
Two pharmacologically validated animal models of inflammatory and mechanical pain are a joint compression model in rats treated with adjuvant or agents that produce joint degeneration. Treatment with clinically used anti-inflammatory agents such as naproxen increases the response threshold of joint compression behavior (see, for example, Wilson AW, et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius SA, and others, Pain (2007) 128, 272-282).
A pharmacologically validated animal model of cancer pain is a mouse model in which the implantation in the calcaneus bone of fibrosarcoma cells produces hyperalgesia. Treatment with clinically used analgesic agents such as morphine increases the threshold of response to mechanical algesic behavior (see, for example, Khasabova et al., J. Neurscience (2008) 28, 11141-52).
EXEMPLIFICATION The invention now generally being described, will be readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and should not limit the invention.
General synthetic methods Method 1 H (X Br Br KHCO3 General conditions for the preparation of 3-bromo-isoxazolines: Alkene (1.2 equiv) and potassium hydroxide carbonate (2.3 equiv) are suspended in ethyl acetate (0.40 M with respect to alkene). N, A / -dibromoformaldoxime (1.0 equiv) was added and the reaction was allowed to stir at 23 ° C for 14-28h. Upon completion as judged by thin layer chromatography analysis, the reaction was partitioned between water and ether-butyl methyl ether and the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexanes) to provide the desired 3-bromo-isoxazoline.
Method 2 OR HO OH General conditions for the preparation of 3-bromo-isoxazolines: A flask is loaded with glyoxylic acid monohydrate (1.0 equiv) and hydroxylamine hydrochloride (1.1 equiv). The mixture was dissolved in water (2.0 M with respect to glyoxylic acid monohydrate) and stirred at 23 ° C for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to provide the desired crude oxime which was used directly in subsequent cycloaddition. The resulting oxime (1.1 equiv) from the first step is suspended in a 3: 1 mixture of dimethoxyethane: water (v / v) (0.15 M with respect to oxime) and cooled to 0 ° C. V / Bromosuccinamide (NBS) (2.0 equiv) was added and the reaction mixture was allowed to stir at 23 ° C for 20 minutes. The resulting mixture is then added to a solution of alkene (1.0 equiv) and potassium bicarbonate (2.5 equiv) in dimethoxyethane (1.50 M with respect to alkene) and the reaction was allowed to stir for 20 h at 23 ° C. Upon completion as judged by thin layer chromatography analysis, the reaction was partitioned between water and methyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired 3-bromo-isoxazoline.
Method 3 HORe NaOH General conditions for the preparation of 3-aryloxy-isoxazolines or 3-heteroaryloxy-isoxazolines: A microwave reaction flask is charged with a given 3-bromo-isoxazoline (1.0 equiv) and an alcohol (for example, a phenol or a hydroxypyridine) ) (3.0 equiv) and dissolved in A / -methylpyrrolidine (0.50 M with respect to soxazoline). Milled sodium hydroxide (2.0 equiv) is added and the mixture sealed and heated in a microwave reaction at 150 ° C for 30 minutes. The reaction was then partitioned between water and fer-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired soxazoline.
Method 4 General conditions for the preparation of 3-aryloxy-isoxazolines or 3-heteroaryloxy-isoxazolines: A flask is charged with a given 3-bromo-isoxazoline (1.0 equiv) and alcohol (for example, a phenol or a hydroxypyridine) (2.0 equiv. ) is added and the reaction is allowed to stir for 20 minutes until all gas evolution ceases. The reaction is then heated to 150 ° C for 1-5 h. After the reaction, it is determined to complete by thin layer chromatography analysis, the reaction was then partitioned between water and ethyl acetate, and the organic layer was washed with 1 N NaOH and brine, and then dried over sodium sulfate, and concentrated in vacuum. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired isoxazoline.
Method 5 General conditions for the preparation of 3 - a r i I or x i -isoxazolines: A flask is charged with a given 3-bromo-isoxazoline (1.0 equiv) and alcohol (for example, a phenol or a hydroxypyridine) (2.0 equiv) and dissolves in N, A / -dimethylformamide or V-methylpyrrolidinone (0.15 M with respect to isoxazole). Cesium carbonate (1.2 to 3 equiv) is added and the reaction is heated to 120 ° C in an oil bath for 1 h. The reaction was then partitioned between water and tert-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (methanol / methylene chloride) to provide the desired isoxazoline.
Method 6 NaHMDS P (Ph) 3MeBr Ri .Rb General conditions for the preparation of alkenes: under a nitrogen atmosphere, 0.25 M methyltriphenylphosphonium bromide (1.1 equiv) dissolved in tetrahydrofurane was cooled to 0 ° C after which the mixture was treated as drops with sodium hexamethyldisilazane ( NaHMDS) in tetrahydrofuran (1.0 M, 1.2 equiv). After stirring an additional 30 minutes at 0 ° C, a given aldehyde or ketone is added and the reaction is allowed to slowly warm to 23 ° C overnight. The mixture was quenched with saturated ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired alkene.
Method 7 nBuü O P (Ph) 3MeBr General conditions for the preparation of alkenes: under a nitrogen atmosphere, 0.15 M methyltriphenylphosphonium bromide (1.5 equiv) dissolved in tetrahydrofurane was cooled to -78 ° C after which the mixture was treated as drops with n-butyl lithium in hexanes (2.5 M, 1.5 equiv). After stirring an additional 1h at -78 ° C, a given aldehyde or ketone is added and the reaction is allowed to slowly warm to 23 ° C overnight. The mixture was saturated ammonium chloride extinguished and concentrated to remove tetrahydrofuran. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired alkene.
Method 8 KOtBu O P (Ph) 3MeBr General conditions for the preparation of alkenes: under a nitrogen atmosphere, 0.12 M methyltriphenylphosphonium bromide (2.5 equiv) was dissolved in tetrahydrofuran after which potassium urea-butoxide (4.0 equiv) was added in six portions. After stirring an additional 1h at 23 ° C, a given aldehyde or ketone is added and the reaction allowed to warm to 55 ° C for 2h. The mixture was saturated ammonium chloride extinguished and concentrated to remove tetrahydrofuran. The mixture was then acidified to pH 5-6 with 1N HCl and extracted with methylene chloride. The organic layer was washed with brine and dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired alkene.
Method 9 Br CH2CHBF3K (1 R 15 R 15 General conditions for the preparation of styrenes: a dry flask under an argon atmosphere was charged with aryl bromide (1.0 equiv), potassium vinyltrifluoroborate (1.2 equiv), 1, 1"-bi (diphenylphosphine) chloride adduct - ferrocene dichloropalladium (ll) methylene (0.02 equiv) and triethylamine (1.0 equiv) and the mixture was suspended in isopropanol (0.25 M with respect to aryl bromide) and heated at 80 ° C for 2-24 h. The mixture was then diluted The organic layer was washed with brine and then dried over magnesium sulfate and concentrated in vacuo.The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes ) to provide the desired styrene.
Method 10 General conditions for the preparation of styrenes: a dry flask under a nitrogen atmosphere was charged with aryl bromide (1.0 equiv), tributylvinyltin (1.1 equiv) and dissolved in toluene (0.3 M with respect to bromide). The resulting mixture was purged further with nitrogen for 10 minutes after which tetrakis (triphenylphosphine) palladium (0.1 equiv) was added and the reaction was refluxed for 1.5 h. The reaction to be completed was then determined by TLC analysis, allowed to cool and loaded directly onto a column of silica gel where it was purified by flash silica gel chromatography (ethyl acetate / hexanes) to provide the desired styrene.
Method 11 General conditions for the hydrolysis of boronic acids of pyridyl and pyrimidinyl to their corresponding phenols: A flask is charged with a given boronic acid or ester (1.0 equiv) and dissolved in tetrahydrofuran (1.1 M, 10 volumes). Sodium perborate (1.0 equiv) is dissolved in water (1.1 M with respect to boronic acid, 10 volumes) and sonicated for 10 minutes. The perborate suspension is then added to the THF solution using tetrahydrofuran (1.6 volumes) to rinse the remaining solid perborate in the reaction mixture. The reaction is allowed to stir at room temperature (reaction is slightly exothermic) after which ammonium chloride is added in three portions (10 eq .iv) and the reaction is cooled to room temperature. After 40 minutes, the reaction was concentrated in vacuo until all the tetrahydrofuran was removed. The resulting solid was collected by vacuum filtration, washed with excess water and dried in a vacuum oven at 40 ° C for 3d to provide the desired phenol in 80% yield.
Method of chiral high performance liquid chromatography Mixtures of enantiomeric or diastereomeric compounds can be separated using known methods, including chiral high performance liquid chromatography (HPLC) and chiral supercritical fluid chromatography (SFC). Exemplary chiral columns useful for separating said mixtures of compounds of the present invention include, but are not limited to, ChiralPak® AD-H, ChiralPak® OD-H, ChiralPak® AY, RegisPack ™ and S, WhelkO® S columns. -1 and LUX ™ Cellulose2. One or more of these columns were used to separate enantiomeric mixtures of compounds of the present invention in order to obtain substantially enantiomerically pure compounds.
Synthesis of exemplary compounds of the formula I The synthesis of exemplary compounds is set forth below. Compounds were tested as inhibitors of human FAAH using the method described in example 351. The activity designated "A" refers to compounds having a K i of less than or equal to 100 nM, "B" refers to compounds that they have a Ki of between 100 nM and 1 micron, and "C" refers to compounds that have a Ki of greater than or equal to 1 micron.
Example 1 l-1a 1-1 b (i-i) 3-Bromo-4,5-dihydroisoxazole I-1 a and l-1b were prepared in 1 step of styrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 225.0 m / z. Activity: B Example 2 l-2a l-2b (1-2) 3-Bromo-4,5-dihydroxisoxazole l-2a and I-2b were prepared in 1 step of 4-fluorostyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. Activity: B Example 3 l-3a l-3b (1-3) 3-Bromo-4,5-dihydroisoxazole I-3a and I-3b were prepared in 1 step of 4-chlorostyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 259.0 m / z. Activity: A (1-4) 3-Bromo-4,5-dihydroxisoxazole I-4a and I-4b were prepared in 1 step of 3-chlorostyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 258.9 m / z. Activity: B 3-Bromo-4,5-dihydroisoxazole l-5a and I-5b were prepared in 1 step of 2-chlorostyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 258.9 m / z. Activity: B OMe (1-6) 3-Bromo-4,5-dihydroxisoxazole I-6a and I-6b were prepared in 1 step of 4-methoxystyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 255.0 m / z. Activity: An.
Example 7 OMe OMe N Br l-7a l-7b (1-7) 3-Bromo-4,5-dihydroisoxazole l-7a and I-7b were prepared in 1 step of 3-methoxystyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 255.0 m / z. Activity: B Example 8 l-8b (1-8) 3-Bromo-4,5-dihydroisoxazole l-8a and I-8 b were prepared in 1 step of 2-methoxystyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 255.0 m / z. Activity: C Example 9 Br ' l-9a l-9b (I-9) 3-Bromo-4,5-dihydroisoxazole l-9a and I-9 b were prepared in 1 step of 4-vinyl biphenyl using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 301.6 m / z. Activity: A Example 10 OR 1-10a 1-10b (1-10) 3-Bromo-4,5-dihydroxisoxazole I-10a and I-10b were prepared in 1 step of 4-phenoxystyrene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 317.0 m / z. Activity: A 3-Bromo-4,5-dihydroisoxazole I-11 a and l-11b were prepared in 2 steps starting with formation of alkene from 3-phenoxybenzaldehyde using method 8 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 317. Ó m / z. Activity: A Example 12 1-12a 1-12b (1-12) 3-Bromo-4,5-dihydroisoxazole I-12 a and l-12b were prepared in 2 steps starting with formation of alkene from 4- (pyridin-3-yloxy) benzaldehyde using method 8 followed by cycloaddition using method 2 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 318.0 m / z. Activity: A Example 13 1-13a 1-13b (1-13) 3-Bromo-4,5-dihydroxyazole II-13a and I-3b were prepared in 2 steps starting with formation of alkene from 4- (pyrimidin-2-yloxy) benzaldehyde using method 8 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 319.0 m / z. Activity: A Example 14 1-14a 1-14b (1-14) 3-Bromo-4,5-dihydroisoxazole I-14a and I-14b were prepared in 2 steps starting with formation of alkene from 4-trifluoromethoxybenzaldehyde using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 309.6 m / z. Activity: A Example 15 1-15a 1-15b (1-15) 3-Bromo-4,5-dihydroisoxazole I-15 ayi-15 b was prepared in 2 steps starting with formation of alkene from 4-isopropoxybenzaldehyde using method 8 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 238.0 m / z. Activity: A Example 16 l-16a l-16b (1-16) 3-Bromo-4,5-dihydroisoxazole I-16 a and I-16 b were prepared in 2 steps starting with formation of alkene from pipronal using method 7 followed by cycloaddition using method 2. These compounds can be separated using methods of chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M-H] - = 269.0 m / z. Activity: A Example 17 1-17b (1-17) 3-Bromo-4,5-dihydroisoxazole I-17 a and I-17 b were prepared using the analogous procedure as in Example 10 that N-chlorosuccinamide was used in place of / V-bromosuccinamide. These compounds can be separated using chiral HPLC methods known in the art. For example, see HPLC method, q u i r a I described herein. [M-H] - = 273.1 m / z. Activity: A Example 18 Me Me 1-18a 1-18b (1-18) 3-Bromo-4,5-dihydroisoxazole I-18 a and I-18 b were prepared in 2 steps starting with formation of alkene from 3- (bromo-phenoxy) -6-methylpyridazine using method 9 followed by cycloaddition using the Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 333.0 m / z. Activity: B Example 19 1-19a l-19b (1-19) 3-bromo-4,5-dihydroisoxazole I-19 a and I-19 b were prepared in 2 steps starting with formation of alkene from 2- (4-bromo-phenyl) -5-phenyl-1, 3,4- oxadiazole using method 9 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 369.0 m / z. Activity: A Example 20 l-20a 1-20 b (1-20) 3-bromo-4,5-dihydroisoxazole l-20a and l-20b were prepared in 2 steps starting with formation of alkene from 4-butoxybenz-aldehyde using method 8 followed by cycloaddition using method 1. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 297.0 m / z. Activity: A Example 21 (1-21) 3-bromo-4,5-dihydroisoxazole I-21 a and I-21 b were prepared in 2 steps starting with the coupling between 4-vinylbenzoic acid and benzyl alcohol as follows: 4-vinylbenzoic acid (1.0 equiv) is dissolved in N, A / -dimethylformamide (0.20 M with respect to acid). Benzyl acid (2.0 equiv) is added followed by EDC (1.05 equiv) and a catalytic amount of DMAP (0.05 equiv). The reaction was allowed to stir at 23 ° C for 14 h after which point the reaction was partitioned between water and fer-butyl methyl ether, and the organic layer was washed with 0.5 M citric acid solution (2x) and sodium bicarbonate solution. saturated sodium (1x), dried over magnesium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired ester. This compound was then converted to the desired 3-bromo-4,5-dihydroisoxazole using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 359.8 m / z. Activity: A Example 22 (1-22) 3-Bromo-4,5-dihydroisoxazole I-22a and I-22 b were prepared using the analogous procedure as Example 21 except that benzylamine was used in place of benzyl alcohol. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 358.9 m / z. Activity: B 3-Phenoxy-4,5-dithiazole l-23a and I-23 b in 1 step were prepared from compound 1-10 and phenol using method 1. These compounds can be separated using HPLC methods chiral known in the art. For example, see chiral HPLC method described herein. [M-H] - = 331.1 m / z. Activity: C Example 24 l-24a l-24b 3-Phenoxy-4,5-dihydroisoxazole I-24a and I-24 were prepared in 1 step from compound 1-10 and 4-fluorophenol using method 4. These compounds can be separated using known chiral HPLC methods. The technique. For example, see chiral HPLC method described herein. [M-H] - = 350.3 m / z. Activity: C Example 25 F l-25a l-25b (1-25) 3-Phenoxy-4,5-dihydroisoxazole I-25a and I-25 b were prepared in 1 step from compound 1-10 and 3-fluorophenol using method 4. These compounds can be separated using HPLC methods chiral known in the art. For example, see chiral HPLC method described herein. [M-H] - = 349.3 m / z. Activity: B Example 26 l-26a l-26b (1-26) 3-Phenoxy-4,5-dihydroxisoxazole I-26 ayt-26 b was prepared in 1 step from compound 1-10 and 3-trif luoromethylphenol using method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 400.3 m / z. Activity: C 3-Phenoxy-4,5-dihydroisoxazole l-27a and l-27b were prepared in 1 step from compound 1-10 and 4-cyanophenol using method 3. These compounds can be separated using chiral HPLC methods known in the art. technique. For example, see chiral HPLC method described herein. [M-H] - = 356.1 m / z. Activity: A 3-Phenoxy-4,5-dihydroisoxazole I-28a and I-28 b were prepared in 1 step from compound 1-10 and 2-cyanophenol using method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 357.3 m / z. Activity: C i-29a l-29b (1-29) 3-phenoxy-4,5-dihydroisoxazole l-29a and l-29b were prepared in 1 step from compound 1-10 and 4-nitrophenol using method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 376.8 m / z. Activity: B 3-Phenoxy-4,5-d-hydroxazoxazole I-30a and I-30b were prepared in 1 step from compound 1-10 and 4-methylsulfonylphenyl using method 4. These compounds can be separated using methods of Chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M-H] - = 409.0 m / z. Activity: A Example 31 3-Phenoxy-4,5-dihydroxazole I-31 a and I-31 b were prepared in 1 step from compound 1-10 and 4-methyl-3-fluorophenol using method 4. These compounds they can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 364.4 m / z. Activity: C A microwave reaction bottle is loaded with the racemic compound 1-10 (1.0 equiv) and aniline (4.0 equiv). The mixture was sealed and heated in a microwave reactor at 150 ° C for 2 h. The reaction was then partitioned between water and methyl-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and the organic layer was washed with brine. sodium and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide 3-amino-4,5-dihydroisoxazole I-32a and I-32b. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 330.1 m / z. Activity: C Example 33 l-33a l-33b (1-33) 1- (4,5-Dihydroisoxazol-3-yl) pyridin-2 (1 H) -one I-33a and I-33 b were prepared in 1 step from the racemic compound 1-10 and 2-hydroxypyridine using the method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. · [M-H] - = 332.1 m / z. Activity: C Example 34 (1-34) A microwave reaction bottle is loaded with the racemic compound 1-10 (1.0 equiv) and 1,2,4-triazole sodium salt (2.0 equiv). The reagents are dissolved in / V-methylpyrrolidine (0.18 M with respect to compound 1-10). The mixture was sealed and heated in a microwave reactor at 100 ° C for 30 min. Excess water is added and a brown solid is removed which is isolated using vacuum filtration and dried to provide the 3- (1 H-1, 2,4-triazol-2-yl) -4,5-dihydroisoxazole l- 34a and I-34 b desired. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 306.1 m / z. Activity: C Example 35 (1-35) Pyrazole (3.0 equiv) was dissolved in N, / V-dimethylformamide (0.60 M with respect to pyrazole) and NaH (60% dispersion in mineral oil, 3.0 equiv) was added and the reaction was allowed to stir under nitrogen for 5 min. After that point the 1-10 racemic compueto was added. The reaction was then heated to 90 ° C for 14 h after which it was cooled and quenched with methanol (0.30 M with respect to pyrazole). The crude mixture was filtered through cotton and purified directly by reversed semi-prep phase chromatography to provide 3- (1 H -pyrazol-1-yl) -4,5-dihydroisoxazole l-35a and l-35b desired. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 306.4 m / z. Activity: C Example 36 l-36a l-36b (1-36) 3- (Pyridin-4-yloxy) -4,5-dihydroisoxazole I-36 a and I-36b were prepared in 1 step from compound 1-10 and 4-hydroxypyridine using method 3. These compounds can be separated using methods of chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M-H] - = 332.1 m / z. Activity: C Example 37 l-37a l-37b (1-37) 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole l-37a and I-37b were prepared in 1 step from racemic compound 1-10 and 3-hydroxypyridine using method 3 or method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 332.1 m / z. Activity: A Example 38 I-38A l-38b (1-38) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole l-38a and I-38b were prepared in 1 step from the racemic compound I-6 and 3-hydroxypyridine using method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 270.1 m / z. Activity: B Example 39 Me02C (1-39) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-39a and I-39b were prepared in 1 step from the racemic compound 1-10 and methyl 5-hydroxy-nicotinate using method 3 or method 5 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 392.2 m / z. Activity: A Example 40 (1-40) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole l-40a and I-40b were prepared in 1 step from the racemic compound 1-10 and 5-hydroxy-2-methylpyridine using method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 346.1 m / z. Activity: A Example 41 (1-41) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxazole I -4 a and I-41b were prepared in 1 step from the racemic compound 1-10 and 5-hydroxy-pyrimidine using method 3. These compounds were they can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 333.1 m / z. Activity: A Example 42 (1-42) 3- (Quinolin-3-yloxy) -4,5-dihydroisoxazole l-42a and I-42b were prepared in 1 step from racemic compound 1-10 and 3-hydroxy-quinoline using method 3. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 382.1 m / z. Activity: A Example 43 (1-43) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole l-43a and I-43b were prepared in 1 step from the racemic compound 1-10 and 5-fluoro-3-hydroxypyridine using method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 350.1 m / z. Activity: A Example 44 3- (methylene-1 H -pyrrolo [2,3-b] pyridin-5-yloxy) -4,5-dihydroisoxazole l-44a and I -44 b were prepared in 1 step from of racemic compound 1-10 and 1-methyl-1H-pyrrolo [2,3-b] pyridin-5-ol using method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 385.1 m / z. Activity: B Example 45 l-45a l-45b (1-45) One bottle is loaded with racemic compound 1-10 (1.0 equiv) and dissolved in methanol (0.05 M with respect to isoxazole). Potassium carbonate (5.0 equiv) was added and the reaction was sealed and heated at 50 ° C for 24 h. The reaction was then partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide 3-methoxy-4,5-dihydroisoxazole l-45a and I-45 b. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 269.1 m / z. Activity: C Example 46 l-46a l-46b (1-46) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole l-46a and I-46b were prepared in 1 step from the racemic compound 1-14 and methyl 5-hydroxy-nicotinate using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 384.0 m / z. Activity: B Example 47 (1-47) The racemic compound 1-39 is dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir at 23 ° C for 24 h after which point the solvent and excess ammonia are removed under a stream of nitrogen to provide a light brown solid which is titrated with hexanes to provide amide l-47a and I -47 b desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 374.0 m / z. Activity: B Example 48 l-48a l-48b (1-48) 3-Bromo-4,5-dihydroisoxazole l-48a and I-48 b were prepared in 1 step from 3 -fe or I-1-propene using method 2. These compounds can be separated using known chiral HPLC methods in the technique. For example, see chiral HPLC method described herein. [M-H] - = 239.0 m / z. Activity: C Example 49 -49a l-49b (1-49) 3-bromo-4,5-dih id roisoxazole l-49a and l-49b were prepared in 1 step from 4-phenyl-1-butene using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 253.0 m / z. Activity: B Example 50 | 50a l-50b (1-50) Phenol (1.0 equiv) is dissolved in ethanol (0.5 M with respect to phenol) and sodium hydroxide (1.0 equiv) is added followed by the addition of 4-bromo-1-butene. The mixture is refluxed for 1 h after which most of the solvent is removed in vacuo. The reaction was then partitioned between water and re-methyl butyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to provide crude alkene which was converted directly to the 3-bromo-4, 5-dihydroisoxazole I-50a and I-50b desired in 1 step using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 269.0 m / z. Activity: B Example 51 1-51 to 1-51 b (1-51) Phenol (1.2 equiv) is dissolved in N, / V-dimethylformamide (0.4 M with respect to phenol) and cesium carbonate (1.3 equiv) is added followed by the addition of 5-bromo-1-pentene (1.0 equiv) and iodide of tetrabutylammonium (0.10 equiv). The mixture is heated at 50 ° C for 16 h. The reaction was then divided between water and methyl fer-butyl ether, and the organic layer was washed with dilute sodium hydroxide solution, brine, dried over sodium sulfate and concentrated in vacuo. The crude alkene was converted directly to the 3-bromo-4,5-dihydroisoxazole I-51 a and I-51 b desired in 1 step using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 283.0 m / z. Activity: A Example 52 l-52a l-52b (1-52) Dissolve 2-phenylethanol (1.0 equiv) in N, / V-dimethylformamide (0.8 M with respect to alcohol) and add crushed sodium hydroxide (2.0 equiv) followed by the addition of allyl bromide (1.0 equiv) and iodide of tetrabutylammonium (0.10 equiv). The mixture is stirred at room temperature for 48 h. The reaction was then partitioned between water and tert-butyl methyl ether, and the organic layer was washed with dilute Na2S203 solution, brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired alkene which was converted directly to the desired 3-bromo-4,5-dihydroisoxazole I-52a and I-52b in 1 step using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 285.6 m / z. Activity: B Example 53 OCF3 H2N H2N O O l-53a l-53b (1-53) The racemic compound 1-46 is dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir at 23 ° C for 72 h after which point the solvent and excess ammonia are removed under a stream of nitrogen to provide a light brown solid which is titrated with hexanes to provide amides l-53a and I-53 b desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 366.0 m / z. Activity: B Example 54 OR l-54a O l-54b (1-54) The racemic compound I-46 is dissolved in ammonia in methylamine (2.0 M in tetrahydrofuran, 0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir at 23 ° C for 72 h after which point the solvent and excess ammonia are removed under a stream of nitrogen to provide a light brown solid which is titrated with hexanes to provide amides l-54a and I-54b desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 380.0 m / z. Activity: A Example 55 l-55a l-55b (1-55) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-55a and I-55b were prepared in 1 step from racemic compound I-46 and methyl 5-hydroxy-nicotinate using method 5 and isolated as a side product of the reaction during flash chromatography on silica gel. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 367.0 m / z. Activity: C Example 56 (1-56) 3- (Pyridin-3-yloxy) -4,5-dithiazole l-56a and I-56b in 1 step were prepared from racemic compound 1-10 and 5-hydroxy-2-trifluoromethylpyridine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 401.5 m / z. Activity: A Example 57 l-57a l-57b d-57) 3- (1 H -pyrrolo [3,2-b] pyridin-6-yloxy) -4,5-dihydro-isoxazole 1-57a and I-57 b were prepared in 1 step from the racemic compound 1-10 and 1 H-pyrrolo [3,2-b] pyridin-6-ol using method 5. These compounds can be separated using known chiral HPLC methods in the technique. For example, see chiral HPLC method described herein. [M-H] - = 370.0 m / z. Activity: A 3-Phenoxy-4,5-dihydroisoxazole I-58a and I-58 b were prepared in 1 step from the racemic compound 1-10 and 3-cyanophenol using method 4. These compounds can be separated using known chiral HPLC methods in the technique. For example, see chiral HPLC method described herein. [M + H] + - 356.8 m / z. Activity! B Example 59 l-59a l-59b (1-59) 3-Phenoxy-4,5-dihydroisoxazole I-59a and I-59 b were prepared in 1 step from racemic compound 1-10 and 2-f luorofenol using method 4. These compounds can be separated using HPLC methods chiral known in the art. For example, see chiral HPLC method described herein. [M + H] + = 350.3 m / z. Activity: B Example 60 l-60a l-60b (1-60) 3-Phenoxy-4,5-dihydroisoxazole I-60a and I-60 b were prepared in 1 step from racemic compound 1-10 and 4-f luoro-3- (trifluoro-methyl) phenol using the method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. Activity: C Example 61 1-61 to 1-61 b (1-61) 3-Phenoxy-4,5-dihydroisoxazole I-61 a and I-61 b were prepared in 1 step from the racemic compound 1-10 and methyl 3-hydroxybenzoate using method 4. These compounds can be separated using HPLC methods chiral known in the art. For example, see chiral HPLC method described herein. [M + H] + = 390.5 m / z Activity: A Example 62 Me02C l-62a l-62b (1-62) 3-Phenoxy-4,5-dihydroisoxazole I-62a and I-62b were prepared in 1 step from racemic compound 1-10 and methyl 4-hydroxybenzoate using method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 389.7 m / z Activity: A 3-Phenoxy-4,5-dihydroxisoxazole I-63a and I -63 b were prepared in 1 step from the racemic compound 1-10 and 3- (methylsulfonyl) phenol using method 4. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 409.0 m / z Activity: C Example 64 l-64a l-64b (1-64) 3-Phenoxy-4,5-dihydroxisoxazole I-64a and I-64 b were prepared in 1 step from racemic compound 1-10 and 3-hydroxybenzenesulfonamide using method 4. These compounds can be separated using methods of chiral HPLC known in the art. For example, see chiral HPLC method described herein. [-H] - = 409.0 m / z Activity: C Example 65 l-65a l-65b (1-65) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-65a and I-65b were prepared in 1 step from the racemic compound 1-10 and 5-methoxy-pyridin-3-ol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 363.2 m / z Activity: A Example 66 l-66a l-66b (1-66) prepared 3- (pyridin-5-yloxy) -4,5-dihydroisoxazole l-66a and I 1 step from racemic compound 1-10 and 5-hydroxy-pyrimidine using method 5. These compounds can be separated using methods of Chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M + H] + = 364.6 m / z Activity: A Example 67 (1-67) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-67a and I-67b were prepared in 1 step from racemic compound 1-10 and methyl 5-hydroxy-picolinate using method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.1 m / z Activity: A Example 68 (1-68) 3- (1 H -pyrrolo [2,3-b] pyridin-5-yloxy) -4,5-dihydro-isoxazole l-68a and I-68 b in 1 step were prepared from the compound 1-10 racemic and 1 Hyrrolo [2,3-b] pyridin-5-ol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 370.0 m / z Activity: A Example 69 l-69a l-69b (1-69) 6- (4,5-Dihydroisoxazol-3-yloxy) furo [3,2-b] pyridine I-69a and I-69 b were prepared in 2 steps from racemic compound 1-10 and furo [3,2- b) pyridin-6-ol using method 5 then furo [3,2-b] pyridin-6-ol is prepared from 6- (4, 4, 5, 5-tetramethyl I- 1, 3, 2 -dioxaborolan-2-yl) furo [3,2-b] pyridine using method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 374.2 m / z Activity: A Example 70 l-70a l-70b (1-70) 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole l-70a and I-70b were prepared in 1 step from racemic compound 1-14 and 3-hydroxy-pyridine using method 5 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 324.1 m / z Activity: A Example 71 1-71 to l-71b (1-71) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-71 a and I-71b were prepared in 1 step from the racemic compound 1-14 and 5-bromo-3-hydroxypyridine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 402.5 m / z Activity: A Example 72 l-72b (1-72) Compound 1-71 racemic (1.0 equiv), phenyl boronic acid (1.1 equiv), potassium acetate (1.0 equiv), cesium carbonate (3.0 equiv) and dichloromethane dichloro adduct [1, 1'-bi (d) phosphino) ferrocene] palladium (II) (14 mol%) were suspended in 1 ml_ DMSO and purged with Ar. The resulting mixture was sealed and heated at 80 ° C for 1 h. The crude mixture was transferred to a separatory funnel with excess water and extracted with methyl urea-butyl ether (2x). The organic layers were combined, dried over NaSO4 and purified using silica gel flash chromatography (2-10% MeOH gradient) to provide 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole. l-72a and I-72b desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 402.3 m / z Activity: B Compound 1-71 racemic (1.0 equiv), boronic acid 3-carbamoylphenyl (1.1 equiv), potassium acetate (1.0 equiv), cesium carbonate (3.0 equiv) and dichloromethane adduct of dichlorof 1.1 '-bi ( diphenylphosphino) ferrocene] palladium (11) (14 mol%) were suspended in 1 ml_ DMSO and purged with Ar. The resulting mixture was sealed and heated at 80 ° C for 1 h. The crude mixture was transferred to a separatory funnel with excess water and extracted with methyl re-methyl ether (2x). The organic layers were combined, dried over Na2SO and purified using silica gel flash chromatography (gradient 2-10% MeOH) to provide the 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole l- 73a and I-73b desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 442.0 m / z Activity: A 3-Bromo-4,5-dihydroisoxazole I-74a and I-74b were prepared in step 1 from methyl 4-vinylbenzoate using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 283.6 m / z Activity: A Example 75 OCF3 (1-75) 3-Bromo-4,5-dihydroisoxazole l-75a and I-75 b were prepared in 2 steps from formation of alkene from 4 '(trifluoromethoxy) -acetophenone using method 6 followed by cycloaddition using method 1 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 323.0 m / z Activity: A Example 76 -76a l-76b (1-76) 3-bromo-4,5-dithiazole l-76a and I-76b were prepared in 2 steps from the formation of alkene from 4'-phenoxy-acetophenone using method 6 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 331.0 m / z Activity: A Example 77 l-77a l-77b (1-77) 3-Bromo-4,5-dihydroisoxazole I-77a and I-77 b were prepared in 1 step from rrans-anethole using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 269.0 m / z Activity: C Example 78 Br Br Me Me l-78a l-78b (1-78) 3-bromo-4,5-di-idroisoxazole l-78a and l-78b were prepared in 2 steps starting with formation of alkene from 4-phenoxybenzaldehyde using method 6 (except that ethyltriphenylphosphonium bromide is used instead of methyltriphenylphosphonium bromide) followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 331.0 m / z Activity: A Example 79 l-82a l-82b (1-82) 3-bromo-4,5-dihydroisoxazole I-82a and I-82 b were prepared in 3 steps from 4-phenoxybenzaldeh as follows: 4-phenoxybenzaldehyde (1.0 equiv) was dissolved in tetrahydrofuran (0.20 M with respect to to tetrahydrofuran) and cooled to 0 ° C. Ethyl magnesium bromide (1.0 M in THF, 1.2 equiv) is added dropwise after which the reaction is allowed to stir at 23 ° C for 24 h. The mixture was quenched with saturated ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then diluted with water and extracted with methyl-butyl ether. The organic layer was washed with water and brine and then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired I-80 alcohol.
The purified I-80 alcohol is then dissolved (0.80 M with respect to alcohol). Phosphorus oxychloride (1.1 equiv) is added and the mixture is heated at reflux for 2 h. After this point the reaction was cooled to 0 ° C and extinguished with the addition of excess water. The mixture was then diluted with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired alkene 1-81.
Me 1-79 1-80 1-81 Then the alkene 1-81 was converted to the desired 3-bromo-4,5-di-idisoxazole I-82a and I-82b using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 331.0 m / z Activity: B Example 80 l-83a l-83b (1-83) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-83a and I-83 b were prepared in 1 step from the racemic compound 1-14 and 3- (5-hydroxy-pyridin-2-) il) methyl benzoate using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 460.1 m / z Activity: B 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole l-84a and I-84b were prepared in 1 step from the racemic compound 1-14 and 3- (5-hydroxy-pyridine) -2-yl) ethyl benzoate using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 474.1 m / z Activity: B Example 82 l-85a (1-85) Compound 1-83 racemic (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCl to provide the desired I-85 a and I-85 b acids as a white solid was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 443.0 m / z Activity: B 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-86a and I-86 b were prepared in 1 step from the racemic compound 1-14 and 6-phenylpyridin-3-ol using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 402.2 m / z Activity: B Example 84 l-87a l-87b (1-87) 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-87a and I-87b were prepared in 1 step from the racemic compound 1-12 and 3-hydroxy-pyridine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 333.5 m / z Activity: A Example 85 l-88a l-88b (1-88) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-88 a and I-88b were prepared in 1 step from the racemic compound I-75 and 3-hydroxy-pyridine using method 5. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 340.2 m / z Activity: B Example 86 l-89a l-89b (1-89) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole l-89a and I-89b were prepared in 1 step from the racemic compound I-76 and 3-hydroxy-pyridine using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 348.4 m / z Activity: A 3-Phenoxy-4,5-dihydroisoxazole I-90a and I-90 b were prepared in 1 step from racemic compound 1-10 and 4-hydroxybenzenesulfonamide using method 4. These compounds can be separated using HPLC methods chiral known in the art. By example, see chiral HPLC method described herein. [M + H] + = 410.8 m / z Activity: A Example 88 1-91 to 1-91 b (1-91) Trans 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-91 a and I-91 b were prepared in 1 step from racemic compound I-78 or I-82 and 3-hydroxypyridine using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 346.2 m / z Activity: C Example 89 BocHN l-92a l-92b (1-92) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-92a and I-92b were prepared in 2 steps from the racemic compound 1-10 and tert-butyl acid ester (5-hydroxypyridin-2-yl) - carbon dioxide using method 5 after the formation of (5-hydroxy-pyridin-2-yl) -carbamic acid tert-butyl ester from 5- (4,4,5,5-tetramethyl-1, 3.2 tert-butyl-dioxa-borolan-2-yl) pyridin-2-ylcarbamate using method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 447.9 m / z Activity: C Example 90 l-93a l-93b (1-93) The racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-92 was dissolved in trifluoroacetic acid (0.20 M with respect to isoxazole) and stirred at room temperature for 1 h. The solvent is then removed in vacuo and the crude residue is azeotroped with toluene (2x) to provide l-93a and I-93b as the TFA salt (white solid). These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 347.1 m / z Activity: A Example 91 l-94a l-94b (1-94) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-93 was dissolved in methylene chloride (0.03 M with respect to isoxazole) after which triethylamine (4.0 equiv) and acetic anhydride (3.0 equiv. ). The reaction was allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with saturated NaHCO 3 (2x) and brine (1x). The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide l-94a acetate and l-94b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 388.1 m / z Activity: A Example 92 l-95a l-95b (1-95) 3-Bromo-4,5-dihydroxysoxazole I-95a and I-95 b were prepared in 2 steps starting with formation of alkene from 1- (4-phenoxy-phenyl) propan-1 -one using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 347.7 m / z Activity: A 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-96a and I-96b were prepared in 1 step from racemic compound 1-14 and 5-hydroxypiicolinic acid methyl ester according to the following procedure : 3-bromo-5- (4- (trifluoromethoxy) phenyl) -4,5-d, 4-isoxazole (1.0 equiv), methyl ester of 5-hydroxypicolinic acid (1.2 equiv) and cesium hydrogencarbonate ( 1.50 equiv) are suspended in A /, A / -dimetlformamdada (0.32 M with respect to dihydroisoxazole). The mixture is then degassed with argon after which it is heated at 130 ° C for 4 h after which point there is only the desired product and corresponding acid visible by LC / MS. The The reaction is allowed to cool to room temperature and is quenched by pouring a solution of ammonium chloride in water (30% by weight, 0.08 M with respect to dihydroisoxazole). The aqueous phase is extracted with ethyl acetate (2x), dried over sodium sulfate, filtered and concentrated to yield a brown solid which could be recrystallized from absolute ethanol to provide 3- (pyridin-3-yloxy) Racemic -4,5-dihydro-isoxazole 1-96 which was isolated by filtration as a white solid (25% yield). These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 383.8 m / z Activity: A Example 94 O O l-97a l-97b (1-97) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-96 was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point it was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCl to provide the desired acid enantiomers I -94a and I-94b as a white solid that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 369.3 m / z Activity: A Example 95 (1-98) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole l-98a and I-98b were prepared in 1 step from the racemic compound 1-10 and 3- (5-hydroxypyridin-2-yl) methyl ester ) propanoic using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 418.1 m / z Activity: A (1-99) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-98 (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCl to provide the desired l-99a and I-99 b acids as a white solid which was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 402.8 m / z Activity: A Example 97 (1-100) The racemic compound I-98 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir at 23 ° C for 72 h after which point the solvent and excess ammonia are removed under a stream of nitrogen to provide a light brown solid which is titrated with hexanes to provide the 1-100a and 1-100 of desired amide as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 404.5 m / z Activity: A Example 98 l-101a l-101b (1-101) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-101 and I-101b were prepared in 1 step from the racemic compound I-9 and 3-hydroxy-pyridine using method 5. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 316.8 m / z Activity: A Example 99 Me Me 1-102a 1-102b (1-102) 3-Bromo-4,5-dihydroxisoxazole 1-102a and 1-102b were prepared in 2 steps starting with formation of alkene from 1 - (biphenyl-4-yl) ethanone using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 315.7 m / z Activity: A Example 100 l-103a l-103b (1-103) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxysoxazole l-103a and 1-103b were prepared in 1 step from the racemic compound I-9 and 5-hydroxy-pyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 318.7 m / z Activity: A Example 101 1-104a 1-104b (1-104) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole 1- 04a and 1- 04b were prepared in 1 step from the racemic compound 1-102 and 5-hydroxy-pyrimidine using method 5. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 332.6 m / z Activity: A Example 102 O O l-105a l-105b (1-105) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroxoxazole 1-97 (1.0 equiv) was dissolved in methylene chloride (0.03M with respect to isoxazole). Thionyl chloride (2.0 equiv) is added and the reaction is stirred for 1 h at room temperature after which point concentrated in vacuo to a beige solid which was azeotroped with toluene (2x). The resulting solid was redissolved in tetrahydrofuran (0.03 M with respect to isoxazole), then glycine methyl ester (1.5 equiv) was added followed by triethylamine (3.0 equiv). The reaction was stirred for 1 h at room temperature after which point it was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with saturated NaHCO 3 solution and brine, dried over magnesium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes) to provide l- 105a and 1-105b of amide as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 437.5 m / z Activity: A Example 103 1-106a 1-106b (1-106) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-105 (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCl to provide the desired I-106a and 1-106b acids as a white solid that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 423.7 m / z Activity: A Example 104 OR Me, OCF-, 1-107a l-107b (1-107) 3- (Pyridin-5-yloxy) -4,5-dihydroxyisoxazole 1-107a and I-107b were prepared by using the analogous procedure as Example 102 except that methylamine was used in place of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 382.5 m / z Activity: A Example 105 Me.
OCF, OCF, 1-108a -108b (1-108) 3- (Pyridin-5-yloxy) -4,5-d-hydroxyisoxazole 1-108a and I-108b were prepared by using the analogous procedure as Example 102 except that dimethylamine was used in place of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 396.6 m / z Activity: B Example 106 or DO NOT.
II -OCF-, OCF3 O ' 1-109a l-109b (1-109) 3- (Pyridin-5-yloxy) -4,5-dihydroxyisoxazole 1-109a and I-109b were prepared by using the analogous procedure as Example 102 except that ethanolamine was used in place of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 409.9 m / z Activity: A Example 107 (IO) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67 (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCl to provide the desired I-110a and 1-110b acids as a white solid that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 376.5 m / z Activity: A Example 108 0 0 Me.
N l-111b ( OR) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67 was dissolved in dimethylamine in methanol (2.0 M in tetrahydrofuran, 0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir at 23 ° C for 72 h after which point the solvent and excess dimethylamine are removed under a stream of nitrogen to provide a light brown solid which is titrated with hexanes to provide 1-111a and 1 - 1b of amide desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 405.1 m / z Activity: A Example 109 1- 12a l-112b (1-112) 3- (Pyridin-5-yloxy) -4,5-dihydroxyisoxazole 1-112a and I-112b were prepared in 1 step from the racemic compound 1-14 and 5- hydroxypyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. Activity: A Example 110 1-113a 1-113b (1-113) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-13a and I-113b were prepared in 2 steps from racemic compound I-75 and 5-hydroxypicol quinic acid methyl ester using method 5 followed by hydrolysis under the same conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 380.7 m / z Activity: A Example 111 -114a 1-114b (?-?4) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-11a and I-114b were prepared from the racemic compound 1-113 by using the analogous procedure as example 102 except that methylamine (2.0M in tetrahydrofurane) was used instead of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 396.4 m / z Activity: A Example 112 l-115a l-115b (1-115) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-115a and I-115b were prepared from the racemic compound 1-113 by using the analogous procedure as example 102 except that ethylamine was used instead of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 411.1 m / z Activity: A OCF3 F-¾C 1-116b -116) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-116a and I-116b were prepared from the racemic compound 1-113 by using the analogous procedure as example 102 except that trifluoroethylamine was used instead of ester glycine methyl. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 461.7 m / z Activity: B Example 114 1-117a l-117b (1-117) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-117a and I-117b were prepared from the racemic compound 1-113 using the analogous procedure as example 102 except that hydroxylamine hydrochloride was used instead of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 398.4 m / z Activity: A Example 115 H? N H7N -OCF W // 1-118a 1-118b (1-118) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-105 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir at 23 ° C for 72 h after which point the solvent and excess ammonia are removed under a stream of nitrogen to provide a light brown solid which is titrated with hexanes to provide 1-118a and | i-118b of amide desired as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 325.1 m / z Activity: B Example 116 1-119a l-119b (1-119) 3- (Pyrimidin-5-yloxy) -4,5-dihydrosioxazole 1-1 9a and I-119b were synthesized in three steps starting with the conversion of 4-bromo-3,3'-di-fluorobiphenyl to its corresponding alkene using method 9 followed by cycloaddition using method 1 followed by displacement with 5-hydroxyprimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 354.3 m / z Activity: A Example 117 l-120a | .120b (1-120) 3-Bromo-4,5-dihydroxyisoxazole 1-120a and 1-120 were prepared in 2 steps starting with the formation of alkene from 3-fluoro-4- (trifluoromethoxy) benzaldehyde using method 8 followed by cyclo-addition using Method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [+ H] + = 327.5 m / z Activity: A Example 118 -OR. Q / = -OCF, 1-121 to 1-121b (1-121) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxysoxazole I-121a and I-121b were prepared in 1 step from the racemic compound 1-120 and 5-hydroxy-pyrimidine using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + Hj + = 344.1 m / z Activity: A Example 119 l-122a l-122b (J-122) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole-22a and I-122b were prepared in 1 step from the racemic compound 1-120 and 5-hydroxypicolinic acid methyl ester using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 400.3 m / z Activity: A Example 120 l-123a l-123b (1-123) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-122 (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCl to provide the desired I-123a and 1-123b acids as a white solid that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 386.3 m / z Activity: A Example 121 Cl Cl -124a 1-124b (1-124) 3-Bromo-4,5-dihydroxyisoxazole I-124a and I-24b were prepared in 2 steps starting with the formation of alkene from 3-chloro-4- (trifluoromethoxy) benzaldehyde using method 8 followed by cyclo- Addition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 345.5 m / z Activity: A Example 122 Cl Cl 1-125a 1- 25b (1-125) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-125 and I-125b were prepared in 1 step from the racemic compound 1-124 and 5-hydroxy-pyrimidine using method 5. These compounds can be separate using chiral HPLC methods known in the art. By example, see chiral HPLC method described herein. [M + H] + = 359.7 m / z Activity: A Example 123 1-126a l-126b (1-126) 3-bromo-4,5-dihydroxisoxazole 1-126a and I-126 b were prepared in 2 steps starting with the formation of alkene from 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde using the method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 305.6 m / z Activity: A Example 124 l-127a l-127b fl-127) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole t-127a and I-127b were prepared in 1 step from the racemic compound 1-126 and 5-hydroxy-pyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 321.8 m / z Activity: B Example 125 O O 1-128a l-128b (1-128) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-128 and I-128b were prepared analogously to compound I-99 as Example 96 except that the racemic compound 1-14 was used as starting material instead of the racemic 1-10 compound. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 398.2 m / z Activity: A Example 126 1-129a 1-129b (1-129) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxisoxazole 1-129a and 1-129b were prepared in 1 step from the racemic compound I-75 and 5-hydroxy-pyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 339.8 m / z Activity: A Example 127 1-130a 1-130b (1-130) 3-bromo-4,5-dihydroisoxazole 1-130a and 1-130 were prepared in 2 steps starting with the coupling between 4-phenoxy acid in 1-boronic acid and 2-bromo-3,3,3-trifluoroprop-1 - as follows: A solution of toluene (0.25 M with respect to boronic acid) is cooled to 0 ° C in a sealed tube after which 2-bromo-3,3,3-trifluoroprop-1-ene point (0.83) equiv) is added followed by palladium tetrakis (2.5 mole%). The mixture is purged with Ar after which point is added a 2.0 M sodium carbonate solution (1.5 equiv) followed by boronic acid (1.0 equiv) in methanol (1.0 M with respect to boronic acid). The mixture was purged a second time with Ar after which point it was heated to 70 ° C in an oil bath for 20h. The reaction was allowed to cool, after which it was transferred to a separatory funnel with excess water and ethyl acetate, washed with 2.0M sodium carbonate solution (1x) and water (2x). The organic layer was dried and concentrated to provide a black oil which was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired alkene as an oil in 35% yield which was converted directly to the 3- desired racemic bromine-4,5-dihydroisoxazole 1-130 using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 385.6 m / z Activity: B 3- (pyrimidin-5-yloxy) -4,5-dihydroxysoxazole I-131 a and 1-131 b were prepared in 1 step from the racemic compound 1-130 and 5-hydroxy-pyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 401.4 m / z Activity: A Example 129 1-132a 1-132 (1-132) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole 1-132a and 1-132b were prepared in 1 step from the racemic compound 1-14 and 2- (methyl-11-pyrimidin-5-ol) using method 5 after 2- (methylthio) -pyrimidin-5-ol is prepared first from 2- (methylthio) -pyrimidin-3-ylboronic acid using method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 372.2 m / z Activity: B Example 130 1-133a 1-133b (1-133) Racemic 3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole 1-132 was dissolved in methylene chloride (0.5 M with respect to isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv) was added. 1 portion and the reaction was allowed to stir at room temperature for 1 h. After the reaction was determined to be complete by LC / MS, the solvent was evaporated. The crude mixture was then redissolved in ether-butylmethyl ether (.5 M) after which hexane was slowly added until a solid precipitated. The solid was then collected via vacuum filtration and washed with 1: 1 hexanes / ether and ethyl ether to provide 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-133a and 1- 33b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 404.1 m / z Activity: A Example 131 1-134a 1-134b (1-134) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-134a and I-134b were prepared in 1 step from the racemic compound 1-14 and 6- (methylthio) -pyridin-3-ol using the method 5 after 6- (methylthio) pyridn-3-ol is prepared first from 6- (methylthio) pyridin-3-1 -boronic acid using method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 372.4 m / z Activity: A Example 132 l-135a 1-135b (1-135) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-135a and I-135b were prepared analogously to compound 1-133 as example 130. These compounds can be separated using HPLC methods chiral known in the art. For example, see HPLC method chiral described herein. [M + H] + = 403.2 m / z Activity: A Example 133 F F 1-136a 1-136b 0-136) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-136a and I-136b were prepared in 1 step from the racemic compound 1-14 and 5-fluoro-6-methoxypyridin-3-ol using the method 5 after 5-fluoro-6-methoxypyridin-3-ol is prepared first from 5-fluoro-6-methoxypyridine-3-boronic acid using method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 373.4 m / z Activity: B Example 134 1-137a 1-137b (1-137) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-137a and I-137b were prepared in 3 steps from 4-butoxybenzaldehyde using method 8 followed by cycloaddition using method 1. The The resulting bromo-4,5-dihydro-isoxazole was reacted with 5-hydroxypicolinic acid methyl ester using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 370.1 m / z Activity: A Example 135 1-138a 1- 38b (1-138) 3- (Pi lid i? -3-i loxi) -4,5-d ih idroxisoxazo I 1-138a and I-138b were prepared in 1 step from compound 1-137 using the analogous hydrolysis conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 357.7 m / z Activity: A Example 136 1-139a 1-139b (1-139) 3- (pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole l-139a and 1-139b were prepared in 3 steps from 4-butoxybenzaldehyde using method 8 followed by cycloaddition using method 1. Bromine The resulting 4,5-dihydro-isoxazole was reacted with 5-hydroxypyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 314.9 m / z Activity: A Example 137 Me Me )- Me OR OR l-140a l-140b (1-140) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-140a and I-140b were prepared in 4 steps from 4- / so-propoxybenzaldehyde using method 8 followed by cycloaddition using method 1. Bromine The resulting 4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 343.5 m / z Activity: A l-141a M41b (1-141) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole 1-141 a and 1-1 1 b were prepared in 1 step from 4- / so-propoxybenza Ideh using method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 299.3 m / z Activity: A Example 139 -142a 1-142b (1-142) 3-bromo-4,5-dihydroxisoxazole l-142a and 1-142b were prepared in 3 steps from 4-vinylphenyl acetate using the conditions of cycloaddition in method 1. The resulting acetate is dissolved in tetrahydrofuran (1.0 equiv, 0.18 M with respect to bromoisoxazole) and cooled to 0 ° C in an ice bath. Lithium hydroxide (3.0 equiv, 1.0 M in water) is added and the reaction is allowed to stir for 30 min after which point it is transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was extracted with saturated ammonium chloride, dried over sodium sulfate and evaporated to provide the desired phenol in quantitative yield which was used directly. The phenol (1.00 equiv) was dissolved in acetonitrile (0.20 M with respect to the starting material) and cooled to 0 ° C in an ice bath. Propargyl bromide (2.0 equiv) was added followed by cesium carbonate (3.0 equiv). The reaction was allowed to stir for 2 h after which it was quenched with saturated ammonium chloride and transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to provide the desired racemic 1-142 alkyne which was purified by flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired racemic compound in 70% yield. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 279.7 m / z Activity: A Example 140 1-143a l-143b (1-143) 3- (pyrimidn-5-yloxy) -4,5-d-hydroxyisoxazole l-143a and 1-143b were prepared in 1 step from the resulting compound 1-142 and 5-hydroxy. -pyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 296.5 m / z Activity: B Example 141 l-144a l-144b (1-144) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole l-144a and I-144b were prepared in 1 step from the racemic compound 1-142 and 5-hydroxypicolinic acid methyl ester using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 353.5 m / z Activity: A Example 142 or 1-145a 1-145b (1-145) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-145 and I-145b were prepared in 1 step from the racemic compound 1-144 using the analogous hydrolysis conditions as in example 94. These compounds were they can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 338.8 m / z Activity: A Example 43 1-146a 1-146b (1-146) 3-Phenoxy-4,5-dihydroxyisoxazole 1-146a and 1-146b were prepared in 1 step from the racemic compound 1-61 using the analogous hydrolysis conditions as in example 94. These compounds can be separated using HPLC methods chiral known in the art. For example, see chiral HPLC method described herein. [M-H] - = 376.2 m / z Activity: B Example 144 1-147b (1-147) 3-Phenoxy-4,5-dihydroxisoxazole 1-147a and 1-147b were prepared in 1 step from the racemic compound I-62 using the analogous hydrolysis conditions as in example 94. These compounds can be separated using methods of chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M-H] - = 375.7 m / z Activity: A Example 145 l-148a l-148b (1-148) 3-Bromo-4,5-d-ih-idroxisoxazole 1-148a and 1-148b were prepared in 1 step from 1-bromo-4-vinylbenzene using method 1. These compounds can be separated using known chiral HPLC methods. The technique. For example, see chiral HPLC method described herein. [M + H] + = 350.5 m / z Activity: A Example 146 Br Br l-149a 1-149b (1-149) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole I-149a and I-149b were prepared in 1 step from the racemic compound 1-148 and 5-hydroxypicolinic acid methyl ester using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 378.4 m / z Activity: A Example 147 1-150a 1-150b (1-150) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-150a and I-150b were prepared in 1 step from the racemic compound 1-149 using the analogous hydrolysis conditions as in example 94. These compounds were they can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 362.6 m / z Activity: A Example 148 1-151 to l-151b (1-151) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-151a and I-151b were prepared in 1 step from the racemic compound 1-14 and 4-h idroxypic acid methyl ester using the method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 384.2 m / z Activity: A Example 149 1-152a 1-152b 0-152) Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 1-151 (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1N HCI to provide the I- 152a and 1-152b desired acids as a white solid that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 368.9 m / z Activity: A Example 150 1-153a l-153b (1-153) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole 1-153a and 1-153b were prepared in 2 steps from 1-chloro-4-inylbenzene using method 1. The resulting bromo-4,5-dihydroisoxazole it was reacted with 5-hydroxypyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 277.3 m / z Activity: B Example 151 1-154a 1-154b (1-154) 3- (pyridin-3-yloxy) -4,5-d-hydroxyisoxazole I-154a and I-154b were prepared in 1 step from the racemic compound I-75 and 6- (furan-3 il) pyridin-3-ol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.3 m / z Activity: A Example 152 1-155a 1-155b (1-155) 3- (pi lid i? -3-i loxi) -4,5-d ih idroxisoxazo I 1-155a and I-155b were prepared from the racemic acid 1-110 according to the following procedure: in a reactor tube of microwave, acetyl hydrate (1.0 equiv) and 1-110 acid (1.0 equi'v) was dissolved in dry acetonitrile (0.1 M each). Added triphenylphosphine supported by polystyrene (3.0 equiv) and trichloroacetonitrile (2.0 equiv), and the mixture was sealed and heated in a microwave reactor at 130 ° C for 2 hours. After this point the reaction was determined as incomplete by LC / MS so that 1.5 additional equivalents of triphenylphosphine resin were added followed by 1.0 additional equivalents of trichloroacetonitrile. He The vessel was resealed and heated for an additional 2 hours at 130 ° C. Upon completion, the concentrated reaction mixture was purified by flash chromatography on silica gel (hexanes / ethyl acetate) to provide the desired racemic 1-705 oxadiazole. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 415.5 m / z Activity: A Example 153 Me Me 1-156a 1-156b (1-156) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-156a and I-156b were prepared using the analogous procedure to Example 152 except that the racemic compound 1-113 was used as the starting acid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 422.0 m / z Activity: A Example 154 OCF, 1-157a 1-157b (1-157) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-157a and I-157b were prepared using the analogous procedure to Example 152 except that the racemic compound I-97 was used as the starting acid . These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 407.2 m / z Activity: A Example 155 OCF-, 1-158a l-158b (1-158) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-158a and I-158b were prepared from racemic 1-113 acid according to the following procedure: acetyl hydrate (1.0 equiv) and acid were dissolved 1-113 (1.0 equiv) in dry dichioromethane (0.1 M each) and were treated with EDC (1.05 equiv) and DMPA (0.10 equiv) after which the reaction mixture was allowed to stir at 23 ° C for 6 h. After completion of the reaction, it was diluted in a separatory funnel with dichloromethane exclosor and water and the organic layer was washed twice each with 0.5 M aqueous citric acid and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to a white solid. This solid was dissolved in dry THF and Lawesson's reagent 1.2 equiv. The mixture was sealed in a tube and heated in a microwave reactor at 115 ° C for 30 min. The concentrated reaction mixture was purified by flash chromatography on silica gel (hexanes / ethyl acetate) to provide the desired racemic 1-158 thiadiazole. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 438.2 m / z Activity: A Example 156 I-159a 1-159b (1-159) 3-Phenoxy-4,5-dihydroxyisoxazole 1-159a and 1-159b were prepared using the analogous procedure to Example 152 except that the racemic compound 1-47 was used as the starting acid. These compounds can be separated using HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 413.6 m / z Activity: A Example 157 1-160a 1-160b (1-160) 3-Phenoxy-4,5-dihydroxyisoxazole 1-160a and 1-160b were prepared using the analogous procedure to Example 152 except that the racemic compound 1-146 was used as the starting acid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 414.4 m / z Activity: A Example 158 1-162b (1-162) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-162a and I-162b were prepared according to the following procedure: Racemic dihydroxyisoxazole 1-161 was prepared in 1 step from compound I-14 and 6. -bromopyridin-3-ol using method 5. Compound 1-161 placed in a microwave flask and then dissolved in dioxane (0.02 M). 2- (Tributylstanyl) thiazole and palladium tetrakis were added and the reaction was purged with Argon. At this point, the reaction was heated in the microwave reactor for 20 min after which there was no starting material by TLC analysis. The mixture is concentrated and purified by flash chromatography on silica gel (hexanes / ethyl acetate) to provide the desired thiazole 1-162 racemic in 50% yield. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 407.3 m / z Activity: A Example 159 1-163a 1-163b (1-163) 3- (Pyridin-3-yloxy) -4,5-dihydroxysoxazole I-163a and I-163b were prepared using the analogous procedure to Example 158 except that 2- (tributylstanyl) oxazole was used in place of 2- (tributylstanil ) thiazole. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 393.2 m / z Activity: A Example 160 1-164a l-164b (1-164) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-64a and I-164b were prepared using the analogous procedure to Example 158 except that the racemic compound I-75 was used instead of compound 1-14 as the material of departure. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 423.4 m / z Activity: A Example 161 1-165b (1-165) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-165a and I-165b were prepared according to the following procedure: racemic 1-161 dihydroisoxazole and sodium carbonate (10.0 equiv) were placed in a flask. microwave. A 2: 2: 1 mixture of toluene, ethanol and water (0.02 M with respect to 1-161) was added followed by 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) -yl) -1H-pyrazole-1-carboxylateboronic acid of fer-butyl (1.5 equiv). The mixture was purged with Ar for 20 min after which point palladium tetrakis (4 mol%) was added, the mixture was sealed and heated in an ice bath at 80 ° C for 7 h. The reaction mixture was then allowed to cool, after which it was transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride. The water layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to provide a crude oil which was purified by flash chromatography on silica gel (hexanes / ethyl acetate) to provide the desired racemic 1-165 pyrazole in 36% yield. performance. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.4 m / z Activity: C Example 162 l-166a l-166b (1-166) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole I-166 a and 1-166b were prepared in 1 step from racemic compound 1 and 5-hydroxy-pyrimidine using method 5. [MH] - = 241.5. m / z Activity: B Example 163 OCF OCF3 1-167a (1-167) 3- (pyridin-3-yloxy) -4,5-d-hydroxyisoxazole 1-67a and I-167b were prepared analogously to compound 1-135 as example 132 except that compound I-75 racemic was used as the bromo-isoxazole starting material. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 417.3 m / z Activity: A Example 164 1-168a l-168b (1-168) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole I-168 a and 1-168b were prepared in 2 steps from 1- (trifluoromethyl) -4-vinylbenzene the cycloaddition conditions of method 1. The bromo- The resulting 4,5-dihydro-isoxazole was reacted with 5-hydroxypyrimidine to provide the racemic compound 1-168 using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 309.8 m / z Activity: B Example 165 1-169a 1-169b (1-169) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-169a and I-169b were prepared in 3 steps from 1- (trifluoromethyl) -4-vinylbenzene using the conditions of cycloaddition of method 1. Bromine The resulting 4,5-dihydro-isoxazole was reacted with 6- (methylthio) pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11) using the method followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 387.2 m / z Activity: A Example 166 -CF, OR 1-170a l-170b (1-170) 3- (pi lid i? -3-i loxi) -4,5-d ih idrox isoxazo I 1-170a and I-170b were prepared in 3 steps from 1- (trifluoromethyl) -4-vinylbenzene using the cycloaddition conditions of method 5. The resulting bromo-4,5-dihydro-isoxazole was reacted with 5-hydroxypicolinic acid methyl ester using method 5 followed by hydrolysis using conditions analogous to example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 353.0 m / z Activity: A Example 167 OCF3 OCF3 N N 2C - ^ l-171a l-171b (1-171) 1- (4,5-Dihydroisoxazol-3-yl) -1H-1, 2,4-triazole-3-carboxylic acid I-171 a and 1-171 b were prepared using the analogous procedure to Example 35 except that compound I -75 racemic was used as the starting bromo-isoxazole and 1H-1,2,4-triazole-3-carboxylic acid methyl ester as the nucleophile. Additionally, at some time during the course of the reaction or formation, the ester hydrolyzed to the corresponding acid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M-H] - = 356.6 m / z Activity: C Example 168 1-172a l-172b (1-172) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-172a and I-172b were prepared in 1 step from the racemic compound I-75 and pyrazolo [1-5]. a] pyridin-2-ol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 378.1 m / z Activity: C Example 169 1-173a 1-173b (1-173) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-173a and I-173b were prepared using the analogous procedure to Example 161 except that 2- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1 / - / - pyrrol-1-carboxylic acid-butyl ester instead of 4- (4,4,5,5-tetramethyl-1, 3,2-dioxa -borolan-2-yl) -1 H-pyrazole-1-y-butylcarboxylate. These compounds can be separated using known chiral HPLC methods in the technique. For example, see chiral HPLC method described herein. [M + H] + = 390.6 m / z Activity: A Example 170 N = N N = N 1-174a l-174b (1-174) 3-Phenoxy-4,5-dihydroxyisoxazole l-174a and 1-174b were prepared in 1 step from the racemic compound 1-14 and 3- (1 / - / - tetrazole-5-i) f ene I using the method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.3 m / z Activity: B Example 171 1-175a l-175b 0-? 5) 3-Phenoxy-4,5-dihydroxyisoxazole 1-175a and 1-175b were prepared in 1 step from the racemic compound 1-14 and 4- (1H-tetrazol-5i) f in or I using the method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 391.6 m / z Activity: B Example 172 C02H -OCF, OCF-, 1-176a 1-176b (1-176) 3-Phenoxy-4,5-dihydroxyisoxazole 1-176a and 1-176b were prepared in 2 steps from the racemic compound 1-14. Bromo-4,5-dihydroisoxazole 1-14 was reacted with 3-hydroxybenzoic acid methyl ester using method 5 followed by hydrolysis using the analogous conditions as in example 94. [M + H] + = 368.0 m / z Activity : C Example 173 l-177a l-177b (1-177) 3-Phenoxy-4,5-dihydroxyisoxazole I-177a and 1-177b were prepared in 2 steps from the racemic compound 1-14. Bromo-4,5-dihydroisoxazole 1-14 was reacted with 3-hydroxybenzoic acid methyl ester using method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using known chiral HPLC methods. The technique. For example, see chiral HPLC method described herein. [M + H] + = 368.0 m / z Activity: B Example 174 N -OCF, OCF, OR l-178a 1-178b (1-178) 3- (Pyridin-3-yloxy) -4,5-d-hydroxyisoxazole 1-178a and I-178b were prepared in 2 steps from the racemic compound 1-14 and 5-hydroxy-picolinonitrile using method 5 then prepared 5-hydroxy-picolinonitrile from 5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-3-yl) picolinonetrile using method 11. These compounds can be separated using methods of Chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M + H] + = 350.0 m / z Activity: B Example 175 1-179a 1-179b (1-179) 3-Bromo-4,5-dihydroxisoxazole 1-179a and 1-179b were prepared in 1 step from 1-pentyl-4-vinylbenzene using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 283.6 m / z Activity: A Example 176 l-180b (1-180) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxysoxazole I-180a and 1-180b were prepared in 1 step from the racemic compound 1-179 and 5-hydroxy-pyrimidine using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 298.7 m / z Activity: A Example 177 l-181a l-181b (1-181) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole I-181 a and I-181b were prepared in 2 steps from the racemic compound 1-179 by reacting 6- (methylthio) pyridine- 3-ol (synthesized from 6- (methylthio) pyridin-3-ylboronic acid using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. . For example, see chiral HPLC method described herein. [M + H] + = 375.4 m / z Activity: A Example 178 OR 1-182a 1-182b (1-182) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-182a and I-182b were prepared in 2 steps from the racemic compound 1-14 by reacting 6- (ethylthio) pyridin-3-. ól (acid synthesized 6- (ethyltio) pyridin-3-ylboronic using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 417.1 m / z Activity: A Example 179 1-183a l-183b (1-183) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-183a and I-183b were prepared in 2 steps from the racemic compound 1-14 by first reacting 1-14 with 6- (cyclopentylthio) pyridine- 3-ol (synthesized from 6- (cyclopentylthio) pyridin-3-ylboronic acid using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. . For example, see chiral HPLC method described herein. [M + H] + = 456.8 m / z Activity: B Example 180 O O Me 1-184a 1-184b (1-184) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole 1-184a and I-184b were prepared in 2 steps from the racemic compound 1-14 by reacting 1-14 with 6 - (/ s). -b utiltio) p iri di? -3-ol (synthesized from 6 - (/ 'so-butylthio) pyridin-3-lboronic acid using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 444.7 m / z Activity: B Example 181 l-185a 1-185b (1-185) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-185a and I-185b were prepared using the procedure analogous to Example 178 except that racemic compound I-75 was used instead of compound I-75 as starting material and 2- (tributylstannyl) oxazole was used in place of 2- (tributylstanyl) thiazole (as in example 158). These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 407.2 m / z Activity: A Example 182 1-186a l-186b (1-186) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-186a and I-186b were prepared using the analogous procedure to Example 161 except that 2-furylboronic acid was used instead of 4- (4, 4, 5, 5-tetra met i I-1, 3, 2-dioxaborolan-2-yl) -1 H-pyrazole-ferro-butylcarboxylate. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.2 m / z Activity: A Example 183 1-187a l-187b (1-187) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole-87a and I-187b were prepared using the analogous procedure to Example 161 except that 5-methyl-furan-2-ylboronic acid it was used in place of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 / - / - pyrazole-1-carboxylic acid fer-butyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.3 m / z Activity: A Example 184 H02C HOzC OCF-, OCF, (1-188) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-188a and I-188b were prepared using the analogous procedure to Example 161 except that 5-boronofuran-2-carboxylic acid was used instead of 4- ( 4,4, 5, 5-tetra-methyl-1,3,2-dioxaborolan-2-yl) -1 / - / - p-aceol-1-carboxylic acid tert-butyl ester. These compounds can be separated using HPLC methods chiral known in the art. For example, see chiral HPLC method described herein. [M + H] + = 435.5 m / z Activity: C Example 185 1-189a l-189b (1-189) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-189a and I-189b were prepared using the analogous procedure to Example 161 except that 1-methyl-5- (4,4,5,5-tetramet L-1,3,2-dioxaborolan-2-yl) -1 / - / - pyrazole was used instead of 4- (4,4,5,5-tetra-methyl-1, 3,2-dioxaborolan- 2-yl) -1 H-pyrazole-1-y-butylcarboxylate. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.2 m / z Activity: A Example 186 Me Me l-190a l-190b (1-190) 3- (Pyridin-3-yloxy) -4,5-dihydroxisoxazole I-190a and I-190b were prepared using the analogous procedure to Example 161 except that 1,3-di methi I-1 acid H-pyrazol-5-ylboronic was used in place of 4- (4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) -1 - / - pyrazole-1-carboxylate of tert-butyl. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 419.4 m / z Activity: A 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-191 and I-191b were prepared using the analogous procedure to Example 161 except that 1-methyl-3- (trifluoromethyl) -1 H-pyrazole- 5-ylboronic was used in place of 4- (4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid re-butyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 473.3 m / z Activity: C Example 188 1-192a 1-192b s-192) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-192a and I-192b were prepared using the analogous procedure to Example 161 except that 1 H-pyrazole-5-ylboronic acid was used instead of 4- (4,4,5,5-Tetra-methyl-1,2,3-dioxaborolan-2-yl) -1 / - / - pyrazol-1-fer-butylcarboxylate. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 391.4 m / z Activity: A Example 189 l-193a l-193b (1-193) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-193a and I-193b were prepared using the analogous procedure to Example 161 except that 5-boronothiophene-2-carboxylic acid was used instead of 4- ( 4,4,5,5-tetramethyl-, 3,2-dioxaborolan-2-yl) -1 - / - p-aceol-1-carboxylic acid tert-butyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 450.6 m / z Activity 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole l-194a and I-194b were prepared according to the following procedure: racemic dihydroisoxazole 1-161, potassium phosphate dibasic (3.0 equiv), 4- (4 , 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) isoxazole (1.2 equiv), and the palladium catalyst (10 mol%) were placed in a microwave flask. Dioxane (0.1 M with respect to 1-161) was added and the mixture was purged with Ar for 20 min after which point the reaction was sealed and heated in an oil bath at 85 ° C for 17 h. The reaction mixture was then allowed to cool, after which it was transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride. The water layer was extracted again with ethyl acetate.
The organic layers were combined, dried over sodium sulfate and concentrated to provide a crude oil which was purified by flash chromatography on silica gel (hexanes / ethyl acetate) to provide the desired racemic pyramide 1-194 in < 5% yield These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.2 m / z Activity: A Example 191 OCF, 1-195a |195b (1-195) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole I-195a and I-195b were prepared according to the following procedure: racemic dihydroxyisoxazole 1-178 (1.0 equiv) was dissolved. in N, / V-dimethylformamide (0.1 M with respect to isoxazole) after which ammonium chloride (3.1 equiv) and sodium azide (1.5 equiv) were added. The reaction was then heated in a hot bath at 120 ° C for 4 h after which point the reaction was transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride, dried over sodium sulfate and concentrated to provide a crude oil which was purified by flash chromatography of silica gel (hexanes / ethyl acetate) to provide the desired racemic tetrazol 1-195. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 393.2 m / z Activity: A Example 192 1-196a 1-196b (1-196) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-196a and I-196b were prepared in 2 steps from the racemic compound 1-175 by first reacting I-75 with 6- (ethylthio) pyridine- 3-ol (synthesized from 6- (ethylthio) pyridin-3-ylboronic acid using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. . For example, see chiral HPLC method described herein. [M + H] + = 431.3 m / z Activity: A Example 193 1-197a 1-197b (1-197) 3- (Pyridin-3-yloxy) -4,5'-dihydroxysoxazole 1-197a and I-197b were prepared in 2 steps from the racemic compound 1-10 by reacting 1-10 with 6- ( methylthio) pyridin-3-ol (synthesized from 6- (methylthio) pyridin-3-ylboronic acid using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 411.4 m / z Activity: A Example 194 N Me 1-198a l-198b (1-198) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-198a and I in 1 step were prepared from the racemic compound I-75 and 6- (1 / - / - pyrazole 1-yl) pyridine -3-ol using method 5 then 6- (1H-pyrazole) pyridin-3-ol was synthesized from 2- (1H-pyrazol-1-yl) -5- (4, 4,5,5-tetramethyl) -1, 3,2-dioxaborolan-2-yl) pyridine using method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 405.3 m / z Activity: A Example 195 1-199a 1-199b (1-199) 3- (Phenoxy) -4,5-dihydroxyisoxazole-99a and I-199b were prepared in 1 step from the racemic compound 1-14 and 3- (3-methyl-1,2,4-oxadiazol-5-yl) ) phenol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.3 m / z Activity: C Example 196 l-200a l-200b (1-200) 3- (Phenoxy) -4,5-dihydroxyisoxazole I-200a and I -200 b were prepared in 1 step from the racemic compound 1-14 and 4- (2-methyl-2H-tetrazol-5-yl) phenol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.4 m / z Activity: B Example 197 1-201 to 1-201 b (1-201) 3- (Phenoxy) -4,5-dihydroxyisoxazole 1-201 a and 1-201 b were prepared in 1 step from racemic compound 1-14 and 4- (1, 3,4-oxadiazole-2-I) pheno I using method 5. These compounds can be separated using chiral HPLC methods known in the art. By example, see chiral HPLC method described herein. [M + H] + = 392.2 m / z Activity: A Example 198 (1-202) 3-bromo-4,5-dihydroxyisoxazole l-202a and l-202b were prepared in 2 steps according to the following procedure: 4-vinylbyl chloride (1.0 equiv) was dissolved in methylene chloride (0.375 with respect to styrene) after which morpholine (3.9 equiv) is added. The reaction is allowed to stir at room temperature for 14 h during which time a white precipitate begins to form. The reaction was then transferred to a separatory funnel with excess water and methylene chloride. The organic layer was washed with water (1x), 1N HCl (1x), saturated sodium bicarbonate (1x) and brine (1x) after which point it was dried over sodium sulfate and concentrated to provide a yellow oil. This crude material was then used directly to form the racemic bromoisoxazole using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 338.7 m / z Activity: B Example 199 Br l-203b l-203b (? -203) 3-bromo-4,5-dihydroxyisoxazole l-203a and I-2 O 3 b were prepared using the analogous procedure as example 198 except that dichmethylamine in tetrahydrofuran (2.0 M) was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 299.3 m / z Activity: A Example 200 l-204a l-204b (1-204) 3-Bromo-4,5-dihydroxisoxazole l-204a and l-204b were prepared using the analogous procedure as example 198 except that methylamine in tetrahydrofuran (2.0 M) was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 282.6 m / z Activity: B Example 201 l-205a l-205b (1-205) 3-Bromo-4,5-dihydroxyisoxazole l-205a and l-205b were prepared in 2 steps according to the following procedure: 4-vinylbenzene-1-sulfonyl chloride (1.0 equiv) was dissolved in methylene chloride ( 0.50 M with respect to styrene) after which morpholine (3.0 equiv) is added. The reaction is allowed to stir at room temperature for 90 min after which point it is transferred to a separatory funnel with excess water and methylene chloride. The organic layer was washed with water (1x), 1N HCl (1x), saturated sodium bicarbonate (1x) and brine (1x) after which point it was dried over sodium sulfate and concentrated to provide a yellow oil. This crude material was then used directly to form the desired racemic bromoisoxazole using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 374.6 m / z Activity: A Example 202 Me Me N N Br Me Me l-206a l-206b (1-206) 3-Bromo-4,5-dihydroxyisoxazole I-206a and I-206b were prepared using the analogous procedure as Example 201 except that dimethylamine in tetrahydrofuran (2.0 M) was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + - 332.6 m / z Activity: A Example 203 O Me O Me II / S-NH S-NH Br Ó Br o l-207a l-207b (I-207) 3-Bromo-4,5-dihydroxyisoxazole I-207a and I-207b were prepared using the analogous procedure as Example 201 except that methylamine in tetrahydrofuran (2.0 M) was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 318.6 m / z Activity: A Example 204 (1-208) 3-Bromo-4,5-dihydroxyisoxazole I-208a and I-208b were prepared using the analogous procedure as Example 198 except that piperidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 339.3 m / z Activity: A Example 205 l-209a l-209b (1-209) 3-Bromo-4,5-dihydroxyisoxazole l-209a and l-209b were prepared using the analogous procedure as example 198 except that pyrrolidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 322.6 m / z Activity: A Example 206 1-210a l-210b (1-210) 3-Bromo-4,5-dihydroxyisoxazole 1-210 a and I-210 b were prepared using the analogous procedure as example 201 except that piperidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 472.6 m / z Activity: A Example 207 1-211a 1-211b (1-211) 3-Bromo-4,5-dihydroxyisoxazole 1-211a and 1-211b were prepared using the analogous procedure as example 201 except that pyrrolidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 358.6 m / z Activity: A Example 208 l-212a I-212D 0-212) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-212a and I-212b were prepared in 2 steps of the racemic compound I-203 first by reacting I-203 with 6- (methylthio) pyridin-3-. ol (6- (methylthio) pyridin-3-ylboronic acid preparation using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 390.4 m / z Activity: B Example 209 OR Me /, 1-2 3a l-213b (1-213) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-213a and I-213b were prepared in 2 steps of the racemic compound I-202 first by reacting I-202 with 6- (methylthio) pyridine- 3-ol (6- (methylthio) pyridin-3-ylboronic acid preparation using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 426.2 m / z Activity: A Example 210 1-214a l-214b (1-214) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-214a and I-214b were prepared in 2 steps of the racemic compound 1-21 first by reacting 1-21 with 6- (methylthio) pyridine- 3-ol (6- (methylthio) pyridin-3-ylboronic acid preparation using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using chiral HPLC methods known in the art. . For example, see chiral HPLC method described herein. [M + H] + = 352.2 m / z Activity: A Example 211 1-215a 1-215b (1-215) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-215a and I-215b were prepared in 2 steps of the racemic compound 1-21. Bromo-4,5-dihydroisoxazole 1-21 was reacted with 5-hydroxy picolinic acid methyl ester using method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using known chiral HPLC methods in the technique. For example, see chiral HPLC method described herein. [M + H] + = 418.3 m / z Activity: B Example 212 1-216a 1-216b (1-216) 3- (pyridin-3-yloxy) -4,5-dihydroxysoxazole 1-216a and I-216b were prepared in 2 steps from 1- (trifluoromethyl) -4-vinylbenzene using the conditions Cycloaddition of the method 1. The 2-bromo-5-hydroxypyridine was reacted using method 5 to provide the racemic compound 1-216. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 389.1 m / z Activity: B Example 213 1-217a l-217b (1-217) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-217a and I-217b were prepared using the analogous procedure as Example 212 except that 3- (1, 3,4-oxadiazole was used. -2-yl) phenol instead of 2-bromo-5- hydroxypyridine. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 376.4 m / z Activity: A Example 214 Me OCF, OCF, 1-218a 1-218b (1-218) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole 1-218a and I-218b were prepared using the analogous procedure as example 161 except that 1-methyl-4- (4,4,5,5 -tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole instead of 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-M) -1 H-pyrazole-1-fer-butyl carboxylate. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 404.8 m / z Activity: A 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-219a and I-219b were prepared using the analogous procedure as Example 161 except that 1-methyl-4- (4,4,5,5 -tetramethyl-1, 3,2-d¡oxaborolan-2-yl) -1 H-pyrazole instead of 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ) -1 H-pyrazole-1-y-butylcarboxylate and racemic bromopyridine 1-216 was used as the starting material instead of 1-161. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 390.3 m / z Activity: A Example 216 l-220a l-220b (1-220) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole l-220a and I-220b were prepared according to the following procedure: acid 1-97 (1.0 equiv) was dissolved in methylene (0.08 M). Oxalyl chloride (1.5 equiv) was added followed by the addition of 1 drop of N, / V-dimethylformamide. The reaction was allowed to stir at room temperature for 20 min after which it was concentrated in vacuo. The crude material was then redissolved in methylene chloride after which methanesulfonamide (1.2 equiv), DMAP (10 mol%) and triethylamine (1.5 equiv) were added. After 3 h, the reaction was determined to be completed by LC / MS analysis. The reaction mixture was then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate and concentrated in vacuo to provide the desired sulfonamide. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 446.1 m / z Activity: A Example 217 N-N 1-221 to 1-221 b (1-221) 3- (Phenoxy) -4,5-dihydroxisoxazole l-221a 1-221b was prepared in 1 step from the racemic compound 1-14 and 3- (4H-1, 2,4-triazole-4-1 I ) pheno I using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.0 m / z Activity: C Example 218 l-222a l-222b (1-222) 3- (Phenoxy) -4,5-dihydroxysoxazole I-222a and I-222b were prepared in 3 steps according to the following procedures: 3- Idroxy benzoic acid methyl ester is reacted with racemic I-75 bromoisoxazole using method 5. The resulting methyl ester (1.0 equiv) is dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight in water) is added and the reaction is allowed to stir for 14 h. The reaction mixture is then concentrated in vacuo and used directly in the next step. Triethylortoacetate (8.0 equiv) is added and the reaction is sealed and heated under reflux for 14 h. The reaction is then transferred to a separating funnel with excess ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes gradient) to provide the oxadiazole 1- 222 desired racemic. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 420.5 m / z Activity: A Example 219 Me l-223a l-223b (1-223) 3- (Phenoxy) -4,5-dihydroxyisoxazole I-223a and I-223b were prepared using the analogous procedure as Example 218 except that racemic compound 1-15 was used instead of compound I-75 as the starting material. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.5 m / z Activity: A Example 220 Me F l-224a l-224b (1-224) 3- (Phenoxy) -4,5-dihydroxysoxazole I-224a and I-224b were prepared in 3 steps according to the following procedures: 3-fluoro-5-hydroxybenzoic acid methyl ester is reacted with bromoisoxazole 1- 14 racemic using method 5. The resulting methyl ester (1.0 equiv) is dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight in water) is added and the reaction is allowed to stir for 14 h. The reaction mixture is then concentrated in vacuo and used directly in the next step. Triethylortoacetate (8.0 equiv) is added and the reaction is sealed and heated at reflux for 14 h. The reaction is then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash silica gel chromatography (ethyl acetate / hexanes gradient) to provide the oxadiazole I- 224 desired racemic. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 424.5 m / z Activity: A Example 221 l-225a l-225b (1-225) 3- (phenoxy) -4,5-dihydroxyisoxazole l-225a and 1-225 b were prepared using the analogous procedure as example 220 except that triethyl ortooformate was used instead of triethylortoacetate to form the desired oxadiazole. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 410.3 m / z Activity: A Example 222 l-226a | -226b (1-226) 3- (Phenoxy) -4,5-dihydroxyisoxazole I-226a and I-226b were prepared using the analogous procedure as Example 220 except that 4-fluoro-5-hydroxybenzoic acid methyl ester was used instead of acid methyl ester 3-Fluoro-5-idroxybenzoic in the first step. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 410.4 m / z Activity: A Example 223 l-227a l-227b (1-227) 3- (Phenoxy) -4,5-dihydroxyisoxazole l-227a and 1-227b were prepared using the analogous procedure as example 222 except that racemic compound 1-75 was used instead of compound 1-14 as starting material . These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 424.4 m / z Activity: A Example 224 l-228a l-228b -228) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole l-228a and I-228b were prepared in 3 steps according to the following procedures: 5-hydroxynicotinic acid methyl ester is reacted with bromoisoxazole 1-75 racemic using method 5. The resulting methyl ester (1.0 equiv) is dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight in water) is added and the reaction is allowed to stir during 14 h. The reaction mixture is then concentrated in vacuo and used directly in the next step. Triethylortoacetate (8.0 equiv) is added and the reaction is sealed and heated at reflux for 14 h. The reaction is then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using silica gel flash chromatography (ethyl acetate / hexanes gradient) to provide oxadiazole I- 228 desired racemic. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 407.5 m / z Activity: A Example 225 l-229a l-229b (1-229) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-229a and I-229b were prepared using the analogous procedure as Example 224 except that triethylortoacetate was used in place of triethyl ortho- formate to form the desired oxadiazole. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 422.0 m / z Activity: A Example 226 l-230a l-230b (1-230) 3- (Phenoxy) -4,5-dihydroxisoxazole l-230a and l-230b were prepared using the analogous procedure as example 224 except that racemic compound 1-14 was used instead of compound 75 as the material of departure. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 393.2 m / z Activity: A 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-231 a and I-231b were prepared in 3 steps according to the following procedures: 5-hydroxynicotinic acid methyl ester is reacted with racemic I-75 bromoisoxazole using method 5. The resulting methyl ester (1.0 equiv) is dissolved in methanol (0.08) after which hydrazine (50 equiv, 50% by weight in water) is added and the reaction is allowed to stir for 14 h. The reaction mixture is then concentrated in vacuo and used directly in the next step. The hydrazide is dissolved in dioxane (0.12 M with respect to hydrazide).
N, / V-carbonidiimidazole (1.2 equiv) is added and the reaction is sealed and heated under reflux for 4 h. The reaction is then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (methanol / dichloromethane gradient) to provide 1, 3, 4 racemic-oxadiazol-2 (3H) -one 1-231 desired. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 423.4 m / z Activity: B Example 228 l-232a l-232b (1-232) 3- (Phenoxy) -4,5-dihydroxisoxazole l-232a and l-232b were prepared in 1 step from the racemic compound I-75 and 4- (1, 3,4-oxadiazole-2-i) pheno I using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.5 m / z Activity: A Example 229 Me K1, Me Me .... Me N OCF3 and OCF, J l-233a (1-233) 3- (Phenoxy) -4,5-dihydroxisoxazole l-233a and l-233b were prepared in 1 step from the racemic compound I-75 and 3-hydroxy- / V, N-dimethylbenzenesulfonamide using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 445.4 m / z Activity: C Example 230 OCF3 l-234a (1-234) 3- (Phenoxy) -4,5-dihydroxyisoxazole l-234a and I-234 b were prepared in 1 step from the racemic compound I-75 and 4- (methylsulfonyl) phenol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 415.6 m / z Activity: B Example 231 l-235a l-235b (I-235) 3- (Phenoxy) -4,5-dihydroxisoxazole l-235a and l-235b were prepared in 1 step from the racemic compound I-75 and 4-hydroxy - / /, N-dimethylbenzenesulfonamide using the method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 445.3 m / z Activity: C Example 232 N-NH l-236b (1-236) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole I-236a and I-236b were prepared in 3 steps according to the following procedures: racemic 1-161 dihydroisoxazole was dissolved (1.0 equiv) in N, N-dimethylformamide (0.1 M). Copper iodide (1.0 equiv) was added followed by trimethylsilylacetate (3.0 equiv) and N, N- or iisopropyl ethylamine (2.0 equiv). Palladium tetrakis (15 mol%) was added and the mixture was sealed and heated in a microwave reactor at 100 ° C for 1 h. The reaction was allowed to cool, after which it was transferred to a separatory funnel with ethyl acetate and water. The organic layer was then washed with water and brine, dried over sodium sulfate, concentrated and purified by flash chromatography on silica gel (ethyl acetate / hexanes gradient). The TMS group was then deprotected by dissolving this material in methanol (0.07 M) and adding potassium carbonate (3.0 equiv). After stirring for 4 h at room temperature, the reaction was transferred to a separatory funnel with ethyl acetate and water. The organic layer was then washed with water and brine, dried over sodium sulfate, concentrated and purified by flash chromatography on silica gel (gradient ethyl acetate / hexanes). The resulting alkyne was then converted to the desired triazole by first dissolving in trimethyl silylazide (80 equiv), purging the reaction mixture with Argon and heating in a microwave reactor at 110 ° C for 3 h. After an additional 4 hours of heating, the reaction was 60% complete by LC / MS analysis, at which point it was concentrated and purified directly by flash chromatography. silica gel (methanol / methylene chloride gradient) to provide the desired racemic triazole 1-236. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 392.9 m / z Activity: A Example 233 l-237a l-237b (L-237) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole l-237a and I-237b were prepared in 2 steps from the racemic compound 1-148 by first reacting 1-148 with 6- (methylthio) pyridine- 3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11) using method 5 followed by oxidation under conditions analogous to example 130. These compounds can be separated using known chiral HPLC methods. The technique. For example, see chiral HPLC method described herein. [M + H] + = 396.6 m / z Activity: A Example 234 l-238a l-238b (1-238) 3- (pyridin-3-yloxy) -4,5-dihydroxysoxazole l-238a and I-238b were prepared in 2 steps from 1- (trifluoromethyl) -4-vinylbenzene using the conditions of Cycloadition of the method 1. Bromo-4, Resulting 5-dihydroisoxazole was reacted with 6- (methylthio) pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 1) using method 5 to provide the compound I- 238. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 355.3 m / z Activity: A Example 235 l-240b (1-240) 3- (pyridin-3-yloxy) -4,5-d-hydroxyisoxazole l-240a and I-240b were prepared in 2 steps according to the following procedures: 6-bromopyridin-3-ol (1.0 equiv) is added and sodium carbonate (10.0 equiv) to a microwave flask. Toluene, ethanol and water (0.16 M, 2: 2: 1 v / v) are added followed by 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2). -yl) -1 H-pyrazole (1.5 equiv). The mixture is purged with argon for 15 min followed by the addition of palladium tetrakis (4 mol%). The reaction tube is then covered with aluminum foil and heated to 80 ° C in an oil bath for 17 h. After cooling the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with water (1x), saturated ammonium chloride (1x) and brine (1x). The aqueous layers were combined and washed with ethyl acetate (1x). The organic layers were then combined, dried over sodium sulfate, concentrated and purified using flash chromatography on silica gel (methanol / methylene chloride gradient) to provide 6- (1-methyl-1 H-pyrazol-4-yl). ) pyridin-3-ol I-239 as a soft solid. This compound is then reacted with racemic 3-bromo-4,5-dihydroisoxazole I-75 using method 5 to provide the desired racemic compound I-240. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 419.3 m / z Activity: A Example 236 1-241 to 1-241 b (1-241) 3- (phenoxy) -4,5-dihydroxisoxazole l-241a and 1-241 b were prepared using the analogous procedure as example 235 except that 1-methyl-5- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-ÍI) -1 / 7-pyrazole instead of 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan -2-il) -1 H-pyrazole as the boronoate in the first step. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.2 m / z Activity: A Example 237 l-242a l-242b (1-242) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole l-242a and I-242b were prepared using the analogous procedure as example 188 except that the racemic compound I-75 was used instead of compound 1-14 as starting material. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 406.3 m / z Activity: A HO ^ -N H H l-243a l-243b (1-1243) 2- (4,5-Dihydroxyisoxazol-3-ylamino) ethanol l-243a and l-243b were prepared in 2 steps in accordance with the following procedures: racemic 1-10-bromo-4,5-dihydroisoxazole 1-10 (1.0 equiv) in n-butanol (0.57 M) followed by the addition of (fer-butyldimethylsilyloxy) -methanamine (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction was sealed and heated in a microwave reaction for 1 h at 150 ° C after which point there was very little product formation by LC / MS analysis. The reaction was then resealed and heated for an additional 24h at 120 ° C in the microwave after transfer to a separatory funnel with excess water and fer-butylmethyl ether. The aqueous layer was washed with fer-butylmethyl ether (2x) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to provide a solid. orange which was purified using flash chromatography on silica gel (ethyl acetate / hexane gradient) to provide the desired silyloyl ether. This compound (1.0 equiv) was then dissolved in methanol (0.02 M) and cooled to 0 ° C in an ice bath. Acetyl chloride (50 equiv) was added dropwise after which the reaction was allowed to stir for 30 min at 0 ° C. The solvent and remaining acetyl chloride were then removed under a stream of nitrogen after which the crude material was purified by flash silica gel chromatography (ethyl acetate / methanol gradient) to provide racemic I-243. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 300.2 m / z Activity: B Example 239 (1-244) 2 - ((4,5-Dihydroxisoxazol-3-yl) (methyl) amino) -acetic acid l-244a and I-244 b were prepared in 2 steps according to the following procedure: 3- bromo-4, 5- dih id ro racemic isoxazole 1-10 was converted to the corresponding 3-amino-4,5-dihydroisoxazole by reacting it with sarcosine ethyl ester under the same conditions as in example 238. The ethyl ester was then hydrolyzed using the analogous conditions as in Example 119 to provide a mixture of racemic I-244. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 327.5 m / z Activity: B Example 240 0H l-245a OH l-245b (1-245) 2- (4,5-D-Hydroxisoxazol-3-ylamino) alcohol l-245a and l-245b alcohol were prepared in 1 step according to the following procedure: 3-bromo-4,5-dihydroxoxazole 1-10 racemic (1.0 equiv) was dissolved in n-butanol (0.64 M) followed by the addition of (S) -2-amino-1-phenylethanol (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is sealed and heated in an oil bath at 120 ° C for 8 h after which it is allowed to cool and then transferred to a separatory funnel with excess water and fer-butylmethyl ether. The aqueous layer was washed with fer-butylmethyl ether (2x) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to provide an orange solid which was purified using flash chromatography on silica gel (gradient toluene hexanes to toluene / ethyl acetate) to provide racemic 1-256 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 374.20 m / z Activity: C Example 241 (1-246) 2- (4,5-Dihydroxyisoxazol-3-ylamino) alcohol l-246a and I-246 b were prepared using the analogous procedure as example 240 except that racemic 3-bromo-4,5-dihydroisoxazole 1-14 was used in instead of 3-bromo-4,5-dihydroisoxazole 1-10 as the starting material and that (R) -2-amino-1-phenylethanol was used instead of (S) -2-amino-1-phenylethanol. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 365.6 m / z Activity: C Example 242 l-248b (1-248) 3- (phenylthio) -4,5-dihydroxisoxazole l-248a and l-248b were prepared in 2 steps according to the following procedure: N, A / -dibromoformaldoxime (1.0 equiv) was dissolved in tetrahydrofuran. Thiophenol (2.0 equiv) was added followed by sodium hydrate (1.98 equiv). After stirring for 1 h, the reaction is concentrated and purified by flash chromatography on silica gel (gradient ethyl acetate / hexanes) to provide the desired diphenyl hydroxycarbonyldiiodithioate I-247. The dithioate (1.0 equiv) is then redissolved in acetonitrile (1.0 M) followed by the addition of 1 - (trifluoro-methoxy) -4-vinylbenzene (2.4 equiv), silver nitrate (1.0 equiv) and potassium carbonate (1.0 equiv). The reaction was allowed to stir for 3 h at room temperature after which point it was concentrated and purified by flash chromatography on silica gel (gradient ethyl acetate / hexanes) to provide 3- (phenylthio) -4,5-dihydro-isoxazole I- 248 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 339.9 m / z Activity: C Example 243 O O (1-249) 3- (Phenylsulfonyl) -4,5-dihydroisoxazole l-249a and l-249b were prepared by the oxidation of racemic 3- (phenylthio) -4,5-dihydroisoxazole 1-248. 3- (phenylthio) -4,5-dihydroisoxazole 1-248 (1.0 equiv) in ethanol (0.15 M) was dissolved followed by the addition of excess hydrogen peroxide in water (30% by weight,> 50 equiv) and 1N HCI (0.29 M). The reaction was stirred at room temperature for 14 h after which it was transferred to a separatory funnel with excess water and methylene chloride. The water layer was extracted with methylene chloride (1x), dried over magnesium sulfate and concentrated to provide crude product which was recrystallized from hexanes to provide 3- (phenylsulfinyl) -4,5-dihydroisoxazole I-249. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 355.5 m / z Activity: C Example 244 l-250a l-250b (1-250) 3- (Phenylsulfonyl) -4,5-dihydroisoxazole l-250a and l-250b were prepared by the oxidation of racemic 3- (phenylsulfinyl) -4,5-dihydroisoxazole 1-249. 3- (phenylsulfinyl) -4,5-dihydroisoxazole 1-249 was dissolved in methylene chloride (0.03 M). M-chloroperbenzoic acid (77% by weight, 2.95 equiv) is added in two portions and the reaction is allowed to stir at room temperature for 14 h after which it is transferred to a separatory funnel with excess water and methylene chloride. The organic layer is washed with saturated sodium bicarbonate (2x), dried over sodium sulfate and concentrated to provide crude solid which is recrystallized from methylene chloride / hexanes to provide 3- (phenylsulfonyl) -4.5. -dried racemic I-250-dihydroisoxazole. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 317.2 m / z Activity: C Example 245 OCF3 OCF3 1-251 to 1-251 b (1-251) 3- (phenylthio) -4,5-dihydroxyisoxazole I-251 a and 1-251 b were prepared using the analogous procedure as example 242 except that methyl 4-mercaptobenzoate was used in place of thiophenol to form the required hydroxycarbomido dithioate. The resulting methyl ester cycloaduct was then hydrolyzed using the analogous conditions as in Example 94 to provide racemic 3- (f e n i 11) -4,5-dihydroisoxazole 1-251. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 384.1 m / z Activity: C Example 246 ) l-253b Me (1-253) N-ethyl- / V-phenyl-4,5-dihydroxyisoxazole-3-amine I-253a and l-253b were prepared in 2 steps according to the following procedure:? /, / V-dibromoformaldoxime (1.05 equiv) was dissolved in acetonitrile. Thiophenol (1.0 equiv) and aniline of / V-ethyl (1.0 equiv) were added and the reaction was allowed to stir at room temperature for 2.5j after which point triethylamine (5.0 equiv) was added. After stirring for 1 h, the solids which have now been precipitated from the reaction are filtered and the filtrate is concentrated and purified directly by flash chromatography on silica gel (gradient ethyl acetate / hexanes with 1% triethylamine) to provide the carbomidothioate. I-252 desired. The carbamimidothioate (1.0 equiv) is then redissolved in acetonitrile (1.0 M) followed by the addition of 1- (trifluoromethoxy) -4-vinylbenzene (2.4 equiv), silver nitrate (1.07 equiv) and potassium carbonate ( 1.17 equiv). The reaction was allowed to stir for 1d at room temperature after which point it was concentrated and purified by flash chromatography on silica gel (gradient ethyl acetate / hexanes with 1% triethylamine) to provide 4,5-dihydroisoxazol-3-amine I -253 racemic I-253. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 352.1 m / z Activity: C Example 247 Me l-255b (1-255) N-methyl-A / -phenyl-4,5-d-hydroxyisoxazole-3-amine I-255a and I -255 b were prepared in 3 steps according to the following procedure: A /, A / -dibromoformaldoxime was dissolved ( 1.05 equiv) in acetonitrile. Thiophenol (1.0 equiv) and 4- (methylamino) benzoic acid methyl ester (1.0 equiv) were added after which point triethylamine (3.0 equiv) was added in 3 portions. After stirring for 3 h, the reaction was transferred to a separatory funnel with excess water and methylene chloride. The organic layer was washed with 1N HCl (2x), dried over magnesium sulfate, concentrated and purified using silica gel flash chromatography (gradient ethyl acetate / hexanes with 0.5% triethylamine) to provide the carbomidothioate I-254 wanted. The carbamimidothioate (1.0 equiv) is then redissolved in acetonitrile (1.0 M) followed by the addition of 1- (trifluoromethoxy) -4-vinylbenzene (1.8 equiv), silver nitrate (2.3 equiv) and potassium carbonate (2.1 equiv). The reaction was allowed to stir for 1d at room temperature after which point it was purified by flash chromatography on silica gel (gradient ethyl acetate / hexanes with 0.5% triethylamine followed by gradient methanol / methylene chloride with 0.5% triethylamine. The resulting racemic methyl ester cycloaduct was then hydrolyzed using the analogous conditions as in example 94 to provide racemic A / -methyl-A / -phenyl-4,5-dihydroisoxazole-3-amine I-255. These compounds can be separated using chiral HPLC methods known in the art, for example, see chiral HPLC method described herein. [M + H] + = 381.5 m / z Activity: C Example 248 l-256a l-256b (1-256) 3- (pyrrolidin-1-yl) -4,5-d-hydroxyisoxazole l-256a and I-256b were prepared using the analogous procedure as example 238 except that pyrrolidine was used instead of (S) -2-ami not - 1-phenylethanol. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 310.3 m / z Activity: C Example 249 l-257a l-257b (1-257) 3- (1-Methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) -4,5-dihydroxyisoxazole l-257a and l-257b were prepared in 1 step from the racemic compound 1-10 and 1 -methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 403.7 m / z Activity: B l-258a l-258b (1-258) 3- (Phenoxy) -4,5-dihydroxyisoxazole l-258a and l-258b were prepared in 1 step from the racemic compound 1-14 and 3- (1, 3,4-oxadiazole-2-i) phene I using method 5. These compounds can be separated using chiral HPLC methods known in the art. By example, see chiral HPLC method described herein. [M + H] + = 392.4 m / z Activity: A Example 251 (1-259) 3- (p i rid i n-1 -yl) -4,5-dihydroxyisoxazole I-259a and I-259b were prepared using the analogous procedure as example 152 except that racemic compound 1-170 was used as the starting acid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 390.7 m / z Activity: A Example 252 l-260a l-260b (1-260) 4,5-D-Hydroxysoxazole-3-α-acetate l-260a and l-260b were prepared in 3 steps according to the following procedures: racemic bromoisoxazole (1.0 equiv) was dissolved in tetrahydrofuran (1.0 M). 1N sodium hydroxide (4.0 equiv) was added followed by allyl alcohol (45 equiv). The reaction was sealed and heated at 60 ° C for 3 h. The reaction mixture was allowed to cool and then transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes gradient). The resulting allylic ether (1.0 equiv) in tetrahydrofuran (0.2 M) was then dissolved. Formic acid (5.0 equiv) was added followed by palladium tetrakis (10 mol%) after which the reaction was allowed to stir for 2 h at room temperature. The reaction mixture was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and purified using flash chromatography on silica gel (ethyl acetate / hexanes gradient). The resulting osoxazolidin-3-one (1.0 equiv) was dissolved in methylene chloride (0.3 M) after which α, β-dimethylamino pyridine (1.0 equiv) and acetic anhydride (1.0 equiv) were added. After stirring at room temperature for 14 h, the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate and concentrated to provide the desired racemic 1-260 acetate. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 297.8 m / z Activity: D Example 253 1-261 to 1-261 b (1-261) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole I-261 a and I-261 b were prepared in 1 step from the racemic compound I-75 and 6- (methylthio) -pyridin-3-ol using the Method 5 after 6- (methylthio) pyridin-3-ol is prepared first from 6- (methylthio) pyridin-3-ylboronic acid using method 11. These compounds can be separated using chiral HPLC methods known in the art. . For example, see chiral HPLC method described herein. [M + H] + = 386.2 m / z Activity: A Example 254 ll-1a 11-1 b (III) 3-Bromo-4,5-dihydroxyisoxazole ll-1a and ll-1b were prepared in 1 step from 4-vinylpyridine using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 226.0 m / z Activity: C 3-Bromo-4,5-dihydroxyisoxazole 11-2 and 11-2 were prepared in 1 step from 3-vinylpyridine using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 226.0 m / z Activity: C 3-Bromo-4,5-dihydroxyisoxazole ll-3a and 11-3 were prepared in 1 step from 2-vinylpyridine using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 226.0 m / z Activity: C 3-Bromo-4,5-dihydroxyisoxazole 11-4 and II-4b were prepared in 2 steps starting with formation of alkene from 1-phenyl-1H-pyrazole-4-carbaldehyde using method 8 followed by cycloaddition using the Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 291.0 m / z Activity: B Example 258 Br ll-5a II -5b (II-5) 3-Bromo-4,5-dihydroxyisoxazole 11-5 and II-5b were prepared in 2 steps starting with formation of alkene from 2-phenyl-1,3-thiazole-4-carbaldehyde using method 8 followed by cycloaddition using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 308.0 m / z Activity: C Example 259 (TT-6) 3-Bromo-4,5-dihydroxysoxazole 11-6 a and II-6b were prepared in 2 steps starting with formation of alkene from 2-phenyl-1,3-thiazole-5-carbaldehyde using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 308.0 m / z Activity: B Example 260 (? -7) 3-Bromo-4,5-dihydroxyisoxazole 11-7 a and ll-7b were prepared in 2 steps starting with formation of alkene a. Starting from 5-fentylthiophene-2-carbaldehyde using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 309.6 m / z Activity: A Example 261 (II-8) 3-Bromo-4,5-dihydroxy-isoxazole 11-8 and II-8b were prepared in 2 steps starting with formation of alkene from 4-fentylthiophene-2-carbaldehyde using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 307.0 m / z Activity: A Example 262 ll-9a H-9b 3-Bromo-4,5-d-hydroxyisoxazole 11-9 a and II-9b were prepared in 2 steps starting with formation of alkene from 6-quinoline-carbaldehyde using method 8 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 276.0 m / z Activity: A Example 263 IMOa H-10b (11-10) 3-Bromo-4,5-d-hydroxyisoxazole 11-10a and 11-10b were prepared in 2 steps starting with formation of alkene from 3-quinoline-carbalde by using method 8 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 276.0 m / z Activity: A Example 264 ll-11a H-11b (11-11) 3-Bromo-4,5-dihydroxyisoxazole 11-11 s and ll-11b were prepared in 2 steps starting with formation of alkene from 6-bromoquino-xaline using method 10 followed by cycloaddition using method 2. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 277.0 m / z Activity: A Example 265 Br Me Me ll-12a 11-12b (? -12) 3-Bromo-4,5-dihydroxyisoxazole 11-12a and 11-12b were prepared in 2 steps starting with formation of alkene from 5-bromo-1-methyl-1H-indole using method 9 followed by cycloaddition using the Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 278.0 m / z Activity: A Example 266 11-13a ll-13b (1M3) 3-bromo-4,5-dihydroxyisoxazole 11-13 and 11-13b were prepared in 2 steps starting with the Boc protection of 2-amino-6-bromobenzo-thiazole as follows: benzothiazole (1.0 equiv) is dissolved in methylene chloride (0.12 M with respect to thiazole). Then add dicarbonate of d i -er-b uti lo (3.0 equiv) followed by the addition of DMAP (0.20 equiv) in five portions. The reaction was allowed to stir for 24 h at 23 ° C after which point there was no more MS by TLC analysis. The reaction was quenched with the addition of methanol (75 equiv) and allowed to stir for 10 min after which the reaction was partitioned between water and methylene chloride, and the organic layer was washed with 0.5 M citric acid solution ( 2x) and saturated sodium bicarbonate solution (1x), dried over magnesium sulfate and concentrated in vacuo to provide a crude solid which was converted directly to the desired 3-bromo-4,5-dihydroisoxazole using method 9 followed by Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 397.0 m / z Activity: B Example 267 (11-14) 1-Allylpiperazine is dissolved in methylene chloride (1.1 M with respect to piperazine). Potassium carbonate (1.5 equiv) was added by di-fer-butyl dicarbonate (1.1 equiv). The reaction was allowed to stir for 16 h after which it was partitioned between water and fer-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to provide crude alkene which was converted directly to 3-bromo-4,5-dihydroisoxazole 11-14a and ll-1b in 1 step using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 347.1 m / z Activity: A Example 268 l-15a 11-15b (II- 15) 3-Bromo-4,5-dihydroxyisoxazole 11-15a and II-15b were prepared in 2 steps starting with formation of alkene from 4-formyl-piperidine-1-carboxylate using method 8 followed by cycloadication using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 366.1 m / z Activity: B Example 269 11-16a ll-16b (11-16) 3-Bromo-4,5-d-hydroxysoxazole 11-1 G and 11-16b were prepared in 2 steps starting with formation of alkene from 4-formyl-piperidine-1-re-butylcarboxylate using the method 8 followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 332.1 m / z Activity: A Example 270 ll-17a ll-17b (II 17) 3-bromo-4,5-dihydroxyisoxazole 11-17a and 11-17 were prepared in 2 steps starting with formation of alkene from 2- (4-chlorof in i I) t-azol-5-ca rba Ideh using method 8 followed by cycloaddition using method 1. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 342.5 m / z Activity: A Example 271 ll-18a 11-18b (11-18) 3-Bromo-4,5-d-hydroxyisoxazole 11-18a and 11-18 fc > in 2 steps starting with formation of alkene from 1 - (2-phenyl Itiazol-5-yl) ethanone using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art . For example, see chiral HPLC method described herein. [M + H] + = 322.3 m / z Activity: A Example 272 ll-19a ll-19b (11-19) 3-Bromo-4,5-dihydroxisoxazole 11-19a and 11-1 Tb were prepared in 2 steps starting with formation of alkene from 2-phenylthiazole-5-carbaldehyde using method 8 except that bromide was used. ethyltriphenylphosphonium instead of methyltriphenylphosphonium bromide followed by cycloaddition using method 1. [M + H] + = 325.1 m / z Activity: A Example 273 -20th ll-20b (II-20) 3-Bromo-4,5-d-hydroxyisoxazole 11-20 and 11-20 were isolated as the trans diastereomers that are also formed during the cycloaddition in Example 272. These compounds can be separated using known chiral HPLC methods. The technique. For example, see chiral HPLC method described herein. [M + H] + = 324.9 m / z Activity: C Example 274 11-21 a 11-21 b (11-21) 3- (pyridin-3-yloxy) -4,5-dihydroxisoxazole 11-21 a and II-21b were prepared in 1 step from compound II-6 and 3-hydroxypyridine using method 5. These The compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 325.1 m / z Activity: A Example 275 ll-22a ll-22b 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 11-22 and II-22b were prepared in 1 step from compound 11-18 and 5-hydroxypyrimidine using method 5. These compounds can be separated using methods of chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M + H] + = 340.4 m / z Activity: A Example 276 ll-23a ll-23b (11-23) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole 11 -23 a and II-23b were prepared in 1 step from compound 11-18 and 3-hydroxypyridine using method 5. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 339.5 m / z Activity: A Example 277 ll-24a ll-24b (11-24) 3-Bromo-4,5-dihydroxyisoxazole 11-24 a and II-24b were prepared in 2 steps starting with formation of alkene from 1- (4-methyl-2-phenylthiazol-5-yl) ethanone using method 8 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 339.0 m / z Activity: B Example 278 Br ll-25a ll-25b (11-25) 3-bromo-4,5-dihydroxyisoxazole 11 -25a and ll-25b were prepared in 2 steps starting with formation of alkene from 5-pyridin-3-ylthiophene-2-carbaldehyde using method 1. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 310.3 m / z Activity: A Example 279 ll-26a ll-26b (11-26) 3- (Pyrimidin-5-yloxy) -4,5-dihydroxyisoxazole 11-26 a and 11-26 b were prepared in 1 step from compound II-25 and 5-hydroxypyrimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [+ H] + = 325.1 m / z Activity: A Example 280 (11-27) 3- (pyridin-3-yloxy) -4,5-dihydroxyisoxazole 11-27 a and II-27b were prepared in 2 steps from the racemic compound II-25 according to the following procedure: 5- methyl ester Single hydroxypicol was reacted using method 5 followed by hydrolysis of methyl ether. The methyl ether of 3- (pyridin-3-yloxy) -4, Racemic 5-dihydroisoxazole II-27 (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH <.; 2 with 1N HCI to provide 11-27 a and M27b of desired acid as a solid white that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 367.5 m / z Activity: A (? -28) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 11-28a and II-28b were prepared in 2 steps from the racemic compound M-6 by first reacting M-6 with 6- (methylthio) pyridine- 3-ol (prepared from 6- (methylthio) pyridine-3-Mboronic acid using method 11) using method 5 followed by oxidation according to the following procedure: 3- (6- (methylthio) pyridine- was dissolved 3-yloxy) -4,5-dihydroisoxazole in methylene chloride (0.5 M with respect to isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv) was added in 1 portion and the reaction was allowed to stir at room temperature for 1h. After determining the reaction to be completed by LC / MS, the solvent was evaporated. The crude mixture was then redissolved in fer-butylmethyl ether (.5 M) after which hexane was slowly added until a precipitate was precipitated. solid. The solid was then collected via vacuum filtration and washed with 1: 1 hexanes / MTBE to provide 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole ll-29a and ll-29b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 404.1 m / z Activity: A Example 282 ll-29a II -29b (11-29) 3- (Pyridin-3-yloxy) -4,5-dihydroxyisoxazole 11-29 and II-29b were prepared in 2 steps from the racemic compound 11-18 by first reacting 11-18 with 6- (methylthio) pyridine- 3-ol (prepared from 6 (methylthio) pyridin-3-ylboronic acid using method 5 followed by oxidation under conditions analogous to example 281. These compounds can be separated using chiral HPLC methods known in the art. see chiral HPLC method described herein. [M + H] + = 417.9 m / z Activity: A Example 283 (? -30) 2- (4,5-Dihydroisoxazol-3-ylamino) -alcohol 11-3 Oa and I f-30 b were prepared in 1 step according to the following procedure: 3-bromo-4,5-di-idisoxazole I- 8 racemic (1.0 equiv) was dissolved in n-butanol (0.64 M) followed by the addition of (S) -2-amino-1-phenylethanol (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is sealed and heated in an oil bath at 120 ° C for 18h after which it was allowed to cool and then transferred to a separatory funnel with excess water and fer-butylmethyl ether. The aqueous layer was washed with ether-butyl methyl ether (2x) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to provide an orange solid which was purified using silica gel flash chromatography (gradient toluene hexanes to toluene / ethyl acetate) to provide racemic II-30 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 374.20 m / z Activity: C Example 284 (? -31) 2- (4,5-Dihydroisoxazol-3-ylamino) alcohol 11-3 a and 11-311 > using the analogous procedure as example 283 except that (f?) - 2-amino-1-phenylethanol was used instead of (S) -2-amino-1-phenylethanol. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 366.4 m / z Activity: C Example 285 (III- 3-Bromo-4,5-dihydroisoxazole 111-1 was prepared in 1 step from methylenecyclohexane using method 1. [M + H] + = 217.0 m / z Activity: A Example 286 -2a lll-2b (III-2) 3-bromo-4,5-dihydroxyisoxazole lll-2a and lll-2b were prepared in 2 steps starting with the formation of alkene from tert-butylcyclohexanone using method 6 followed by cycloaddition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 273.1 m / z Activity: B Example 287 (111-3) 3-Bromo-4,5-dihydroxyisoxazole III-3a and III-3b were prepared in 2 steps starting with the formation of alkene from 4-phenylcyclohexanone using method 6 followed by cycloaddition using method 1. These compounds can separate using methods of Chiral HPLC known in the art. For example, see chiral HPLC method described herein. [M + H] + = 293.0 m / z Activity: A Example 288 Br (III-4) 3-Bromo-4,5-dihydroxyisoxazole III-4a and III-4b were prepared in 2 steps starting with the formation of alkene from 1,4-dioxaspiro [4.5] decan-8-one using method 6 followed by cycloaddition using method 1. [M + H] + = 275.0 m / z Activity: C Example 289 lll-8a lll-8b 011-8) 4-Methylenecyclohexane-carboxylic acid ethyl ester is prepared from the Wttig reaction in 4-oxocyclohexanecarboxylate using method 3. This ester is reduced to compound III-5 according to the following procedure: To a solution of aluminum hydrate of lithium (4.0 equiv) in diethyl ether (1.0 M with respect to hydrate) is added ethyl 4-oxocyclohexanecarboxylate in diethyl ether (2.0 M with respect to ester). The reaction is heated to reflux for 2 h after which it is cooled in an ice bath and quenched with subsequent additions of isopropanol, 50% NaOH in water, and water. The mixture is then filtered and the filter cake washed with excess diethyl ether. The filtrate is then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to provide a clear oil which is used without further purification.
Compound 111-5 (1.0 equiv) is then dissolved in pyridine (0.90 M with respect to alcohol). P-Toluene-sulfonyl chloride (1.1 equiv) is added and the reaction is allowed to stir for 16 h after which it is quenched with a few drops of water, diluted with excess methylene chloride and washed with water , Diluted HCl and brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide an almost white solid which was used directly without further purification.
Then phenol (1.2 equiv) was dissociated in N, N-dimethylformamide (0.20 M with respect to tosylate). Cesium carbonate (1.3 equiv) is added followed by compound III-6 (1.0 equiv) and TBAI (0.10 equiv). The reaction was heated at 40 ° C for 19 h after which point it was diluted with fer-butyl methyl ether and washed with dilute NaOH, water and brine and then dried over sodium sulfate. Concentration in vacuo provides compound III-7 as a clear oil that is used without further purification.
The crude alkene was converted directly to the desired d-astereomers 3-bromo-4,5-dihydroisoxazole 111-8 and a-8b in 1 step using method 2. These compounds can be separated using chiral HPLC methods known in the art. . For example, see chiral HPLC method described herein. [M + H] + = 323.6 m / z Activity: A Example 290 (III-9) 3-Bromo-4,5-dihydroxyisoxazole III-9 was prepared in 2 steps starting with the formation of alkene from 1- (1-butoxycarbonyl) -4-piperidone using method 7 followed by cycloaddition using method 1 or method 2. [M + H] + = 318.1 m / z Activity: A Example 291 Br 111-10a lll-IOb Oii-to) 3-Bromo-4,5-dihydroxyisoxazole 111-10 and 111-101 were prepared in 2 steps starting with the formation of alkene from 1- (fer-butoxycarbonyl) -3-piperidone using method 7 followed by cyclo-addition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 318.1 m / z Activity: C Example 292 11th lll-11b (III-ll) 3-Bromo-4,5-dihydroxisoxazole III-11a and III-11b were prepared in 2 steps starting with the formation of alkene from N- (tert-butoxycarbonyl) -3-pyrrolidone using method 7 followed by cycle -addition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 304.7 m / z Activity: B Example 293 lll-12a -12b (111-12) 3-Bromo-4,5-dihydroxisoxazole 111-12a and 111-12 fc were prepared. in 2 steps starting with the formation of alkene from 1- (fer-butoxycarbonyl) -4-oxoazepane using method 7 followed by cyclo-addition using method 1. These compounds can be separated using known chiral HPLC methods in the technique. For example, see chiral HPLC method described herein. [M + H] + = 332.1 m / z Activity: A Example 294 lll-13a | 13b (?? - 13) 3-bromo-4,5-dihydroxyisoxazole lll-13a and 111-13 b were prepared in 2 steps starting with the formation of alkene from N- (tert-butoxycarbonyl) -nortropionone using method 7 followed by cyclo- Addition using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 344.1 m / z Activity: C Example 295 (111-14) 3-Bromo-4,5-dihydroxyisoxazole III-9 was prepared in trifluoroacetic acid (0.20 M with respect to isoxazole) and stirred at room temperature for 1 h. The solvent is then removed in vacuo and the crude residue is azeotroped with toluene (2x) to provide 111-14 as the TFA salt (white solid) [M + H] + = 218.0 m / z Activity: C Example 296 Br Me (111-15) 3-Bromo-4,5-dihydroxyisoxazole 111-14 was prepared in methylene chloride (0.03 M with respect to isoxazole) after which triethylamine (4.0 equiv) and acetic anhydride (3.0 equiv) were added. The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with diluted HCl, diluted with NaOH and then brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide crude matreial which was purified using flash chromatography on silica gel (ethyl acetate / hexanes) to provide acetate 111-15 as a white solid. [M + H] + = 260.0 m / z Activity: C Example 297 (TII-16) 3-Bromo-4,5-dihydroxyisoxazole 111-14 is dissolved in methylene chloride (0.05 M with respect to isoxazole) after which triethylamine (4.0 equiv) and benzoyl chloride (1.25 equiv) are added. The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with diluted HCl, diluted with NaOH and then brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide acetate 111-16 as a white film. [M + H] + = 332.0 m / z Activity: A Example 298 (?? - 17) 3-Bromo-4,5-dihydroxyisoxazole 111-14 is dissolved in methylene chloride (0.05 M with respect to isoxazole) after which triethylamine (4.0 equiv) and benzoyl chloride (1.25 equiv) are added. The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with diluted HCl, diluted with NaOH and then brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide acetate 111-17 as a white film. [M + H] + = 358.0 m / z Activity: A Example 299 (?? - 18) 3-Bromo-4,5-dihydroxyisoxazole 111-14 is dissolved in methylene chloride (0.05 M with respect to isoxazole) after which triethylamine (4.0 equiv) and benzoyl chloride (1.25 equiv) are added. The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with diluted HCl, diluted with NaOH and then brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide acetate 111-17 as a white film. [M + H] + = 352.0 m / z Activity: A Example 300 (111-19) 3-Bromo-4,5-dihydroxyisoxazole 111-14 is dissolved in methylene chloride (0.06 M with respect to isoxazole) after which triethylamine (2.5 equiv) and be nza Id eh id o (1.25 equiv) are added followed by Sodium triacetoxyborohydrate (1.5 equiv). The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with dilute NaOH and then brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes) to provide / V-benzylpiperidine 111-19 as a white solid. [M + H] + = 308.1 m / z Activity: A Example 301 Cl (??-twenty) 3-Bromo-4,5-dihydroisoxazole III-20 was prepared using the analogous procedure as Example 300 except that 4-chlorobenzaldehyde was used instead of benzene. [M + H] + = 342.6 m / z Activity: A Example 302 OMe (111-21) 3-Bromo-4,5-dithiazole 111-21 was prepared using the analogous procedure as Example 300 except that 4-methoxybenzaldehyde was used instead of benzaldehyde. [M + H] + = 338.7 m / z Activity: A Example 303 (111-22) 3-Bromo-4,5-dihydroisoxazole III-22 was prepared using the analogous procedure as Example 300 except that 2-pyridinecarboxaldehyde was used instead of benzene. [M + H] + = 312.1 m / z Activity: B Example 304 (111-23) 3-Bromo-4,5-dihydroisoxazole 111-23 was prepared using the analogous procedure as Example 300 except that 3-pyridinecarboxaldehyde was used instead of benzaldehyde. [M + H] + = 312.4 m / z Activity: B Example 305 Me (ITI-24) 3-Bromo-4,5-dihydroisoxazole III-24 was prepared using the analogous procedure as Example 300 except that 4-methylbenzaldehyde was used instead of benzaldehyde. [+ H] + = 322.5 m / z Activity: A Example 306 (111-25) 3-Bromo-4,5-dihydroisoxazole III-25 was prepared using the analogous procedure as Example 300 except that 3,4-dichlorobenzaldehyde was used instead of benzaldehyde. [M + H] + = 378.6 m / z Activity: A Example 307 3-Bromo-4,5-d-hydroxazole 111-26 was prepared using the analogous procedure as Example 300 except that 4-trif luoromethylbenzaldehyde was used instead of benzaldehyde. [M + H] + = 376.6 m / z Activity: A Example 308 (m-27) 3-Bromo-4,5-dihydroisoxazole III-27 was prepared using the analogous procedure as Example 300 except that 3-chlorobenzaldehyde was used instead of benzaldehyde. [M + H] + = 342.6 m / z Activity: A Example 309 (111-28) 3-Bromo-4,5-d-hydroxazoxazole 111-28 was prepared using the analogous procedure as Example 300 except that hydrocinnamaldehyde was used in place of benzaldehyde. [M + H] + = 336.7 m / z Activity: A Example 310 3-bromo-4,5-dihydroisoxazole III-29 is dissolved in N, Ad im and i-formamide (0.05 M with respect to isoxazole) after which potassium carbonate (3.0 equiv) is added followed by potassium iodide ( 0.2 equiv) and 2-bromoethylbenzene (3.0 equiv). The reaction was heated to 70 ° C in an oil bath for 16 h after which point it was purified directly using flash chromatography on silica gel (ethyl acetate / hexanes) to provide amine III-29 as an oil. [M + H] + = 324.6 m / z Activity: A Example 311 Br (111-30) 3-Bromo-4,5-dihydroisoxazole 111-30 was prepared using the analogous procedure as example 290 except that 1-phenyl-4-piperidone was used instead of 1- (re-butoxycarbonyl) -4-piperidone. [M + H] + = 297.0 m / z Activity: B Example 312 (111-31) 3-Bromo-4,5-dihydroisoxazole III-30 was dissolved in chloroform (0.01 M with respect to isoxazole) after which bromide (1.0 equiv) was added. The reaction was allowed to stir for 16 h after which point it was diluted with water and washed with saturated Na 2 CO 3. The organic layer was then dried over sodium sulfate and concentrated in vacuo to provide 111-31 as a yellow solid. [M + H] + = 377.0 m / z Activity: B 3-Bromo-4,5-dihydroisoxazole 111-32 was prepared using the analogous procedure as Example 300 except that cyclohexanecarboxaldehyde was used instead of benzaldehyde. [M + H] + = 390.5 m / z Activity: A Example 314 (?? - 33) 3-Bromo-4,5-dihydroisoxazole 111-33 was prepared using the analogous procedure as example 300 except that pivaldehyde was used instead of benzaldehyde. [M + H] + = 290.5 m / z Activity: B Example 315 (??-3. 4) 3-Bromo-4,5-dihydroisoxazole III-34 was prepared using the analogous procedure as example 297 except that hydrocinnamaldehyde was used in place of benzoyl chloride. [M + H] + = 352.8 m / z Acti idad: A Example 316 (?? - 35) 3-Bromo-4,5-dihydroisoxazole III-35 was prepared using the analogous procedure as example 299 except that methyl chloroformate was used instead of benzyl chloroformate. [M + H] + = 378.8 m / z Activity: B Example 317 (?? - 36) 3-Bromo-4,5-dihydroisoxazole III-36 was prepared using the analogous procedure as example 299 except that / so-butyl chloroformate was used instead of benzyl chloroformate. [M + H] + = 318.7 m / z Activity: A Example 318 (111-37) 3-Bromo-4,5-dihydroxoxazole 111-37 was prepared using the analogous procedure as Example 299 except that phenyl chloroformate was used instead of benzyl chloroformate. [M + H] + = 340.7 m / z Activity: A Example 319 (?? - 38) 3-Bromo-4,5-d-hydroxazole III-38 was prepared using the analogous procedure as Example 299 except that 2,2,2-trichloroethyl chloroformate was used instead of benzyl chloroformate. [M + H] + = 394.5 m / z Activity: B Example 320 OMe (111-39) 3-Bromo-4,5-dihydroisoxazole 111-14 was dissolved in methylene chloride (0.05 M with respect to isoxazole) after which triethylamine (5.0 equiv) and carbonyl dümidazole (1.25 equiv) were added. The reaction was allowed to stir for 2 h after which point anisyl alcohol (2.5 equiv) was added followed by catalytic tetrabutylammonium hydrogen sulfate and 50% aqueous sodium hydroxide (0.10 M with respect to isoxazole). The heterogeneous mixture was allowed to stir for 16 h after which point it was diluted with ethyl acetate. The water layer was washed an additional two times with ethyl acetate after which the organic layers were combined, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (acetate). ethyl / hexanes) to provide carbamate III-39 as a white solid. [M + H] + = 382.9 m / z Activity: A Example 321 Cl (111-40) 3-Bromo-4,5-dihydroisoxazole III-40 was prepared using the analogous procedure as Example 320 except that 4-chlorobenzyl alcohol was used instead of anisyl alcohol. [M + H] + = 388.8 m / z Activity: A Example 322 (111-41) 3-Bromo-4,5-dihydroisoxazole 111-413 and 111-411 were prepared using the analogous procedure as Example 320 except that sec-phenethyl alcohol was used instead of anisole alcohol. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 368.8 m / z Activity: A Example 323 lll-42a lll-42b lll-42c lll-42d (111-42) Dissolve 3-cyclopentene-1-ol (1.0 equiv) in N, N-or im et i I-formamide (0.80 M with respect to alcohol) and treat with TBAI (0.10 equiv) followed by ground sodium hydroxide (2.0 equiv). Then benzyl bromide (1.2 equiv) was added and the reaction was allowed to stir for 48 hours at room temperature. The reaction is then diluted with f-butyl methyl ether and washed with dilute Na2S203 and brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes) to provide the desired cycloalkene as a colorless oil. This compound then became 3-bromo-4,5- dihydroisoxazole 111-42 using the cycloaddition procedures outlined in method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 295.0 m / z Activity: B Example 324 lll-43a lll-43b (111-43) 3-Bromo-4,5-dihydroisoxazole 111-3 and 111-431> were prepared in 1 step from N- (tert-butoxycarbonyl) -2,5-dihydro-1 / - / - pyrrole using method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 290.0 m / z Activity: B Example 325 lll-44a lll-44b (111-44) 3-Bromo-4,5-dihydroisoxazole 111-43 racemic in trifluoroacetic acid (0.20 M with respect to isoxazole) was dissolved and stirred at room temperature for 1 h. The solvent is then removed in vacuo and the crude residue is azeotroped with toluene (2x) to provide a trifluoroacetic acid salt as a white solid which was dissolved in methylene chloride (0.05M with respect to isoxazole) after which it is added triethylamine (4.0 equiv) and benzyl chloroformate (1.25 equiv). The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with dilute HCl, dilute NaOH and brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes) to provide carbamate III-44 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 324.6m / z Activity: A Example 326 lll-45a lll-45b (111-45) 3-Bromo-4,5-dihydroisoxazole 111-43 racemic in trifluoroacetic acid (0.20 relative to isoxazole) was dissolved and stirred at room temperature for 1 h. The solvent is then removed in vacuo and the crude residue is azeotroped with toluene (2x) to provide a trifluoroacetic acid salt as a white solid which was dissolved in methylene chloride (0.06M with respect to isoxazole) after which it is added triethylamine (2.5 equiv) and 4-chlorobenzaldehyde (1.25 equiv) followed by sodium triacetoxyborohydrate (1.5 equiv). The reaction is allowed to stir for 16 h after which point it is diluted with ethyl acetate and washed with dilute NaOH and brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using flash chromatography on silica gel (ethyl acetate / hexanes) to provide carbamate III-45 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 316.6m / z Activity: C Example 327 (111-46) 3- (Pyridin-3-yloxy) -4,5-d-hydroxazole 111 -46 was prepared in 1 step from compound 111-18 and 3-idroxypyrldine using method 5. [M + H ] + = 369.4 m / z Activity: A Example 328" (111-47) 3-Chloro-4,5-dihydroisoxazole III-47 was prepared in 2 steps starting with formation of alkene from 1 - (urea-butoxycarbonyl) -4-piperidone using method 6 followed by cycloaddition using method 2 except that used / V-chlorosuccinamide instead of N-bromosuccinamide. [M + H] + = 274.9 m / z Activity: A Example 329 Cl (JII-48) 3-Chloro-4,5-dihydroisoxazole 111-48 was prepared using the analogous procedure as example 301 except that 3- was used. chloro-4,5-dihydroisoxazole 111-47 instead of 3-bromo-4,5-dihydro-isoxazole 111-9. [M + H] + = 298.6 m / z Activity: A Example 330 (111-49) 3-Bromo-4,5-dihydroxoxazole 111-49 was prepared using the analogous procedure as example 300 except that 4-ethynylcarboxaldehyde was used instead of benzaldehyde. [M + H] + = 335.1 m / z Activity: A Example 331 (111 - 50) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-50 was prepared in 1 step from compound III-49 and 3-hydroxypyridine using method 5. [M + H] + = 348.6 m / z Activity: A 3- (pyridin-3-yloxy) -4,5-dihydroxoxazole 111-51 was prepared in 1 step from compound III-20 and 3-hydroxypyridine using method 5. [M + H] + = 358.1 m / z Activity: A Example 333 011-52) 3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole 111-52 in 1 step was prepared from compound III-20 and 5-hydroxypyrimidine using method 5. [M + H] + = 360.2 m / z Activity: A Example 334 III-53 III-54 3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole 111-54 was prepared in 3 steps from the synthesis of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 111-53 of compound 111 -9 and 5-hydroxypyrimidine using method 5. Compound 53 was then deprotected using conditions analogous to Example 295 and then converted to the desired product 111-54 using the analogous procedure as Example 297 except that hydrocinnamaldehyde was used instead of benzoyl [M + H] + = 367.7 m / z Activity: B Example 335 Cl (IH-55) 3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole III-55 was prepared in 3 steps from compound III-9 using the analogous procedure to Example 334 except that 4-chlorobenzoyl chloride was used instead of hydrocinnamaldehyde chloride. [M + H] + = 372.9 m / z Activity: A Example 336 (111-56) 3- (Pyrimidin-5-yloxy) -4,5-dihydrosioxazole 111-56 was synthesized in two steps from compound 111-3 initiating with deprotection using conditions analogous to Example 295. The resulting trifluoroacetic acid salt (1.0 equiv) then it is dissolved in methylene chloride (0.11 M with respect to isoxazole) after which phenyl isocyanate (1.5 equiv) is added followed by pyridine (5.0 equiv). The reaction is allowed to stir overnight at room temperature after which point the reaction was transferred to a separatory funnel with excess water and methylene chloride. The organic layer was washed with saturated sodium bicarbonate (2x), dried over magnesium sulfate and concentrated to provide a white solid which was purified by flash chromatography on silica gel (gradient ethyl acetate / methanol). [M + H] + = 353.6 m / z Activity: C Example 337 (111-57) 3- (Pyridin-5-yloxy) -4,5-dihydrosioxazole 111-57 was synthesized in two steps from compound 111-53 starting with deprotection using conditions analogous to Example 295. The resulting trifluoroacetic acid salt (1.0 equiv) then it is dissolved in methylene chloride (0.11 M with respect to isoxazole) after which 5,5,5-trifluoropentanoic acid (1.5 equiv), EDC (1.5 equiv) and triethylamine (3.0 equiv) are added. The reaction is allowed to stir for 14 h at room temperature after which point the reaction was transferred to a separatory funnel with excess water and methylene chloride. The organic layer was washed with saturated sodium bicarbonate (2x), dried over magnesium sulfate and concentrated to provide a white solid which was purified by flash chromatography on silica gel (gradient ethyl acetate / methanol). [M + H] + = 373.7 m / z Activity: C Example 338 (111-58) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole 111-58 was prepared in 3 steps from compound 111-16 in accordance with the following procedures: 6- (methylthio) pyridine-3- was prepared ol from 6- (methylthio) pyridin-3-ylboronic acid using method 11. Then 3-bromo-4,5-dihydroxoxazole was reacted with 6- (methylthio) pyridin-3-ol using the method The 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole was dissolved in methylene chloride (0.5 M with respect to isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv) was added in 1 portion and the The reaction was allowed to stir at room temperature for 1 h. After determining that the reaction was completed by LC / MS, the reaction was transferred to a separatory funnel with excess water and methylene chloride. The organic layer was washed with saturated sodium bicarbonate (2x), and 1N NaOH (1x), dried over magnesium sulfate, and concentrated to provide a white solid which was purified by flash chromatography on silica gel (acetate gradient). ethyl / methanol). [M + H] + = 415.8 m / z Activity: B Example 339 (?? - 59) 3- (Pyrrolidin-1-yl) -4,5-dihydroisoxazole III-59 was prepared in 1 step according to the following procedure: 3-bromo-4,5-dihydroisoxazole 111-18 (1.0 equiv) was dissolved in n-butanol (0.64 M) followed by the addition of pyrrolidine (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is sealed and heated in an oil bath at 120 ° C for 18 h after which it was allowed to cool and then transferred to a separatory funnel with excess water and tert-butyl methyl ether. The aqueous layer was washed with fer-butylmethyl ether (2x) and the combined organic layers were washed with brine.were dried over magnesium sulfate and concentrated to provide an orange solid which was purified using flash chromatography on silica gel (ethyl acetate / hexanes gradient) to provide 111-59 as a white solid. [M + H] + = 345.4 m / z Activity: C Example 340 (111-60) I- (4,5-dihydroisoxazol-3-yl) -1-methyl-pyrrolidinium III-60 iodide was synthesized according to the following procedure: 3- (pyrrolidin-1-yl) -4,5-di was dissolved hid roi soxazol III-59 in methanol (0.044 M) followed by the addition of methyl iodide (0.022 M). The reaction was allowed to stand for 72 h after which it was concentrated and purified using high pressure liquid chromatography (0.1% formic acid). The desired fractions were lyophilized to provide the desired product plus some impurities that were removed by washing the solid with hexanes. Activity: C Example 341 Br ll | .62b (II 1-62) 3-bromo-4,5-dihydroisoxazole 111-62 a and 11162b were synthesized in three steps according to the following procedures: phenyl boronic acid (2.0 equiv) was suspended in toluene (0.23 M with respect to boronic acid) and heated until a solution is found. The solvent evaporates and this process is repeated. The resulting anhydride is then redissolved in methylene chloride (0.23 M). 6-Hydroxy-3,4-dihydronaphthalen-1 - (2H) -one (1.0 equiv), triethylamine (5.0 equiv) and copper acetate (0.95 equiv) are added and the reaction is sealed and stirred for 16 h at room temperature. The mixture is then transferred to a separatory funnel with excess methylene chloride and water. The organic layer is then washed with water, dilute sodium hydroxide and brine. The organic layer is dried with sodium sulfate, and concentrated to provide 111-61 as a brown oil which is converted directly to racemic 3-bromo-4,5-dihydroisoxazole III-62 using method 5 followed by method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 359.5 m / z Activity: A lll-63a lll-63b 3-Bromo-4,5-dihydroisoxazole 111-63 a and IM63b were prepared using the analogous procedure as Example 341 except that 5-hydroxy-2,3-dihydro-1 H-inden-1 -one was used instead of 6-hydroxy-3,4-dihydro-naphthalene-1 (2H) -one as the starting material in the first step. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 343.7 m / z Activity: A Example 343 lll-64a ||| -64b (111-64) 3- (pyridin-5-yloxy) -4,5-dihydroisoxazole lll-60a and 1116 O b were prepared in 1 step from the racemic compound III-63 and 5-hydroxy-pyrimidine using the method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein.
[M + H] + = 361.2 m / z Activity: A Example 344 llf-66b (111-66) 3-Bromo-4,5-dihydroisoxazole 111-66 a and III-66b were synthesized in four steps in accordance with the following procedures. A 250 mL round bottom flask with 10/30 thermometer port is fitted with a stir bar, analog thermometer, and Allihn condenser. Add 3- (3- (trifluoromethoxy) phenyl) -propanoic acid (0.22 mol, 1.0 equiv), dissolved in thionyl chloride I or (6.0 equiv), and refluxed in an oil bath for 1 h during which time the temperature internal 78-82 ° C in one hour. In this At this time, the condenser is replaced with a short path head and the thermometer with an inlet for a dry argon jet, and the volatiles removed by distillation. When the distillation is complete, cyclohexane (100 ml_) is added to the pot and distilled in the same manner to provide the desired acid chloride in quantitative yield as a brown oil that is used directly. A 2L 3-neck round bottom flask is then fitted with a mechanical stirrer, thermocouple probe, and a 250 mL pressure equalized drip funnel. It is loaded with aluminum trichloride (0.233 mol, 1.08 equiv) and methylene chloride (0.24 M), then stirred 45 minutes to dissolve as much as possible. The reaction is then cooled in an ice bath to an internal temperature of <25 ° C. A solution of acid chloride (1.0 equiv, 0.215 mol) in 200 ml of methylene chloride is added via an addition funnel in 15 min. After completing the addition, the ice is removed from the bath and replaced with water at room temperature (bath temperature at 18 ° C) and the reaction proceeded for 2 h more, at which point the reaction is indicated to be completed by TLC and analysis of LC / MS. The reaction mixture is then treated with ice (500 g, and then water (600 mL) after which the mixture is stirred for 1 h until all the solids have dissolved.The combined organics are washed with water (250 mL, 1 x), saturated sodium bicarbonate (250 mL, 1x), brine (250 mL, 1x), dried over magnesium sulfate and concentrated to provide 5- (trifluoromethoxy) -2,3-dih dro-1 H-inden-1 -one III-65 as a pink solid in quantitative yield.This material is then converted directly to racemic 3-bromo-4,5-dihydroisoxazole III-66 using method 5 followed by method 1 These compounds can be separated using chiral HPLC methods known in the art, For example, see chiral HPLC method described herein. [M + H] + = 335.6 m / z Activity: A Example 345 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-67a and III-67b were prepared in 2 steps from the racemic compound III-66 and 6- (methylthio) pyridin-3-ol using the Method 5 after 6- (methio Itio) - pyridin-3-ol is first prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11. These compounds can be separated using known chiral HPLC methods. The technique. For example, see chiral HPLC method described herein. [M + H] + = 396.7 m / z Activity: A Example 346 lll-68a lll-68b (111-68) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole 111-68 a and l-68b were prepared in 1 step from the racemic compound III-67 using analogous oxidation conditions as in Example 338. These compounds can be separate using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 429.4 m / z Activity: A (II 1-70) 3- (pyrid i? -3-i loxi) -4,5-d i hydro isoxazo I II I-70 a and 111-70 b were prepared in 2 steps in accordance with the following procedures: 6-Bromopyridin-3-ol (1.0 equiv) and sodium carbonate (10.0 equiv) are added to a microwave flask. Toluene, ethanol and water (0.16 M, 2: 2: 1 v / v) are added followed by 1-methyl-4- (4, 4,5,5-tetramethyl, 3,2-dioxaborolan-2-yl) - 1 H-pyrazole (1.5 equiv). The mixture is purged with argon for 15 min followed by the addition of palladium tetrakis (4 mol%). The reaction tube is then covered with aluminum foil and heated to 80 ° C in an oil bath for 17 h. After cooling the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with water (1x), saturated ammonium chloride (1x) and brine (1x). The aqueous layers were combined and washed with ethyl acetate (1x). The organic layers were then combined, dried over sodium sulfate, concentrated and purified using flash chromatography on silica gel (methanol / methylene chloride gradient). This compound is then reacted with racemic 3-bromo-4,5-dihydroisoxazole III-66 using method 5 to provide the desired racemic compound III-70. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 430.0 m / z Activity: A Example 348 111-71 to lll-71b (111-71) 3- (pyridin-3-yloxy) -4,5-dihydroxoxazole II I-71 a and 111-71 b were prepared using the analogous procedure as Example 347 except that 1-methyl-5 was used. - (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole instead of 1-methyl-4- (4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole as the boronoate in the first step. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 430.0 m / z Activity: A Example 349 (111-73) 3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-73a and III-73b were prepared in 3 steps according to the following procedures: 5-hydroxynicotinic acid methyl ester is reacted with (1.0 equiv) dissolve in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight in water) is added and the reaction is allowed to stir for 14 h. The reaction mixture is then concentrated in vacuo and used directly in the next step. The organic layer was then washed with brine, dried over sodium sulfate and concentrated in vacuo to provide crude material which was purified using silica gel flash chromatography (gradient methanol / methylene chloride) to provide the desired oxadiazole III-72. . This compound is then reacted with racemic 3-bromo-4,5-dihydroisoxazole III-66 using method 5 to provide the desired racemic compound III-73. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 419.5 m / z Activity: A Example 350 lll-74a lll-74b (?? - 74) The enantiomers of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole 111 -74a and lll-74b were prepared in 2 steps in accordance with the following procedures: 3-bromo-4,5-hydroisoxazole Racemic III-66 with 5-hydroxynicotinic acid methyl ester using method 5. The resulting ester (1.0 equiv) was dissolved in 1: 1 tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH < 2 with 1 N HCl to provide the desired racemic III-74 acid as a white solid that was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC method described herein. [M + H] + = 395.5 m / z Activity: A Example 351 Inhibition of human FAAH Preparation of human FAAH: COS-7 cells were split the day before, 1: 5 in 150 mm x 25 mm culture dishes (Corning Inc., Cat. No. 430599). Transient transfection occurred at 30-40% confluence in accordance with FuGENE 6 Transfection Reagent (Roche, Cat. No. 11814 443 001).
Transfection procedure: The FuGENE transfection reagent (45μ? _) Was added to 1410 μ? _ Of medium (DMEM, serum free without pen / strep) in a 15 mL conical tube and incubated at room temperature for 5 minutes, followed by the addition of FAAH plasmid DNA (15 pg) (OriGene Cat. No. TC119221, Accession No. of GenBank NM_001441.1, 0.67 pg / uL) and another 15 minute incubation at room temperature. The resulting solution was added in a dish of 30-40% confluent COS-7 cells in the form of drops. The cell dish COS-7 was subsequently incubated for 48 hours. The cells are then harvested.
Harvesting procedure: Medium was aspirated from the dishes and the cells were rinsed with 10ml of PBS. The PBS was removed and 3 mL of PBS was added to the dish. The dish was scraped to resuspend the cells, and the posterior cell suspension collected in a 15 mL conical tube. The cells were pelleted by centrifugation at 1200 rpm for 5 minutes in an overhead bath centrifuge. The PBS was removed and the cell pellet was frozen in liquid nitrogen and stored at -80 ° C.
Purification of COS-7 cells - FAAH: (1) Fractionation: Frozen cellular balls of transient infections were thawed in ice and resuspended in 12.5mM Hepes pH 8.0, 100mM NaCl, 1mM EDTA (10 mL / 0.2 g cell bead). The beads were homogenized and then sonicated to produce cell extract. The cell extract was subsequently centrifuged at 1000 g to eliminate cell debris. The ball was discarded and the supernatant centrifuged at 13,000 g for 20 minutes. The ball membrane found FAAH. The supernatant was discarded and the ball resolubilized. (2) Re-solubilization: The fraction of interest, (13,000g, membrane fraction) was resuspensed in 2.5 mL of resuspension buffer (20mM Hepes pH 7.8, 10% v / v Glycerol, 1mM EDTA, 1% Triton X -100) and the sample incubated on ice for 1 hour and then centrifuged to remove any particulate matter. The supernatant containing solubilized human FAAH was aliquoted and frozen in liquid nitrogen and stored at 80 ° C until used. (3) Characterization: Protein concentration determined by Bradford assay.
SDS gel and Western blot to confirm presence of FAAH FAAH activity test Test of 96 Km determination wells Test of 96 wells of linear dependence Test 384 wells of Ki determination of standard compound Human FAAH assay; Experimental protocol: a 0.1 mg / mL solution of human FAAH was formed in a FAAH reaction regulator, and 24 ul pipetted into a 384-well plate. Thereto 1 pL of a 3-fold serially diluted inhibitor was added from a solution of DMSO material. The FAAH solution and inhibitor were incubated for 30 minutes at room temperature. The FAAH reaction was initiated by the addition of 25 pL of 40 μ? of arachidonoyl amide in FAAH reaction regulator, producing a final reaction human FAAH preparation concentration of 0.05 mg / ml and concentration of AMC-Arachidonoyl substrate of 20 μ ?, 50 pL reaction volume. The reaction was allowed to proceed for 4 hours at room temperature. The reaction was stopped by the addition of 25 μ? of 12 μ? a uetoheterocycle (Cayman Chemicals, catalog # 10435). The microtiter plate was read in the forecast plate reader.
The crude fluorescence was plotted on the y axis and the concentration of the inhibitor on the x axis gives a curve of inhibition of dose response. The data were adjusted to an equation of competitive inhibition of site, arranging the Km for the human enzyme at 12 μ? and 9 μ ?, respectively.
Other assays that can be used to determine the inhibition of FAAH by the compounds of the present invention include: (1) a fluorescence based assay for fatty acid amide hydrolase compatible with high throughput screening as described in Manjunath et al. , Analytical Biochemistry (2005) 343: 143-151; and (2) a high production selection for the discovery of fatty acid amide hydrolase inhibitors using a fluorescent microsome based assay. Wang et al., Biomolecular Screening (2006) 1-9.
Example 352 Evidence for covalent complex formation between FAA Serine-241 and Isoxazolines Treatment of rat FAAH protein with the irreversible active site-directed inhibitor f methoxy arachidonyl luorophosphonate results in a crystal structure in which methoxy arachidonyl phosphonate is covalently bound to the side chain of Ser-241 (Bracey et al., Science (2002) 298: 1793-1796).
Based on these data, it is hypothesized that the isoxazoline compounds of the present invention form covalent complexes with the nucleophilic side chain of Ser-241. This hypothesis is consistent with the kinetic data, with the nucleophilic attack involving the proposed union of the isoxazoline electrophile by the active site Ser-241, resulting in the elimination of the leaving group from the cytosolic site, and the subsequent formation of an isoxazoline adduct. of covalent enzyme. Subsequent recovery of activity would involve a deacylation reaction, which would occur inefficiently, if at all, for the covalent enzyme isoxazoline adduct.
Recovery of activity experiments was performed via a jump dilution method that involved rapidly diluting the enzyme-inhibitor complex 5 times below its apparent Ki, and measuring activity as a function of time. Little or no enzyme activity was recovered over a period of two hours, indicating essentially irreversible inhibition, or very slowly hydrolysable complex, supporting the anterior hypothesis.
OTHER MODALITIES Those skilled in the art will recognize or be able to ensure by using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Said equivalents should be encompassed by the following claims.

Claims (102)

  1. CLAIMS composed of the formula (I) Ra (I) pharmaceutically acceptable salts thereof, each of Ra, Rb and Rc independently is selected from H, Ci.i0 alkyl and perhaloalkyl, Rd is the group -L-Z, and Z is selected from the aryl of each of Ra, Rb and Rc independently is selected from -H, alkyl of Ci.i0 and perhaloalkyl of Ci-io, Rd is a group -LZ, and Z is selected from heterocyclyl of 3-14 members and 5-14 member heteroaryl; Ra and Rd come together to form a fused ring of carbocyclyl of C3-10 or heterocyclyl of 3-14 members, and Rb and Rc independently are selected from -H, alkyl of d., 0 and perhaloalkyl of Cn.i0; or (V) Rc and Rd come together to form a spiro-fused ring of carbocyclyl of C3-10 or heterocyclyl of 3-14 members, and Ra and Rb independently are selected from-H, C1-10alkyl and perhaloalkyl from C1-10; L is a covalent bond or a divalent C1-6 hydrocarbon group, wherein one, two or three methylene units of L are optionally and independently replaced with one or more oxygen, sulfur or nitrogen atoms; G is selected from -CN, -N02, -S (= 0) Re, -S02Re, -S02NRfRe, -P02Re, -P02ORe, -P02NRfRe, - (C = 0) Re, - (C = 0) ORe , - (C = 0) NRfRe, -Br, -I, -F, -Cl, -ORe, -ON RfRe, -ONRf (C = 0) Re, -ONRfS02Re, -ONRfP02Re, -ONRfP02ORe, -SRe, - OS02Re, -N RfS02Re, -OP02Re, -OP02ORe, -NRfP02Re, -NRfP02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, -NRf (C = 0) Re , -NRf (C = 0) ORe, -0 (C = 0) NRfRe, -NRf (C = NRf) NRfRe, -0 (C = NRf) NRfRe, - N Rf (C = N Rf) 0 Re, - [N (Rf) 2Re] + X ", where X" is a counter ion; where each Re is selected from C1-10 alkyl, C2-io alkenyl. C2-io alkynyl. C3-io carbocyclyl, C6.14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each Rf attached to a nitrogen atom, independently, is selected from -H, C 4 alkyl, or an amino protecting group; or Re and Rf are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring; C1-6 alkyl, C6.14 aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C3 carbocyclyl. 0, Ci.6 hydrocarbon group > C2-10 alkenyl and C2-10 alkynyl, independently, is substituted or unsubstituted. 2. - The compound according to claim 1, wherein each Ra, R and Rc is independently -H, C 1 io alkyl, or C1-10 perhaloalkyl, Rd is the group -LZ, and Z is C6 aryl- 14 3. - The compound according to claim 1, wherein each Ra, Rb and Rc is independently -H, C1- 0 alkyl, or C1-10 perhaloalkyl, Rd is the group -LZ, and Z is 3-heterocyclyl. 14 members 4. - The compound according to claim 1, wherein each Ra, Rb and Rc is independently -H, C 1 io alkyl, or Ci-10 perhaloalkyl, Rd is the group -LZ, and Z is heteroaryl 5- 14 members 5. - The compound according to claim 1, wherein L is a covalent bond or a divalent hydrocarbon group of C1-6, wherein one, two or three methylene units of L 'are replaced with one or more oxygen atoms. 6. The compound according to claim 5, wherein L is a covalent bond. 7. The compound according to claim 5, wherein L is an unsubstituted divalent C 1-6 hydrocarbon group, wherein a methylene unit of L is replaced with an oxygen atom. 8. - The compound according to claim 5, wherein L is -O-. 9. The compound according to claim 1, wherein Ra, Rb and Rc is independently -H, Ci-3 alkyl or C1-3 perhaloalkyl. 10. - The compound according to claim 9, wherein each Ra, Rb and Rc is independently -H, -CH3 or -CF3. 11. The compound according to claim 10, wherein Ra and Rb are -H and R ° is -CH3 or -CF3. 12. The compound according to claim 10, wherein R and R ° are -H and Ra is -CH3 or -CF3. 13. - The compound according to the rei indication 10, wherein each of Ra, Rb and Rc is -H. 14. - The compound according to the rei indication 1, wherein Ra and Rd join to form a carbocyclyl-fused ring of C3.i0, and Rb and Rc are independently -H, C-alkyl or perhaloalkyl of C ^ -io . 15. The compound according to claim 14, wherein Rb and Rc are both -H. 16. The compound according to claim 1, wherein Ra and Rd come together to form a fused ring of heterocyclics of 3-14 members, and Rb and Rc are independently -H, C 1-10 alkyl or Ci perhaloalkyl. 17- 17. The compound according to claim 16, wherein Rb and Rc are both -H. 18. The compound according to claim 1, wherein R ° and Rd come together to form a spiro-fused carbocyclyl ring of C3.10, and Ra and Rb are independently -H, C1.10 alkyl or C-perhaloalkyl. -10. 19. The compound according to claim 18, wherein Ra and R are both -H. 20. - The compound according to claim 1, wherein Rc and Rd come together to form a spiro-fused ring of 3-14 members, and Ra and Rb are independently -H, Ci-10 alkyl or Cyclo-perhaloalkyl. i0. 21. The compound according to claim 20, wherein Ra and Rb are both -H. 22. The compound according to claim 2, wherein Z is phenyl. 23. - The compound according to claim 22, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof; wherein z is 0, 1, 2, 3, 4 or 5; Y each R15 is independently fluorine, bromine, chlorine and iodine, - CN, -NO2, -N3, -S02H, -SO3H, -OH, -OR16, -ON (R18) 2, -N (R1 N (R18) 3 + X \ -N (OR17) R18, -SH, -SR16, -SSR17, -C (= 0) R16, -C02H, -CHO, -C (OR17) 2, -C02R16, -OC (= 0) R16, -OC02R16, -C (= 0) N (R18) 2l -OC (= 0) N (R18) 2, -NR18C (= 0) R16, -NR18C02R16, -NR18C (= 0) N (R18) 2, -C (= NR18) R16, -C (= NR18) OR16, -OC (= NR18) R16, -OC (= NR18) OR16, -C (= NR18) N) R18) 2, - OC (= NR18) N (R18) 2 > -NR 8C (= NR18) N (R18) 2, C (= 0) NR18S02R16, -NR18S02R16, -S02N (R18) 2, -S02R16, -S02OR16, -OS02R16, -S (= 0) R16, -OS (= 0) R16, -Si (R16) 3, - Osi (R16) 3l C (= S) N (R 8) 2 > -C (= 0) SR16, -C (= S) SR16, -SC (S) SR16, -P (= 0) 2R16, -OP (= 0) 2R16, -P (= 0) (R16) 2, -OP (= 0) (R16) 2, -OP (= 0) (OR17) 2l P (= 0) 2N (R18) 2 > -OP (= 0) 2N (R18) 2, -P (= 0) (NR18) 2, -OP (= 0) (NR18) 2 > -NR18P (= 0) (OR 7) 2, -NR18P (= 0) (NR18) 2, -P (R 7) 2, -P (R17) 3, -OP (R17) 2, -OP (R17) 3, -B (OR17) 2, -BR 6 (OR17), C1-10 alkyl, d-??? perhaloalkyl, C2-0 alkenyl, C2 alkynyl. 0, C3.14 carbocyclyl, 3-14 membered heterocyclyl, C6-yl aryl, and 6-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R 9 groups; or two vicinal groups R15 are replaced with the group -0 (C (R2) 2) i20- wherein each R2 is independently H, C-i -6 alkyl or halogen; where each instance of R16 is independently selected from Ci_10 alkyl, perhaloalkyl from CM0i alkenyl of C2.10, alkynyl of C2.10, carbocyclyl of C3- | 4, heterocyclyl of 3-14 members, aryl of C6-i4 and heteroaryl of 5-14 members wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R 8 independently is selected from hydrogen, hydrogen, -OH, -OR16, -N (R7) 2, -CN, -C (= 0) R16, -C (= 0) N (R 7) ) 2, -C02R16, -S02R16, -C (= NR17) OR16, -C (= NR17) N (R17) 2, -S02N (R17) 2, -S02R17, -S02OR17, -SOR16, -C (= S ) N (R17) 2, -C () 0) SR17, -C (= S) SR17, -P (= 0) 2R16, -P (= 0) (R16) 2, -P (= 0) 2N ( R 7) 2, -P (= 0) (NR 17) 2, C 1 -0 alkyl, C 1 -10 perhaloalkyl, C 2 -io alkenyl. C2-io alkynyl. C3-1o carbocyclyl, 3-14 membered heterocyclyl, C6.14 aryl and 5-14 membered heteroaryl, or two R17 groups attached to an N atom come together to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R17 is independently selected from hydrogen, C1.10 alkyl, C1.10 perhaloalkyl, C2-io alkenyl. C2-io alkynyl > carbocyclyl of C3-0, heterocyclyl of 3-14 members, aryl of C6.14 and heteroaryl of 5-14 members, or two groups R7 attached to an atom of N come together to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R19 is independently selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR20, - ON (21) 2 > -N (R21) 2, -N (R21) 3 + X-, -N (OR20) R21, -SH, -SR20, -SSR20, -C (= 0) R20, -C02H, -C02R20, -OC ( = 0) R20, -OC02R2 °, -C (= 0) N (R21) 2, -OC (= 0) N (R21) 2, -NR21C (= 0) R2 °, -NR21C02Ree, -N R21 C ( = 0) (R21) 2, -C (= NR21) OR20, -OC (= NR21) R20, -OC (= NR21) 0R20, -C (= NR21) N (R21) 2, -OC (= NR21) N (R21) 2l -NR 1C (= NR2) N (R21) 2, -NR2 S02R20, -S02N (R21) 2, -S02R20, -S02OR2 °, -OS02R2 °, -S (= 0) R20, -If (R20) 3, -OSi (R20) 3, -C (= S) N (R21) 2l -C (= 0) SR2 °, -C (= S) SR20, -SC (= S) SR20, -P (= 0) 2R20, -P (= 0) 2R20, -P (= O) (R20) 2, -OP (= O) (R20) 2, -OP (= O) (OR 0) 2, alkyl of C1.6, C1-6 perhaloalkyl, C2-6 alkenyl. C2.6 alkynyl, C3 carbocyclyl. 0, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R22 groups, or two R 9 geminal substitutes can be put together to form = 0 or = S; each instance of R20 independently is selected from Ci .6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl C2.6 alkynyl, C3_i carbocyclyl 0, 3-10 membered heterocyclyl, C6-io aryl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R21 independently is selected from hydrogen, C-, 6- alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2.6 alkynyl, C3_i carbocyclyl, 3-10 membered heterocyclyl, C6.10 aryl and 3-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R22 is independently halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -alkyl of OC1-6, -ON (alkyl of d6) 2, -N (Ci_6 alkyl) ) 2, -N (alkyl of d ^ X, -NH (C-6 alkyl) 2X, -NH2 (C 1-6 alkyl) X, -NH 3X, -N (OC 1-6 alkyl) ( de), -N (OH) (C 1-6 alkyl), -NH (OH), -SH, -alkyl of Sd.6, -SS (C 1-6 alkyl), -C (= 0) NH 2 > -C (= 0) N (C 1, 6 alkyl) 2, -OC (= 0) NH (C 1-6 alkyl), -NHC (= 0) (C 1-6 alkyl), - N (C1.6 alkyl) C (= 0) (C1-6 alkyl), -NHC02 (C1-6 alkyl), -NHC (= 0) N (C1-6 alkyl) 2, -NHC ( = 0) NH (Ci-6 alkyl), -NHC (= 0) NH 2, -C (= NH) 0 (alkyl of d-6), -OC (= NH) (alkyl of de), -OC ( = NH) alkyl of OC1-6, -C (= NH) N (C, 6 alkyl) 2, -C (= NH) NH (alkyl of de), -C (= NH) NH2, -OC ( = NH) N (alkyl of) 2, -OC (NH) NH (C 1-6 alkyl), -OC (NH) NH 2, -NHC (NH) N (C 1, 6 alkyl) 2, -NHC (= NH) NH2, NHS02 (Ci-6 alkyl), -S02N (de-alkyl), -S02NH (de alkyl), -S02NH2, -S02C1-6alkyl, -S02alkyl of Od-e, - OS02 C1-6alkyl, -SOalkyl of Ci-6, -Si (to I qui of C1.6) 3, -OSi (alkyl of de, -C (= S) N (C1.6alkyl) 2, C (= S) NH (C, .6 alkyl), C (= S) NH2, -C (= 0) S (alkyl of), -C (= S) S-Ci alkyl. , -SC (= S) S-Ci-6 alkyl, -P (= 0) 2 (Ci-6 alkyl), -P (= 0) (d-eh alkyl. -OP (= 0) (C1.6 alkyl) 2, -OP (= 0) (OC alkyl, .6) 2, Ci-6 alkyl, Ci-6 perhaloalkyl, C2.6 alkenyl, alkynyl of C2-6, carbocyclyl of C3.10, heterocyclyl of 3-10 members, aryl of C6_i0 and heteroaryl of 5-10 members; or two gem-like R22 substitutes can be put together to form = 0 or = S; where X "is a counterion. 24. The compound according to claim 23, wherein R 5 is fluorine, bromine, chlorine and iodine, -OR16, -C (= 0) N (R18) 2, -S02N (R18) 2, C1-10 alkyl , perhaloalkyl of Ci.10, alkenyl of C2. 10, C2-io alkynyl, C6-14 aryl or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups . 25. The compound according to claim 23, wherein z is 1 or 2. 26. The compound according to claim 25, wherein z is 1. 27. - The compound according to claim 26, wherein the compound is of the formula: or a pharmaceutically acceptable thereof 28. The compound according to claim 27, wherein the compound is of the formula: or a pharmaceutically acceptable thereof; wherein R16 is C-10 alkyl, C1.10 perhaloalkyl, C2-io alkenyl, C2-io alkynyl, C3.10 carbocyclyl. 3-14 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R19. 29. The compound according to claim 28, wherein the compound is of the formula: or a pharmaceutically acceptable thereof. 30. The compound according to claim 28, wherein the compound is of the formula: or a pharmaceutically acceptable thereof. 31. The compound according to claim 27, wherein the compound is of the formula: or a pharmaceutically acceptable thereof. 32. - The compound according to claim 25, wherein z is. 33. The compound according to claim 32, wherein the compound is of the formula: R15 34. The compound according to claim 33, wherein the compound is of the formulas: or a pharmaceutically acceptable thereof. 35. The compound according to claim 4, wherein Z is a 5-membered heteroaryl. 36. - The compound according to claim 35, wherein the compound is of the formula: or a pharmaceutically acceptable thereof; wherein Y1, Y2, Y3 and Y4 independently are selected from CH, CR15, O, S, N or NR1B, with the proviso that at least one of Y1, Y2, Y3 and Y4 is O, S, N or NR18; Y each R ñ is independently fluorine, bromine, chlorine and iodine, - CN, -N02, -N3, -S02H, -S03H, -OH, -OR16, -ON (R18) 2, -N (R 8) 2, - N (R18) 3 + X ", -N (OR 7) R18, -SH, -SR 6, -SSR17, -C (= 0) R16, -C02H, -CHO, -C (OR17) 2, -C02R16 , -OC (= 0) R16, -OC02R16, -C (= 0) N (R18) 2, - OC (= 0) N (R18) 2, -NR18C (= 0) R16, -NR 8C02R16, -NR 8C (= 0) N (R18) 2, - C (= NR18) R16, -C (= NR18) OR16, -OC (= NR18) R16, -OC (= NR18) OR16, -C (= NR18) N ) R18) 2, -OC (= NR18) N (R18) 2, -NR18C (= NR 8) N (R18) 2, C (= 0) NR 8S02R16, -NR 8S02R16, -S02N (R 8) 2, -S02R16, -S02OR16, -OS02R16, -S (= 0) R16, -OS (= 0) R16, -Si (R16) 3, -Osi (R16) 3, C (= S) N (R18) 2, -C (= 0) SR16, -C (= S) SR16, -SC (S) SR16, -P (= 0) 2R16, -OP (= 0) 2R16, -P (= 0) (R16) 2, -OP (-0) (R 6) 2, -OP (= 0) (OR17) 2, P (= 0) 2N (R 8) 2, -OP (= 0) 2N (R18) 2, -P (= 0) (NR18) 2, -OP (= 0) (NR18) 2, -NR18P (= 0) (OR17) 2, -NR 8P (= 0) (NR 8) 2, -P (R 17) 2, -P (R 17) 3, -OP (R 17) 2, -OP (R 17) 3, -B (OR17) 2 > -BR16 (OR17), C1-10 alkyl > perhaloalkyl of CT.IO, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-4 aryl, and 6-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups; or two vicinal groups R15 are replaced with the group -0 (C (R2) 2) 120- where each R2 is independently H, C1-6 alkyl or halogen; where each instance of R 6 independently is selected from C 1-10 alkyl, CMA perhaloalkyl, C2_io alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R 9 groups; each instance of R18 independently is selected from hydrogen, hydrogen, -OH, -OR16, -N (R17) 2, -CN, -C (= 0) R16, -C (= 0) N (R17) 2, -C02R16, -S02R16, -C (= NR17) OR16, -C (= NR17) N (R17) 2, -S02N (R17) 2, -S02R17, -S02OR17, -SOR16, -C (= S) N (R 7) 2, -C () 0) SR 17, -C (= S) SR 17, -P (= 0) 2R 16, -P (= 0) (R 16) 2, -P (= 0) 2N ( R17) 2, -P (= 0) (NR17) 2, Ci.10 alkyl, perhaloalkyl of CMo, alkenyl of C2-i0, alkynyl of C2.i0, carbocyclyl of C3.i0, heterocyclyl of 3-14 members , aryl of C6.i and heteroaryl of 5-14 members, or two groups R7 fixed to an N atom is put together to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2 , 3, 4 or 5 groups R19; each instance of R17 is independently selected from hydrogen, C ^-io-alkyl, perhaloalkyl from C-10, alkenyl from C2-io. C2-io alkynyl. carbocyclyl of C3.i0, heterocyclyl of 3-14 members, aryl of C6.14 and heteroaryl of 5-14 members, or two groups R17 attached to an atom of N join to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R19 is independently selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR20, -ON (R21) 2, -N (R21) 2, -N ( R21) 3 + X-, -N (OR20) R21, -SH, -SR20, -SSR20, -C (= 0) R20, -C02H, -C02R2 °, -OC (= 0) R20, -OC02R2 °, -C (= 0) N (R21) 2, -OC (= 0) N (R21) 2, -NR21C (= 0) R20, -NR21C02Ree, -N R21 C (= 0) (R21) 2, -C (= NR2) OR20, -OC (= NR21) R20, -OC (= N R2) 0 R20, -C (= NR21) N (R21) 2, -OC (= NR21) N (R21) 2, -NR21C (= NR21) N (R 1) 2, -NR21S02R20, -S02N (R21) 2, -S02R20, -S02OR20, -OS02R20, -S (= 0) R20, -Si (R20) 3, -OSi (R20) 3, -C (= S) N (R21) 2, -C (= 0) SR20, -C (= S) SR20, -SC (= S) SR20, -P (= 0) 2R20, -P (= 0) 2R20, -P (= O) (R20) 2, -OP (= O) (R20) 2, -OP (= O) (OR20) 2, C1-6 alkyl, C1-6 perhaloalkyl, alkenyl of C2.6, C2.6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6.10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R22 groups, or two R 9 gem substitutes can be put together to form = 0 or = S; each R20 instance independently is selected from Ci.6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl. C2-6 alkynyl, C3-0 carbocyclyl, 3-10 membered heterocyclyl, C6-yl aryl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is substituted independently with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R21 independently is selected from hydrogen, d-6 alkyl. perhaloalkyl of d-6 > C2-6 alkenyl. alkynyl of d-6, carbocyclyl of C3.10, heterocyclyl of 3-10 members, aryl of C6.10 and heteroaryl of 3-10 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is substituted independently with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R22 is independently halogen, -CN, -N02, -N3, -S02H, -SO3H, -OH, -alkyl of OC1-6, -ON (alkyl of d-6) 2, -N (Ci alkyl) .6) 2, -N (Ci-6 alkyl) 3X, -NH (C1.6 alkyl) 2X, -NH2 (Ci-6 alkyl) X, -NH3X, -N (Od.6 alkyl) (C6 alkyl), -N (OH) (C1-6 alkyl), -NH (OH), -SH, -S6 alkyl, -SS (de alkyl), -C (= 0) NH2, -C (= 0) N (alkyl of, -OC (= 0) NH (Ci.6 alkyl), -NHC (= 0) (alkyl of d.6), -N ( d.6) C (= 0) (C 1-6 alkyl), -NHC02 (C 1-6 alkyl), -NHC (= 0) N (C, 6 alkyl) 2l -NHC (= 0) NH (C 1-6 alkyl), -NHC (= 0) NH 2, -C (= NH) 0 (alkyl of d-6), -OC (= NH) (Ci.6 alkyl), -OC (= NH) ) alkyl of OC1-6, -C (= NH) N (C1-6 alkyl) 2, -C (= NH) NH (C1-6 alkyl), -C (= NH) NH2I -OC ( = NH) N (C 1-6 alkyl) 2, -OC (NH) NH (C 1 -s alkyl), -OC (NH) NH 2 1 -NHC (NH) N (alkyl of, -NHC (= NH) NH2, -NHS02 (Ci.6 alkyl), -S02N (C1.6 alkyl) 2, -S02NH (alkyl of). -S02NH2 >; -S02alkyl of d-e, -S02alkyl of OC1-6, -OS02alkyl of d-6, -SOalkyl of C1-6, -Si (Ci-6alkyl) 3, -OSi (C1.6alkyl) 3 > -C (= S) N (C 1-6 alkyl) 2, C (= S) NH (CJ alkyl), C (= S) NH 2, -C (= 0) S (C 1 alkyl) -6), -C (= S) S-alkyl of, -SC (= S) S-alkyl of d.6l -P (= 0) 2 (alkyl of d.6), -P (= 0) (Ci-6 alkyl) 2, -OP (= 0) (alkyl of d_6) 2, -OP (= 0) (alkyl of OC, .6) 2, alkyl of d-6, perhaloalkyl of d-6. C2-6 alkenyl. C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6.10 aryl, and 5-10 membered heteroaryl; or two gem-like R22 substitutes can be put together to form = 0 or = S; where X "is a counterion. 37. The compound according to claim 36, wherein R15 is fluorine, bromine, chlorine, iodine, -OR 6, -C (= 0) N (R 8) 2, -S02N (R 8) 2, alkyl d -io. perhaloalkyl of d-io. C2 alkenyl. 10, C2-i0 alkynyl, C6.14 aryl or 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R 9 groups . 38. - The compound according to claim 36, wherein Y1 is S, Y3 is N, and Y2 and Y4 are independently CH or CR15. 39. The compound according to claim 38, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof. 40. - The compound according to claim 36, wherein Y1 is S, Y3 is N, and Y2 and Y4 are independently CH or CR15. 41. The compound according to claim 40, wherein the compound is of the formulas: or a pharmaceutically acceptable form thereof. 42. - The compound according to claim 1, wherein the compound is of the formula: Rc or a pharmaceutically acceptable form thereof; where: W20, W21, W22 and W23 independently are CH2, CHR 5, C (R15) 2 or NR18; s is 0, 1 or 2; Y each R15 is independently fluorine, bromine, chlorine and iodine, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR16, -ON (R18) 2, -N (R18) 2, -N ( R18) 3 + X ", -N (OR17) R18, -SH, -SR16, -SSR17, -C (= 0) R16, -C02H, -CHO, -C (OR17) 2, -C02R16, -OC ( = 0) R16, -OC02R16, -C (= 0) N (R18) 2, -OC (= 0) N (R18) 2, -NR18C (= 0) R16, -NR18C02R16, -NR18C (= 0) N (R18) 2, -C (= NR18) R1Q, -C (= NR18) OR16, -OC (= NR18) R 16, - OC (= NR 18) 0 R16, -C (= NR18) N) R 8) 2, -OC (= NR18) N (R18) 2, -NR18C (= NR18) N (R18) 2, C (= 0) NR18S02R16, -NR 8S02R16, -S02N (R 8) 2, -S02R16, -S02OR16, -OS02R16, -S (= 0) R16, -OS (= 0) R16, -Yi (R16) 3, -Osi (R16) 3, C (= S) N (R18) 2, -C ( = 0) SR16, -C (= S) SR16, -SC (S) SR16, -P (= 0) 2R16, -OP (= 0) 2R16, -P (= 0) (R16) 2, -OP ( = 0) (R16) 2, -OP (= 0) (OR17) 2, P (= 0) 2N (R 8) 2, -OP (= 0) 2N (R18) 2, -P (= 0) ( NR18) 2, -OP (= 0) (NR18) 2, -NR18P (= 0) (OR17) 2, -NR18P (= 0) (NR18) 2, -P (R17) 2, -P (R17) 3 , -OP (R17) 2, -OP (R17) 3, -B (OR17) 2, -BR16 (OR17), alkyl of d-10, perha loa Iq ui lo of Ci-io, alkenyl of C2-io >C2-10 alkynyl. C3-4 carbocyclyl, 3-14 membered heterocyclyl, C6-aryl, and 6-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups R19; or two vicinal groups R15 are replaced with the group -0 (C (R2) 2) 120- where each R2 is independently H, C1-6 alkyl or halogen; where each instance of R 6 independently is selected from C10 alkyl, perhaloalkyl Ci.i0, C2-io alkenyl. C2-io alkynyl. carbocyclyl of C3-i4, heterocyclyl of 3-14 members, aryl of C6.14 and heteroaryl of 5-14 members wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2 , 3, 4 or 5 groups R19; each instance of R18 is independently selected from hydrogen, hydrogen, -OH, -OR16, -N (R17) 2, -CN, -C (= 0) R16, -C (= 0) N (Rir) 2, -C02R16, -S02R16, -C (= NR17) OR16, -C (= NR17) N (R17) 2, -S02N (R7) 2, -S02R17, -S02OR17, -SOR16, -C (= S) N (R17) 2, -C () 0) SR17, -C (= S) SR17, -P (= 0) 2R16, -P (= 0) (R16) 2, -P (= 0) 2N (R17) 2, -P (= 0) (NR17) 2, alkyl of C-0, perhaloalkyl of C ^ o, alkenyl of C2. 0, C2-io alkynyl. carbocyclyl of C3. 0, 3-14 membered heterocyclyl, Ce-14 aryl and 5-14 membered heteroaryl, or two R 17 groups attached to an N atom come together to form a 3-14 membered heterocyclyl ring or 5-6 membered heterocyclyl ring. 14 members, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R17 is independently selected from hydrogen, alkyl of C-0, perhaloalkyl of Ci. 0, C2-io alkenyl. C2.io alkynyl carbocyclyl of C3.i0, heterocyclyl of 3-14 members, aryl of C6-4 and heteroaryl of 5-14 members, or two groups R17 attached to an atom of N join to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R19 is independently selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR20, -ON (R2) 2, -N (R21) 2, -N ( R2) 3 + X-, -N (OR20) R21, -SH, -SR20, -SSR20, -C (= 0) R20, -C02H, -C02R20, -OC (= 0) R2 °, -OC02R2 °, -C (= 0) N (R21) 2, -OC (= 0) N (R21) 2, -NR21C (= 0) R20, -NR21C02Ree, -NR21C (= 0) (R21) 2, -C (= NR21) OR20, -OC (= NR21) R20, -OC (= NR21) OR20, -C (= NR21) N (R21) 2, -OC (= NR21) N (R21) 2, -NR21C (= NR 1) ) N (R21) 2, -NR21S02R20, -S02N (R21) 2, -S02R20, -S02OR20, -OS02R20, -S (= 0) R20, -Si (R0) 3, -OSi (R20) 3, - C (= S) N (R21) 2, -C (= 0) SR20, -C (= S) SR20, -SC (= S) SR20, -P (= 0) 2R20, -P (= 0) 2R20 , -P (= O) (R20) 2, -OP (= O) (R20) 2, -OP (= O) (OR20) 2, Ci-6 alkyl, C1-6 perhaloalkyl, C2 alkenyl. 6, C2.6 alkynyl, C3-0 carbocyclyl, 3-10 membered heterocyclyl, C6-yl aryl and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently it is substituted with 0, 1, 2, 3, 4 or 5 R22 groups, or two gem substitutes R19 can be put together to form = 0 or = S; each R20 instance independently is selected from C1-6alkyl, Ci-6 perhaloalkyl, C2-6alkenyl, alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R21 independently is selected from hydrogen, C -6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, aryl of C6.10 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R22 is independently halogen, -CN, -N02, -N3. -S02H, -S03H, -OH, -alkyl of OC1-6, -ON (alkyl of d.6) 2, -N (C1-6alkyl) 2, -N (C1.6alkyl) 3X, - NH (Ci_6 alkyl) 2X, -NH2 (de-alkyl), -NH3X, -N (Ci-6 alkyl-alkyl), -N (OH) (d-6 alkyl), -NH ( OH), -SH, -alkyl of SC, .6, -SS (Ci.6 alkyl), -C (= 0) NH2, -C (= 0) N (C1-6 alkyl) 2, -OC (= 0) NH (alkyl of), -NHC (= 0) (alkyl of de), -N (alkyl of de) C (= 0) (alkyl of d.6), -NHC02 (alkyl of d. 6), -NHC (= 0) N (C1.6 alkyl) 2, -NHC (= 0) NH (C1-6 alkyl), -NHC (= 0) NH2, -C (= NH) 0 ( to Iq ui lo of d- 6), -OC (= NH) (C1-6 alkyl), -OC (= NH) alkyl of 0C1-6, -C (= NH) N (C1-6 alkyl) 6) 2, -C (= NH) NH (C, .e) alkyl, -C (= NH) NH2, -OC (= NH) N (C, .6 alkyl) 2, -OC (NH) NH (C1-6 alkyl), -OC (NH) NH2, -NHC (NH) N (Ci.6 alkyl) 2, -NHC (= NH) NH2, NHS02 (C1-6 alkyl), -S02N (C1.6 alkyl) 2, -S02NH (C1-6 alkyl), -S02NH2, -S02C1-6alkyl, -S02alkyl of 0C1-6l -OS02alkyl of C1-6l -SOalkyl of d.6, - S i (to I qui I of C1 - 6) 3, -OS, (C 1 e alkyl, -C (= S) N (C 1-6 alkyl) 2, C (= S) NH (C 1-6 alkyl), C (= S) ) NH 2, -C (= 0) S (C 1-6 alkyl), -C (= S) S- C 1-6 alkyl, -SC (= S) S- C 1-6 alkyl, -P (= 0) 2 (C ^ .6 alkyl), -P (= 0) (C6 alkyl) 2, -OP (= 0) (Ci.6 alkyl) 2, -OP (= 0) (alkyl) of OC1-6) 2, Ci-6 alkyl, C6 -6 perhaloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6.10 aryl, and 5-10 membered heteroaryl; or two gem-like R22 substitutes can be put together to form = 0 or = S; where X "is a counterion. 43. - The compound according to claim 42, wherein s is 0. 44. The compound according to claim 42, wherein W20, W2, W22 and W23 independently are CH2 > CHR 5, C (R15) 2 or NR18. 45. The compound according to claim 44, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof. 46. The compound according to claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof; wherein W24, W25, W26, W27, W28 and W29 independently are CH2, CHR15, C (R15) 2 or NR18, optionally wherein W25 and W26 are substituted with a fused C6 aryl ring or 6-membered heteroaryl ring merged t and v independently are 0 or 1; Y each R15 is independently fluorine, bromine, chlorine and iodine, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR16, -ON (R18) 2, -N (R18) 2, -N ( R18) 3 + X-, -N (OR17) R18, -SH, -SR16, -SSR 7, -C (= 0) R16, -C02H, -CHO, -C (OR17) 2) -C02R16, -OC (= 0) R16, -OC02R16, -C (= 0) N (R8) 2, -OC (= 0) N (R8) 2, -NR18C (= 0) R16, -NR18C02R16, - NR 18 C (= O) N (R 18) 2, - C (= NR18) R16, -C (= NR 8) OR16, -OC (= NR18) R16, -OC (= NR18) OR16, -C (= NR18) N) R18) 2, -OC (= NR 8) N (R18) 2l -NR18C (= NR18) N (R8) 2, C (= 0) NR 8S02R16, -NR18S02R16, -S02N (R18) 2, - S02R16, -S02OR16, -OS02R16, -S (= 0) R16, -OS (= 0) R16, -Si (R6) 3) -Osi (R16) 3l C (= S) N (R18) 2, - C (= 0) SR16, -C (= S) SR16, -SC (S) SR16, -P (= 0) 2R16, -OP (= 0) 2R16, -P (= 0) (R16) 2, - OP (= 0) (R 6) 2, -OP (= 0) (OR17) 2, P (= 0) 2N (R18) 2, -OP (= 0) 2N (R18) 2, -P (= 0 ) (NR18) 2l -OP (= 0) (NR18) 2l -NR 8P (= 0) (OR17) 2, -NR18P (= 0) (NR18) 2, -P (R17) 2, -P (R17) 3, -OP (R17) 2, -OP (R17) 3, -B (OR17) 2, -BR16 (OR17), Ci.i0 alkyl, C1- 0 perhaloalkyl, C2.10 alkenyl, C2 alkynyl -io, carboc iclyl of C3.14, heterocyclyl of 3-14 members, aryl of C6-1 and heteroaryl of 6-14 members wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2 , 3, 4 or 5 groups R19; or two neighborhood R15 groups are replaced with the -0 group. { C { R2) 2) -20- wherein each R2 is independently H, C1-6 alkyl or halogen; where each instance of R16 independently is selected from C1-10 alkyl, C1- 0 perhaloalkyl, C2-io alkenyl, C2.10 alkynyl, C3.1 carbocyclyl, 3-14 membered heterocyclyl, C6 aryl. .14 and 5-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R18 independently is selected from hydrogen, hydrogen, -OH, -OR16, -N (R17) 2, -CN, -C (= 0) R16, -C (= 0) N (R17) 2, -C02R16, -S02R16, -C (= NR17) OR16, -C (= NR17) N (R17) 2, -S02N (R17) 2, -S02R17, -S02OR17, -SOR16, -C (= S) N ( R 7) 2, -C () 0) SR17, -C (= S) SR17, -P (= 0) 2R16, -P (= 0) (R16) 2, -P (= 0) 2N (R17) 2, -P (= 0) (NR17) 2, Ci .- alquilo alkyl, Ci.io perhaloalkyl, C2.10 alkenyl, C2-io alkynyl, C3-0 carbocyclyl, 3-14 heterocyclyl members, C6-14 aryl and 5-14 membered heteroaryl, or two R17 groups attached to an N atom join together to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl ring, wherein each alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R 9 groups; each instance of R17 is independently selected from hydrogen, Ci-10 alkyl, C-0 perhaloalkyl, C2-io alkenyl. C2-io alkynyl. carbocyclyl of C3.i0, heterocyclyl of 3-14 members, aryl of C6-14 and heteroaryl of 5-14 members, or two groups R17 attached to an atom of N join to form a heterocyclyl ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each R19 instance is independently selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR20, -ON (R21) 2, -N (R21.) 2, -N (R21) 3 + X-, -N (OR20) R21, -SH, -SR20, -SSR20, -C (= 0) R20, -C02H, -C02R20, -OC (= 0) R20, -OC02R2 °, -C (= 0) N (R21) 2, -0C (= 0) N (R21) 2, -NR21C (= 0) R20, -NR2 C02Ree, -NR21 C (= 0) (R21) 2, -C (= NR21) OR20, -OC (= NR21) R20, -OC (= NR21) OR20, -C (= NR21) N (R21) 2, - OC (= NR21) N (R21) 2, -NR21C ( = NR2) N (R2) 2, -NR 1S02R20, -S02N (R21) 2l -S02R20, -S02OR20, -OS02R20, -S (= 0) R °, -Yi (R20) 3, -OSi (R0) 3, -C (= S) N (R21) 2, -C (= 0) SR20, -C (= S) SR20, -SC (= S) SR20, -P (= 0) 2R20, -P (= 0) 2R20, -P (= O) (R20) 2, -OP (= O) (R20) 2, -OP (= O) (OR20) 2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2 alkynyl -6, carbocyclyl of C3.10, heterocyclyl of 3-10 members, aryl of C6-io and heteroaryl of 5-10 members, wherein each alkyl, alkenyl, alkynyl, carbokcyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0 , 1, 2, 3, 4 or 5 groups R22, or two gem substitutes R19 can be put together to form = 0 or = S¡ each R20 instance independently is selected from Ci.e alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-0 carbocyclyl, 3-10 membered heterocyclyl, C6 aryl -io and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R21 independently is selected from hydrogen, C1-6 alkyl, C6 -6 perhaloalkyl, C2-6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, aryl of C6.io and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R22 is independently halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -alkyl of OC1-6, -ON (C1-6alkyl) 2, -N (C1-alkyl) -6) 2, -N (C 1-6 alkyl) 3X, -NH (d 6 alkyl) 2X, - NH2 (alkyl of d.6) X, -NH3X, -N (OCi-6 alkyl) (C1-6 alkyl), -N (OH) (C1-6 alkyl), -NH (OH) , -SH, -alkyl of SC1-6, -SS (d-β alkyl), -C (= 0) NH2, -C (= 0) N (C, 6 alkyl) 2, -OC (= 0) NH (C 1-6 alkyl), -NHC (= 0) (C 1-6 alkyl), -N (C 1-6 alkyl) C (= 0) (C 1-6 alkyl), -NHC02 ( C 1-6 alkyl), -NHC (= 0) N (alkyl of d-6) 2, -NHC (= 0) NH (alkyl of Ci.e), -NHC (= 0) NH 2, -C (= NH) 0 (alkyl of), -OC (= NH) (alkyl of d.6), -OC (= NH) alkyl of OC1-6, -C (= NH) N (alkyl of 0, -5) 2, -C (= NH) NH (d-β alkyl), -C (= NH) NH 2, -OC (= NH) N (alkyl of de -OC (NH) NH (alkyl of d. 6), -OC (NH) NH2, -NHC (NH) N (C1-6 alkyl) 2, -NHC (= NH) NH2> -NHS02 (C1-6 alkyl), -S02N (C1 alkyl) -6) 2, -S02NH (alkyl of d.6), -S02NH2l -S02alkyl of C1-6, -S02alkyl of Od. 6, -OS02alkyl of d-6, -SOalkyl of Ci.e, -Si ( C 1-6 alkyl) 3, -OSi (alkyl of d.6) 3, -C (= S) N (alkyl of d.6) 2, C (= S) NH (alkyl of de), C (= S) NH2, -C (= 0) S (alkyl of d.6), -C (= S) S-alkyl of Ci-6, -SC (= S) S-Ci.e alkyl, - P (= 0) 2 (alkyl of d-6), -P (= 0) (alkyl of d-6) 2, -OP (= 0) (C 1-6 alkyl) 2, -OP (= 0) (alkyl of OC1-6) 2, alkyl of, perhaloalkyl of d.6) alkenyl of C2.6, alkynyl of C2-6, carbocyclyl of C3-io, heterocyclyl of 3-10 members, aryl of C6-io and 5-10 membered heteroaryl; or two geminal R22 substitutes can be put together to form = 0 or = S; where X "is a counterion. 47. - The compound according to claim 46, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof: 48. The compound according to claim 46, wherein t is 0, v is 1 and W25 and W26 are substituted with a fused C6 ring of argon, and wherein W27 and W28 are independently CH2, CHR15 and C (R15) 2. 49. - The compound according to claim 48, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof; wherein z is 0, 1, 2, 3 or 4; Y each R 5 is independently fluorine, bromine, chlorine and iodine, CN, -N02, -N3, -S02H, -S03H, -OH, -OR16, -ON (R18) 2, -N (R18) 2, N (R18) ) 3 + X ", -N (OR17) R18, -SH, -SR16, -SSR17, -C (= 0) R16, -C02H, CHO, -C (OR17) 2, -C02R16, -OC (= 0) ) R16, -OC02R16, -C (= 0) N (R18) 2, OC (= 0) N (R18) 2, -NR18C (= 0) R16, -NR18C02R16, -NR18C (= 0) N (R18) 2, C (= NR18) R16, -C (= NR18) OR16, -OC (= NR18) R16, -OC (= NR18) OR16, C (= NR18) N) R 8) 2, -OC (= NR18) N (R18) 2, -NR18C (= NR18) N (R18) 2, C (= 0) NR18S02R16, -NR18S02R16, -S02N (R18 ) 2, -S02R16, -S02OR16, -OS02R16, -S (= 0) R16, -OS (= 0) R16, -Yi (R16) 3, -Osi (R6) 3, C (= S) N ( R18) 2) -C (= 0) SR16, -C (= S) SR16, -SC (S) SR16, -P (= 0) 2R16, -OP (= 0) 2R16, -P (= 0) ( R 6) 2 > -OP (= 0) (R16) 2, -OP (= 0) (OR17) 2, P (= 0) 2N (R18) 2 > -OP (= 0) 2N (R18) 2, -P (= 0) (NR18) 2, -OP (= 0) (NR18) 2 > -NR 8P (= 0) (OR 17) 2l -NR 8P (= 0) (NR 18) 2, -P (R 17) 2, -P (R 17) 3, -OP (R 17) 2, -OP (R 17) 3 , -B (OR17) 2) -BR16 (OR17), alkyl of 1-10, perhaloalkyl of C1.10, alkenyl of C2.10, alkynyl of C2.10, carbocyclyl of C3-14, heterocyclyl of 3-14 members, C6-14 aryl and 6-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R19 groups; or two vicinal R 5 groups are replaced with the group -0 (C (R2) 2) 120- wherein each R 2 is independently H, C 1-6 alkyl or halogen; where each instance of R16 is independently selected from alkyl of d.10. C1-10 perhaloalkyl, C2.10 alkenyl, C2-io alkynyl. carbocyclyl of C3. , 3-14 membered heterocyclyl, C6-i4 aryl and 5-14 membered heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups R19; each instance of R 8 independently is selected from hydrogen, hydrogen, -OH, -OR16, -N (R17) 2, -CN, -C (= 0) R16, -C (= 0) N (R17) 2 , -C02R16, -S02R16, -C (= NR17) OR16, -C (= NR17) N (R17) 2, -S02N (R7) 2 > -S02R17, -S02OR17, -SOR16, -C (= S) N (R17) 2, -C () 0) SR17, -C (= S) SR17, -P (= 0) 2R16, -P (= 0 ) (R16) 2, -P (= 0) 2N (R17) 2, -P (= 0) (NR 7) 2, Ci-i0 alkyl, perhaloalkyl of C-10, alkenyl of C2-io. C2-io alkynyl. C3-10 carbocyclyl, 3-14 membered heterocyclic, C6-14 aryl and 5-14 membered heteroaryl, or two R17 groups attached to an N atom come together to form a heterocyclic ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R17 is independently selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl) C2-i0 alkenyl, C2-10 alkynyl, C3.10 carbocyclyl, 3-14 membered heterocyclic, aryl of C6.14 and 5-14 membered heteroaryl, or two R17 groups attached to an N atom join to form a heterocyclic ring of 3-14 members or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R19 groups; each instance of R19 is independently selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR20, -ON (R21) 2, -N (R21) 2, -N ( R21) 3 + X-, -N (OR20) R21, -SH, -SR20, -SSR20, -C (= 0) R20, -C02H, -C02R20, -OC (= 0) R20, -OC02R2 °, - C (= 0) N (R21) 2, -OC (= 0) N (R1) 2, -NR21C (= 0) R20, -NR21C02Ree, -N R21 C (= 0) (R21) 2 > -C (= NR21) OR20, -OC (= NR2) R20, -OC (= NR21) OR20, -C (= NR21) N (R21) 2, -OC (= NR 1) N (R21) 2, - NR21C (= NR21) N (R21) 2, -NR21S02R20, -S02N (R21) 2, -S02R20, -S02OR20, -OS02R20, -S (= 0) R20, -Si (R0) 3) -OSi (R? 0) 3, -C (= S) N (R21) 2, -C (= 0) SR2 °, -C (= S) SR20, -SC (= S) SR20, -P (= 0) 2R2 °, -P (= 0) 2R20, -P (= O) (R20) 2, - OP (= O) (R20) 2, -OP (= O) (OR20) 2, C1-6 alkyl, C1-6 perhaloalkyl, C2.6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl , 3-10 membered heterocyclyl, C6-io aryl and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 R22 groups, or two gem substitutes R19 can be put together to form = 0 or = S; each R20 instance independently is selected from C1-6alkyl, 0-6 perhaloalkyl, C2.6alkenyl, C2-6 alkynyl. C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-io aryl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R22; Y each instance of R21 independently is selected from hydrogen,?, -? alkyl, C-i_6 perhaloalkyl, C2_6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, C6-io and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R22 groups; Y each instance of R22 is independently halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -alkyl of OCi.6, -ON (alkyl of d. 6) 2, -N (Ci-6 alkyl) 2. -N (Ci.6 alkyl) 3X, -NH (C ^ X alkyl, -NH2 (C1.6 alkyl) X, -NH3X, -N (OC1-6 alkyl) (C1-6 alkyl), -N (OH) (alkyl of de), -NH (OH), -SH, -alkyl of Sd.6, -SS (C1-6 alkyl), -C (= 0) NH2, -C (= 0) N (C1.6 alkyl) 2, -OC (= 0) NH (C1-6 alkyl), -NHC (= 0) (C1-6 alkyl), -N (C1-6 alkyl) 6) C (= 0) (Ci.6 alkyl), -NHC02 (C1-6 alkyl), -NHC (= 0) N (C1-6 alkyl) 2, -NHC (= 0) NH (alkyl) C1-6), -NHC (= 0) NH2, -C (= NH) 0 (C ^ 6 alkyl), -OC (= NH) (C1-6 alkyl), -OC (= NH) alkyl of OC, .6, -C (= NH) N (C 1-6 alkyl) 2, -C (= NH) NH (C 1-6 alkyl), -C (= NH) NH 2, -OC (= NH) N (C 1-6 alkyl) 2 >; -OC (NH) NH (C1-6 alkyl), -OC (NH) NH2, -NHC (NH) N (Ci-6 alkyl) 2, -NHC (= NH) NH2, NHS02 (d. 6), -S02N (C ^ e alkyl, -S02NH (C1-6 alkyl), -S02NH2, -S02C1-6alkyl, -S02alkyl of OC1-6, -OS02alkyl of C -6, -SOalkyl of C1 -6, - S i (to I qui I of C1-5) 3, -OSi (Ci.6 alkyl) 3, -C (= S) N (C1-6 alkyl) 2, C (= S ) NH (Ci.6 alkyl), C (= S) NH2, -C (= 0) S (alkyl of 01-6), -C (= S) S-C1-6 alkyl, -SC (= S) S-Ci_6 alkyl, -P (= 0) 2 (alkyl of 0, 6), -P (= 0) (Ci.6 alkyl) 2, -OP (= 0) (alkyl of d. 6) 2, -OP (= 0) (alkyl of Od.6) 2, C1-6 alkyl, perhaloalkyl of Ci-6, alkenyl of C2.6, alkynyl of C2-6, carbocyclyl of C3.i0, eterocyclyl of 3-10 members, C6-io aryl and 5-10 membered heteroaryl, or two gem R22 substitutes can be put together to form = 0 or = S; where X "is a counterion. 50. The compound according to claim 49, wherein W27 and W28 are both CH2 groups. 51. The compound according to claim 50, wherein the compound is of the formula: or a pharmaceutically acceptable form thereof. 52. The compound according to any of the preceding claims, wherein G is selected from Cl, -Br, -I, -ORe, -ON RfRe, -ONRf (C = 0) Re, -ONRfS02Re, -ONRfP02Re, -ONRfP02ORe, -SRe, -OS02Re, -NRfS02Re, -OP02Re, -OP02ORe, -NRfP02Re, -N RfP02ORe, -OP02NRfRe, -0 (C = 0) Re, -0 (C = 0) ORe, -NRfRe, - NRf (C = 0) Re, -NRf (C = 0) ORe, -0 (C = 0) NRfRe, -NRf (C = NRf) NRfRe, -0 (C = NRf) NRfRe, NRf (C = NRf) ORe, y - [N (Rf) 2Re] + X ~ where X- is a counter ion. 53. The compound according to claim 52, wherein G is -ORe. 54. The compound according to claim 53, wherein Re is C 6-14 aryl. The compound according to claim 54, wherein Re is phenyl. 56. The compound according to claim 55, wherein Re is a monosubstituted phenyl. 57. The compound according to claim 54, wherein Re is a phenyl group of the formula: where: x is 0, 1, 2, 3, 4 or 5; Y each Rh is, independently, fluorine, bromine, chlorine, iodine, - CN, -N02, -N3, -S02H, -S03H, -OH, -OR1, -ON (Rk) 2, -N (Rk) 2, -N (Rk) 3 + X ", -N (OR!) Rk, -SH, -SR? -SSRCC, -C (= 0) R? -C02H, -CHO, -C (ORj) 2, -C02R \ -OC (= 0) Ri, -OC02R \ -C (= 0) N (Rk) 2, -OC (= 0) N (Rk) 2, -NRkC (= 0) R¡, -NRkC02R¡, - NRkC (= 0) N (Rk) 2, -C (= NRk) Ri, -C (= NRk) OR \ -OC (= NRk) Ri, -OC (= NRk) ORi, -C (= N Rk) N) Rk) 2, -OC (= NRk) N (Rk) 2, -NRkC (= NRk) N (Rk) 2, -C (= 0) NRkS02R \ -NRkS02R \ -S02N (Rk) 2, -S02R ¡, -S02OR \ -OS02R \ -S (= 0) Ri, -OS (= 0) R¡, -Si (R¡) 3, -Osi (R¡) 3, -C (= S) N (Rk) ) 2, -C (= 0) SR \ -C (= S) SR¡, -SC (S) SR \ -P (= 0) 2R \ OP (= 0) 2R¡, -P (= 0) ( R1) 2, -OP (= 0) (R1) 2, -OP (= 0) (OR1) 2, -P (= 0) 2N (Rk) 2, -OP (= 0) 2N (Rk) ) 2, -P (= 0) (NRk) 2, -OP (= 0) (NRk) 2, -N RkP (= 0) (OR ') 2, -NRkP (= 0) (NRk) 2, - P (R1) 2, -P (R1) 3, -OP (R1) 2, -OP (R1) 3, -B (OR1) 2, -BR '(OR1), C-alkyl !., 0, perhaloalkyl of C1-10, alkenyl of C2.10, alkynyl of C2.10, carbocyclyl of C3.4, heterocyclyl of 3-14 members, aryl of C6-14 and hetero rile of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of R 'independently is selected from Ci alkyl. 0l perhaloalkyl of C-10, alkenyl of C2.- | 0, C2-io alkynyl > carbocyclyl of C3.14, heterocyclyl of 3-14 members, aryl of C6-14 and heteroaryl of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of Rk is independently selected from hydrogen, -OH, -OR, -N (R,) 2, -CN, -C (= 0) R, -C (= 0) N (Ri) 2 , -C02R \ -S02R \ -C (= NRi) ORi, -C (= NRi) N (Ri) 2, -S02N (Rj) 2, -S02R \ -S02ORj, -SOR ', -C (= S) N (R,) 2, -C (= 0) SRj, -C (= S) SRi, -P (= 0) 2Ri, -P (= 0) (Ri) 2, -P (= 0) 2N ( Rj) 2, -P (= 0) (NRj) 2, alkyl of d.10, perhaloalkyl of Ci.-io, C2-io-alkynyl alkenyl of C2-io. carbocyclyl of C3-14. 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, or two R 'groups attached to an N atom come together to form a 3-14 membered heteroaryl ring or 5-14 heteroaryl ring members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of R, independently is selected from hydrogen, C- | alkyl. 0, perhalo C1-10 alkyl, C2-io alkenyl, C2.10 alkynyl, C3-I4 carbocyclyl, 3-14 membered heterocyclyl, Ce.i4 aryl and 5-14 membered heteroaryl, or two R groups Fixed to an atom of N are joined to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 groups Rm; each instance of Rm independently is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -N3, -S02H, -S03H, - OH, -OR °, -ON (Rn) 2, -N (Rn) 2, -N (Rn) 3 + X ", -N (OR °) Rn, -SH, -SR °, -SSR °, - C (= 0) R °, -C02H, -C02R °, -OC (= 0) R °, -OC02R °, -C (= 0) N (Rn) 2, -OC (= 0) N (Rn) 2, -NRnC (= 0) R °, -NRnC02R °, NRnC (= 0) N (Rn) 2, -C (= NRn) R °, -C (= NRn) OR °, -OC (= NRn) R °, OC (= NRn) OR °, -C (= NRn) N) Rn) 2, -OC (= NRn) N (Rn) 2 > NRnC (= NRn) N (Rn) 2, -NRnS02R °, -S02N (Rn) 2, -S02R °, -S02OR °, -OS02R °, -S (= 0) R °, -OS (= 0) R °, -Si (R °) 3, -OSi (R °) 3, -C (= S) N (Rn) 2, -C (= 0) SR °, -C (= S) SR °, -SC (S) SR °, -P (= 0) 2R °, -OP (= 0) 2R °, -P (= 0) (R °) 2, -OP (= O) (R0) 2, -OP ( = O) (OR0) 2, C 1-6 alkyl, C 6 -perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups, or two gem Rm substitutes can be put together to form = 0 or = S; each instance of R ° independently is selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl. C2.6 alkynyl, C3_i carbocyclyl, 3-10 membered heterocyclyl, C6-1 aryl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups; each Rn instance is independently selected from hydrogen, d.6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, aryl of C6-i4 and 5-10 membered heteroaryl, or two Rn groups attached to an N atom come together to form a 5-14 membered heterocyclyl ring or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups; Y each instance of R independently is fluorine (-F), bromine (- Br), chlorine (-CI) and iodine (-I), -CN, -N02, -N3, -S02H, -S03H, -OH, -alkyl of OCi.6, -ON (alkyl of 1-6) 2, -N (Ci.6 alkyl) 2, -N (Ci 6 alkyl) 3X, -NH (C1.6 alkyl) 2X, -NH2 (C1-6 alkyl) X, -NH3X, -N (alkyl of Od-6) (alkyl of d-β). -N (OH) (C1-6 alkyl), -NH (OH), -SH, -alkyl of SC1-6, -SS (alkyl of de), -C (= 0) NH2, -C (= 0 ) N (alkyl of, -OC (= 0) NH (C1-6 alkyl), NHC (= 0) (C1-6 alkyl), -N (C1.6 alkyl) C (= 0) (alkyl of), -NHC02 (alkyl of), -NHC (= 0) N (alkyl of de) 2, NHC (= 0) NH (alkyl of de), -NHC (= 0) NH2, -C (= NH) 0 (to Iq ui lo of d-6), -OC (= NH) (alkyl of C, .6), -OC (= NH) alkyl of OC, .6, -C (= NH) N (alkyl of) 2, -C (= NH) NH (at Iq of de), -C (= NH) NH2, -OC (= NH) N (alkyl of, -OC (NH) NH (at Iqu i lo of d.6), -OC (NH) NH2, -NHC (NH) N (C1.6 alkyl) 2, -NHC (= NH) NH2, NHS02 (alkyl of ), -S02N (C1-6 alkyl) 2, -S02NH (de alkyl), -SO2NH2, -S02alkyl of d-6, -S02alkyl of OC, .6, - OS02alkyl Ci-6, -SOalkyl Ci-6, -Si (Ci.6alkyl) 3, -OSi (C1-6alkyl) 3, -C (= S) N (C1.6alkyl) 2 , C (= S) NH (C 1-6 alkyl), C (= S) NH 2, -C (= 0) S (C 1-6 alkyl), -C (= S) S-C 1 alkyl -6, -SC (= S) S-C 1-6 alkyl, -P (= 0) 2 (C 1-6 alkyl), -P (= 0) (C 1-6 alkyl) 2. -OP (= 0) (C1.6 alkyl) 2, -OP (= 0) (OC alkyl, .6) 2, Ci-6 alkyl, C1.6 perhaloalkyl, C2_6 alkenyl, C2 alkynyl -6 > carbocyclyl of C3.10, heterocyclyl of 3-14 members, aryl of C6-14 and heteroaryl of 5-14 members; or two gem Rp substitutes can be put together to form = 0 or = S; where X "is a counterion. 58. The compound according to claim 57, wherein Rh is fluorine, bromine, chlorine, iodine, -CN, -N02, -OH, -OR \ -SR \ -N (Rk) 2, -N (Rk) 3 + X ", -C (= 0) Ri, -C02R \ -C02H, -OC (= 0) R1, -OC02R \ -C (= 0) N (Rk) 2, -OC (= 0) N ( Rk) 2, -NRkC (= 0) R \ -NRkC02R¡, -NRkC (= 0) N (Rk) 2, -C (= 0) NRkS02R¡, -NRkS02R¡, -S02N (Rk) 2, -S02R Ci_i0 alkyl, C6 aryl, or 5-6 membered heteroaryl, wherein each alkyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3 or 4 Rm groups, and wherein X "is a counter ion . 59. The compound according to claim 58, wherein Rh is -C (= 0) R \ -C02H, -S02R¡, or 5-membered heteroaryl independently substituted with 0 or 1 Rm group. 60. The compound according to claim 59, wherein the 5-membered heteroaryl is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl. 61. The compound according to claim 57, wherein the phenyl group is a monosubstituted phenyl group of any of the formulas: 62. The compound according to claim 57, wherein the phenyl group is a disubstituted phenyl group of any of the formulas: 63. The compound according to claim 53, wherein G is -0R6 is: CN 564 64. The compound according to claim 53, wherein Re is 5-14 membered heteroaryl. 65. The compound according to claim 64, wherein Re is a 6-membered heteroaryl. 66. The compound according to claim 65, wherein Re is a pyrindinyl group. 67. The compound according to claim 66, wherein Re is a monosubstituted pyrindinyl group. 68. The compound according to claim 66, wherein Re is a 3-pyridinyl group. 69. - The compound according to claim 66, wherein Re is a pyrindinyl group of the formula: x is 0, 1, 2, 3 or 4, and each R is, independently, fluorine, bromine, chlorine, iodine, -CN, -N02, -N3, -S02H, -S03H, -OH, -OR -ON (Rk) 2, -N (Rk) 2, - N (Rk) 3 + X ", -N (OR!) Rk, -SH, -SR? -SSRCC, -C (= 0) R? -C02H, -CHO, -C (ORi) 2, -C02R? -OC (= 0) Rj, -OC02R \ -C (= 0) N (Rk) 2, -OC (= 0) N (Rk) 2, -NRkC (= 0) Rj, -NRkC02Rj, - NRkC (= 0) N (Rk) 2, -C (= NRk) R \ -C (= NRk) OR \ -OC (= NRk) Ri, -OC (= NRk) OR \ -C (= NRk) N ) Rk) 2, -OC (= NRk) N (Rk) 2, -NRkC (= NRk) N (Rk) 2, -C (= 0) NRkS02R¡, -NRkS02R \ -S02N (Rk) 2, -S02Ri , -S02OR \ -OS02R¡, -S (= 0) Ri > -OS (= 0) R \ -S¡ (R¡) 3, -Osi (R¡) 3, -C (= S) N ( Rk) 2, -C (= 0) SR \ -C (= S) SR¡, -SC (S) SR¡, -P (= 0) 2R \ -OP (= 0) 2R¡, -P (= 0) (R¡) 2, -OP (= 0) (R¡) 2, -OP (= 0) (OR¡) 2, -P (= 0) 2N (Rk) 2, -OP (= 0) 2N (Rk) 2, -P (= 0) (NRk) 2, -OP (= 0) (NRk) 2, -NRkP (= 0) (ORj) 2, -NRkP (= 0) (NRk) 2, -P (R1) 2, -P (R ') 3, -OP (R') 2, -OP (Rj) 3, -B (ORi) 2, -BR '(OR'), C-alkyl 10, perhalo C1-10 alkyl, C2.0 alkenyl, C2-10 alkynyl, C3.1 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and oaryl of 5-14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of R 'independently is selected from C 1 -io alkyl, perhaloalkyl of C-i.m, alkenyl of C2_i0, alkynyl of C2.10, carbocyclyl of C3.1, heterocyclyl of 3-14 members, aryl of C6. 4 and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each Rk instance is independently selected from hydrogen, -OH, -OR1, -N (Rj) 2, -CN, -C (= 0) R \ -C (= 0) N (R \) 2, -C02R¡, -S02R¡, -C (= NR ') OR \ -C (- NR') N (R¡) 2, -S02N (Rj) 2, -S02R¡, - S02OR ', -SOR¡ , -C (= S) N (Rj) 2 > -C (= 0) SRj, -C (= S) SRj, -P (= 0); 2R \ -P (= 0) (R¡) 2, -P (= 0) 2N (Rj) 2, - P (= 0) (NRi) 2, alkyl of d.10, perhaloalkyl of C1-10, alkenyl of C2-io. C2-10 alkynyl, C3 carbocyclyl. 4, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, or two Rj groups attached to an N atom come together to form a heterocyclyl ring of 3-14 members or heteroaryl of 5- 14 members, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rm groups; each instance of R 'independently is selected from hydrogen, Ci_10 alkyl, Ci-0 perhaloalkyl, C2-io-C2-io alkynyl alkenyl, C3i carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, or R1 groups attached to an N atom come together to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0 , 1, 2, 3, 4 or 5 Rm groups; each instance of Rm independently is selected from fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-I), -CN, -N02, -N3, -S02H, -SO3H, - OH, -OR °, -ON (Rn) 2, -N (Rn) 2, -N (Rn) 3 + X \ -N (OR °) R ", -SH, -SR °, -SSR °, - C (= 0) R °, -C02H, -C02R °, -OC (= 0) R °, -OC02R °, -C (= 0) N (Rn) 2, -OC (= 0) N (Rn) 2, -NRnC (= 0) R °, -NRnC02R °, NRnC (= 0) N (Rn) 2, -C (= NRn) R °, -C (= NRn) OR °, -OC (= NRn) R °, OC (= NRn) OR °, -C (= NRn) N) Rn) 2, -OC (= N Rn) N (Rn) 2, NRnC (= NRn) N (Rn) 2, -NRnS02R °, -S02N (Rn) 2, -S02R °, -S02OR °, -OS02R °, -S (= 0) R °, -OS (= 0) R °, -Si (R °) 3, -OSi (R °) 3, -C (= S) N (Rn) 2, -C (= 0) SR °, -C (= S) SR °, -SC (S) SR °, -P (= O) 2R0, -OP (= 0) 2R °, -P (= 0) (R °) 2, -OP (= 0) (R °) 2, -OP ( = 0) (OR °) 2, C 1-6 alkyl perhaloalkyl of C 1-6 > C2-6 alkenyl, C2.6 alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups, or two gem Rm substitutes can be put together to form = 0 or = S; each instance of R ° independently is selected from Ci.6 alkyl > Ci.6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3_10 carbocyclyl, 3-10 membered heterocyclyl, C6.14 aryl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl , carbocyclyl, heterocyclyl, aryl and heteroaryl independently are substituted with 0, 1, 2, 3, 4 or 5 Rp groups; each Rn instance is independently selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2.6 alkynyl, C3.10 carbocyclyl, 3-10 membered heterocyclyl, aryl of C6.14 and 5-10 membered heteroaryl, or two Rn groups attached to an N atom come together to form a 3-14 membered heterocyclyl ring or 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3, 4 or 5 Rp groups; Y each instance of Rp independently is fluorine (-F), bromine (-Br), chlorine (-CI) and iodine (-1), -CN, -N02, -N3l -S02H, -S03H, ^ OH, -alkyl OC | .6, -ON (C1.6 alkyl) 2, -N (C1-C6 alkyl) 2, -N (Ci.6-alkyl) 3X, -NH (C1.6-alkyl) 2X, -NH2 (C 1-6 alkyl) X, -NH 3X, -N (OCi-6 alkyl) (C 1-6 alkyl), -N (OH) (C 1-6 alkyl), -NH (OH), -SH , -alkyl of SC1-6, -SS (C 1-6 alkyl), -C (= 0) NH 2, -C (= 0) N (C 1-6 alkyl) 2, -OC (= 0) NH ( C1-6 alkyl), NHC (= 0) (Ci-6 alkyl), -N (Ci.6 alkyl) C (= 0) (C1-6 alkyl), -NHC02 (alkyl), of C1-6), -NHC (= 0) N (C 1-6 alkyl) 2, NHC (= 0) NH (C 1-6 alkyl), -NHC (= 0) NH 2, -C (= NH) 0 (at which C, 6), -OC (= NH) (C 1-6 alkyl), -OC (= NH) alkyl of OC 1-6, -C (= NH) N (alkyl) of Ci.6) 2, -C (= NH) NH (C 1-6 alkyl), -C (= NH) NH 2, -OC (= NH) N (C, 6 alkyl) 2, - OC (NH) NH (at Iq of C1-8), -OC (NH) NH2, -NHC (NH) N (Ci-6 alkyl) 2, -NHC (= NH) NH2, NHS02 (alkyl) Ci-6), -S02N (C, .6 alkyl) 2, -S02NH (C1 alkyl) -6), -S02NH2, -S02C1-6alkyl, -S02alkyl of OC1-6, -OS02alkyl of Ci-6, -SOalkyl of C1-6, -Si (to Iq one of C1.6) 3, -OSi (C 1-6 alkyl) 3, -C (= S) N (C 1-6 alkyl) 2, C (= S) NH (C 1-6 alkyl), C (= S) NH 2, -C (= O) S (C 1-6 alkyl), -C (= S) S-C 1-6 alkyl, -SC (= S) S- C 1-6 alkyl -P (= 0) 2 ( Ci-6 alkyl), -P (= 0) (C1.6 alkyl) 2, -OP (= 0) (C1.e alkyl) 2, -OP (= 0) (OC alkyl, _6) 2, Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2.6 alkynyl, C3.i0 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 heteroaryl. members; or two gem Rp substitutes can be put together to form = 0 or = S; where X "is a counterion. 70. The compound according to claim 69, wherein h is fluorine, bromine, chromium, iodine, -CN, -N02, -OH, -OR1, -SR -N (Rk) 2, -N (Rk) 3 + X ", -C (= 0) R \ -C02R¡, -C02H, -OC (= 0) R \ -OCOzR1, -C (= 0) N (Rk) 2, -OC (= 0) N (Rk) 2, -NRkC (= 0) Rj, -NRkC02Rj, -NRkC (= 0) N (Rk) 2, -C (= 0) NRkS02R \ -NRkS02R \ -S02N (Rk) 2, -S02R C1.10 alkyl, C6 aryl or 5-6 membered heteroaryl, wherein each alkyl, aryl and heteroaryl independently is substituted with 0, 1, 2, 3 or 4 Rm groups, and wherein X "is a counterion. 71. The compound according to claim 70, wherein Rh is -C (= 0) R, -C02H, -S02R or 5-membered heteroaryl independently substituted with 0 or 1 Rm group. 72. The compound according to claim 71, wherein the 5-membered heteroaryl is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl. 73. The compound according to claim 68, wherein the pyridinyl group is a 3-pyridinyl group of the formulas: 74. The compound according to claim 66, wherein G is -ORe of the formulas: 572 573 75. The compound according to claims 1-74, wherein the compound is substantially enantiomerically pure form. 76. The compound according to claim 1, wherein the compound is a compound of the formulas: 1-1 to I-76, I-77, I-78, I-82, I-83 to I-90, 1 -91, I-92 to I-238, I-240 to I-246, I-248 to I-251, I-253, I-255 to 1-261, 11-1 to 11-18, 11-19 , II-20, 11-21 to 11-31, 111-1 to III-4, III-8 to 111-41, III-42, III-43 to III-60, 111 -62 to III-64, III -66 to III-68, III-70, 111-71, III-73, or III-74, or a pharmaceutically acceptable form thereof: Compound G Ra Rc 1-10 -Br | H 1-17 -Cl -H -H I-23 -H -H I-24 e -H -H I-25 -H -H F XOA 1-26 -? -? 1-27 FIA A -? NC ^ -? 1-28 -? -? CN 1-29 -? -? 1-30 Me. J? -? -? 1-31 -? -? I-32 -? -? e? » I-33 -? -? I-34 6? -? -? ? ? I-35 -? -? I-36 -? -? I-37 -? -? I-39 -? -? Me02C ^^ OA I-40 Me. / ?. -? -? 1-41 -? -? d0A 1-42 -H 1-43 -H 1-44 Me -H- JL0A 1-45 -OMe -H -H 1-47 -H -H H2N. JL0A 0 1-56 F3C N -H -H 1-57 -H H 1-58 CN -H -H 1-59 -H -H F 1-60 CF3 -H -H 1-61 C02Me -H -H 0L0A I-62 -H -H I-63 Me -H- 0 = S = 0 1-64 NH2 -? -? 0 = S = 0 1-65 -? -? 1-66 MeO ^ N -? -? 1-67 Me02C. / N. -? -? 1-68 H N -? -? 1-69 -? -? 1-90 H2N / P -? -? 1-92 BocHN ^. -? -? 1-93 V -? -? 1-94 XV -? -? 1-98 I 0 V -? -? MeO. / \ ^? ^ Y" 1-99 0 XV -? -? -100 0 k -? -? ^ NL ?2? / X / \ ^ -110 H02C? -? -? U ^ oA 1-111 -H -H Me k ^ 0 1-146 C02H -H 1-147 H02C ^^ -H -H 1-155 Me -H- 1-159 Me -H- 1-160 Me -H- 1-197 -H -H Me ^ S / 0 N I-243 - H - H H I-244 -H -H 0 Me I-245 -H -H OH I-256 - H -H I-257 Me -H -H 1-260 0 -H -H Me 0 1-78 -Br -CH3 -H (cis) 1-82 -Br -CH3 -H (trans) 1-91 -CH3 -H (trans) I-76 -Br -H-CH3 I-89 -H - C H 3 1-130 -Br -HCF3 1-131 o. -H -CF3 I-95 -Br -H - C H 2 C H 3 N '° \ / = \ r c Ra Compound G Ra Rc 1-14 -Br -H -H I-46 -H -H I-53 -H -H 0 I-54 -H -H 0 I-55 -H -H H02C ^^ OX I-70 -H -H 1-71 -H -H 1-72 N -H -H 1-73 NH2 ^ -H -H 1-83 -H -H 1-84 0 U-oX -H H EtOsXJl ^ 0 k 0A ' 1-85 -H -H or UL0A 1-86 -H -H 1-96 0 -H -H 1-97 MX 0 > -H H -105 0 -H -H -106 0 -H -H H N -107 0 -H -H -108 -? -? MeA Me -0? X -109 0 -? -? -112 -? -? -118 -? -? -128 0 -? -? -132 MeS ^ -? -? -133 -? -? -134 MeS -? -? -135 -? -? Me ^ Q // 0? -136 MeO ^ N -? -? -151 -? -? -152 -? -? -157 Me -? -? -161 -H -H -162 -H -H -163 -H -H -165 -H -H -173 -H -174 N = N -H - H ^ NH -175 N-NH -H - H -176 C02H - H -H -177 H02? C ^? ^ ?? - H -H -178 -H -H -182 0 - H -H -183 -H -H -184 -H -H * 0 ^ ?? -186 -H -H X0A -187 -H -H -188 H02C ^ f jl N -H -H -189 -H -H I k ^ JL? -190 Me -H -H -191 -H -H Me -192 -H ??? N H L 1 -193 -H -H -194 -H -195 -H -H N H 1 1-199 Me -H- I-200 -H -H 1-201 -H 1-218"Me" O- -H -H I-220 -H -H 1-221 N-N -H -H V I-223 Me -H- ? V = N ? I-224 Me -H- "= ??? I-225 / = n, -H -H ?? * 1-226 / = "-? -? 1-230 A -? -? 1-236? ~ ?? -? -? 1-246 -? -? ? ?? 1-248 -? -? 1-249 -? -? 0 1-250 -? -? o o 1-251 -? -? I-253 -? -? I-255 -? -? Me I-258 -? -? ???? I-75 -Br -? -CH3 1-88 -H-CH3 -113 H02C N -H -CH3 -114 0 -H -CH3 -115 or -H-CH3 -116 -H -CH3 -117 -H -CH3 -129 -H -CH3 -154 -H -CH3 -156 Me -H -CH3 -158 Me -H -CH3 -164 fl -H -CH3 1-167 -H -CH3 Me ^ S N 1-171 * XV N \ -H -CH3 H02C ^ 1-172 -H-CH3 ??? 1-185 -H-CH3 1-196 -H-CH3 1-198 -H-CH3 I-222 Me -H-CH3 ° ?? I-227 -H-CH3 O ^ N I-228 - H-CH3 ? ¾? 0? I-229 Me - H -CH3 1-231 0 -? -CH3 -NH I-232 / =? -? -CH3 I-233 Me ", Me ? -? -CH3 or = s = o I-234 Me ^ P -? -CH3 I-235 Me -? -CH3 ? ? I-240 Me -? -CH3 1-241 -? -CH3 I-242 -? -CH3 1-261 MeS ^ N -? -CH3 kA0A Compound G 1-168 -H 1-169 -H Me- N 1-170 H02C N -H -H 1-216 -H 1-217 -H -H 1-219 Me -H- I-238 MeS. .N. -H H ??? I-259 Me -H- R15 ~ i ^ 0CF3 Ra Compound G Ra Rc R15 = halogen 1-120 -Br -H -H -F 1-121 -H -H -F 1-122 Me02C ^ N ^ -H -H -F 1-123 H02C ^ -H -H -F 1-124 -Br -H -H -Cl 1-125 -H -H -Cl lV - ° -Rie Ra Compound G Ra Rc R16 = unsubstituted alkyl, alkynyl 1-142 -Br -H -H 1-143 -H 1-144 MeC ^ C ^ N -H -H 1-145 H < NC N -H -H 1-140 H02C N -H - H Me V-Me 1-141 -H -H Me O »V-Me \ 1-15 -Br -H -H Me V-Me 1-137 Me02C. JvL -H -H n-buti what 1-138 H02C -H - H n-buti lo 1-139 -H -H n-buti what I-6 -Br -H -H -CH3 I-38 -H -H -CH3 I-77 -Br -CH3 -H-CH3 (trans) G \ R - 7 Ra Compound G Ra Rc R1S = alkyl, ari lo I-20 -Br -H-n-butyl 1-180 -H -H n-butyl 1-181 O -H -H n-buti what 1-179 -Br -H -H n-pentyl 1-102 -Br - H -CH3 -C6H5 1-104 -H -CH3 -C6H5 I-9 |¾ -Br -H -H -C6H5 1-101 -H -H -C6H 5 1-103 -H -H -CeH 5 Compound G R = halogen I-3 -Br -Cl 1-153 -Cl 1-148 -Br -Br 1-149 e02 (-Br? 0? 1-150 H02C N -Br I-237 -Br Me ^ N I-2 -Br -F Ra C N Compound G Ra Rc 1-12 -Br -H -H I-87 -H -H Ra Compound G Ra Rc 1-1 -Br -H -H 1-166 -H -H R2 2 Ra Compound G Ra Rc R2 = H, halogen 1-126 -Br -H -H -F, -F 1-127 -H -H -F, -F 1-16 -Br -H -H -H Ra Laugh Compound G Ra Rc R18 I-22 -Br -H -H, -CH2Ph 1-214 0 -H -H H, -CH2Ph 1-215 H02C N -H -H H, -CH2Ph I-203 -Br -H -H -CH3, -CH3 1-212 -H -H -CH3, -CH3 Me // 0 /. I-202 -Br -H -H I-204 -Br -H -H -H, -CH3 I-208 -Br I-209 -Br -H -H Compound G Ra Rc I-205 -Br -H - H I-207 -Br -H -H -H, -CH3 I-206 -Br -H -H -CH3, -CH3 1-210 -Br -H -H 1-211 -Br -H -H -H -H -CH3, -CH3 6'X) L O? Cl Cl N'0v / = Br I-4 I-5 OMe MeO Br ^^ I-7 I-8 1-11 1-13 F F < ^ N 1-119 Me 1-18 1-19 1-21 0 NA N '° v I-49 I-48 1-51 I-50 jl) - < \ -C02 e I-52 I-74 Compound G Ra Rc 11-6 -Br -H -H 11-21 -H -H II-28 || 0 -H -H 11-18 -Br -H -CH3 eleven - . eleven - . 11 -22 -H-CH3 eleven - . 11 - 23 -H-CH3 II-29 -H-CH3 Me ^ SP N 11-19 -Br -CH3 -H (cis) eleven - . eleven - . 11 -20 -Br -CH3 -H (trans) Ra l N Compound G Ra Rc II-25 -Br -H -H 11 -26 - H -H II-27 H02C ^ -H -H Compound G Ra Rc 11-8 -Br -H -H 11-31 -H OH II-30 -H -H l H OH N? '° v / - \ ? -? N-R18 RA Compound G R Ra Rc 11-15 -Br -H -H 11-16 -Br -H -H or Br Br ^^ "" ^ 11-1 11 - 2 N '° v / N = \ 11 - 3 n-4? II-5 II-7 Br \ - / 11-9 11-10 N '° A Br \ / Br ^^ (N Jl 11-11 Me 11-12 N '° v / = \ H 11-13 0 ^ 11-14 Me II-24 11-17 Compound G R18 III-27 -Br III-48 -Cl 111-51 III-52 111-18 -Br O III-46 III-59 & 111 -. 111 -. 111 -. 111 -. 111 -. 111 - 60 Me 0 111-16 -Br 111 -. 111 -. 111 -. 111 -. 111 -. 111 -. 111 -. 111 -. 111 -. 111 -. 111 -. 111 - 58 6 x 111 -49 -Br Ib 111 - 50 \ % III-9 -Br or- III-47 -Cl ° o- 111-53 or 111-14 -Br -H 111-15 -Br Me 111-17 -Br 111-19 -Br III-20 -Br Cl 111-21 -Br O e III-22 -Br 111 - 23 -Br III-24 -Br Me III-25 -Br Cl III-26 -Br CF3 111-28 -Br 111-29 -Br 111-30 -Br 111-31 -Br 111 - 32 -Br 111 - 33 -Br 111 - 34 ^ 0 -Br 111 -35 -Br OMe III-36 0 -Br K ° "\ V_-Me Me III-37 -Br 111 - 33 -Br ° ~ VCI Cl Cl III-39 -Br OMe 111-40 -Br Cl 111-41 or i- < < Me -Br III-54 < ? III-55 or F 1 A Cl 111 - 56 F 1 A 111-57? 0 ?? _ / F 1 A I- -CF3 R18 (fusion of cis ring) Compound G III-43 -Br V 0 xx x III-44 -Br 0 III-45 -Br N-0 J / TV JR15 Compound G R 111 -63-Br III-64 111 - 66 -Br -OCF3 III-67 MeS ^ N -OCF3 111 - 68? ^ ?? -OCF3 Me ^ s' ° N 111 - 70 Me -OCF3 111-71 -OCF3 III-73 -OCF3 N < JL0X III-74 -OCF3 Br Br III-1 111-2 BrXX) Br? 111 - 3 111-4 Br 111-8 111-10 o / 0 111-11 111-12 111-13 III-42 (fusion of cis ring)? -? N '° \ M Br ~ "^ III-62 77. - The compound according to claim wherein the compound is: -3a I-3b 604 1-16a 1-16b 1-19a l-19b 606 607 608 Me \ l-44a l-44b -OR MeO / \ MeO l-45a l-45b "OCF-, e02C O Me02C l-46a l-46b l-48a l-48b -0 N ~ °, Br O Br 'O l-52a l-52b l-60a 1-60 b C02Me DO NOT. / = 1-61 to 1-61 b Me02C l-62a l-62b l-63a l-63b l-85a l-85b l-92a -92 b 615 1-105a l-105b O o 1-106a OR 1-107a OR 1-108a 1-108b O O OR 1-113a 1-113b l-121a 21b F 1-122a 1-122b F 1-125a 1-125b F 1-126a l-126b F 1-127a 0 1-129a l-129b 1-133a l-133b 1-138a 1-138b -O, / = \ Me? ¾ ^ 0 · 1-139a 1-139b Me H02C N) - Me H02C -OR l-140a l-140b Me - Me -OR OR l-141a Br l-142a - or 1-143a l-143b // OR 1-144a 1-144b 1-145a 1-145b 1-146a l-146b H02C H02C -OR 1-147a 1-147b l-151a l-151b H02C O H02C 1-152a 1-153a 1-153b OCF, Me Me ~ o Me 1- 56a l-156b 1-157a 1-157b 1-159a Me I-162a I-162b 1-166a 1-166b 1-170a 1-170b OCF-, OCF-, Me 1-171 to l-171b OCF, 1-172b OCF, 0CF3 1-173a = N N = OCF, 0 l-174a l-174b OCF-, l-175a l-175b C02H -OCF, OCF-, OR 1-1 6a l-176b H02C -O OCF, OR Do not OCF, OR l-178a 1-178b 1-182a 1-182b OR 1-183a Me or' 1-184a OCF, 1-185a OCF, l-186a 1-186b OCF, H02C OCFq 1-189a 1-189b 1-190a l-190b F, C l-191a l-191 b OCF, OCF-, 1-192a 1-192b H02C OCF, OCF, I-194a I-194b 1-196a 1-196b l-201a 1-201 b HN-Me l-204a l-204b l-205a l-205b 0 e Br O Me l-206a l-206b Q Me Br O l-207a l-207b OR Br l-208a Br l-209a l-209b 1-21 Oa l-210b 1-211a 1-211b , 0 O Me O 'N-Me Me 1-212a 1-212b Me ^ / ^? - Or Me? ¾¾ / ^? - O f 1-213a l-213b 1-216a 1-216b -CF OR 1-217a l-217b OCF, 1-218a l-218b 631 l-230a l-230b O. OCF3 OCF3 1-231 b 1-231 a OCF3 l-232a Me.k ,, Me Me.k ,, Me N N OCF3 OCF3 or = s = o OR' l-233b l-233a OCF3 OCF3 N -O Me OR l-234b l-234a l-237b l-237a 634 O l-249a O l-249b l-256a l-256b 11-1 Oa IMOb 11-11a 11-11b ll-17a ll-17b 639 ll-26b lll-3a lll-3b l-8b or O lll-10a -10b Br Br or -11a -11b N Br OR 111-12a -12b N ' Br lll-13a Me Br IIJ-41a lll-41b H H H Br Br Br OR O? l-42a lll-42b III-42C l-42d -43a -43b III-66a III-66b SMe SMe F3CO F3CO ' lll-67a lll-67b -Me F CO F3CO -68a N-Me F3CO ÍII-70b F, CO F3CO lll-71a -71b F3CO F3CO F, CO l-74a -74b a pharmaceutically acceptable form thereof. 78. - The compound according to claim 1, wherein the compound is: 644 N VCH3 OR 0CF3 or or a pharmaceutically acceptable form thereof. 79. The compound according to claim 78, wherein the compound is an (R) -enantiomer. 80. - The compound according to claim 1, wherein the compound is OR OCF3 or a pharmaceutically acceptable form thereof. 81. - The compound according to claim 1, wherein the compound is or a pharmaceutically form thereof. 82. - The compound according to claim 1, wherein the compound is OCF3 or a pharmaceutically acceptable form thereof. 83. - The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable form thereof. 84. - The compound according to claim 1, wherein the compound is OCF3 or a pharmaceutically acceptable form thereof. 85. - The compound according to claim 1, wherein the compound is OCF3 or a pharmaceutically acceptable form thereof 86. - The compound according to claim 1, wherein the compound is CF3 or a pharmaceutically acceptable form thereof. 87. - The compound according to claim 1, wherein the compound is OCF, or a pharmaceutically acceptable form thereof 88. - The compound according to claim where the compound is H3C OCF3 or a pharmaceutically acceptable form thereof. 89. - The compound according to claim 1, wherein the compound is OCF, or a pharmaceutically acceptable form thereof 90. - The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable form thereof. 91. - The compound according to claim wherein the compound is OCF3 or a pharmaceutically acceptable form thereof. 92. - The pharmaceutical composition comprising a compound according to claims 1-91, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient thereof. 93. A method of treating a condition mediated by FAAH which comprises administering to a subject in need thereof a therapeutic effective amount of a compound according to claims 1-91 or a pharmaceutically acceptable form thereof. 94. The method according to claim 93, wherein the condition mediated with FAAH is a painful condition, an inflammatory condition, an immune disorder, a central nervous system disorder, a metabolic disorder, a cardiac disorder or glaucoma. 95. - The method according to claim 94, wherein the condition mediated with FAAH is a painful condition selected from neuropathic pain, central pain, deadening pain, chronic pain, post-operative pain, pre-operative pain, nociceptive pain , acute pain, noninflammatory pain, inflammatory pain, pain associated with cancer, pain of wounds, burning pain, pain associated with medical procedures, pain resulting from itching, painful vegija syndrome, pain associated with premenstrual dysphoric disorder, associated pain with premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with preterm labor, pain associated with withdrawal symptoms of drug addiction, joint pain, arthritic pain, lumbosacral pain, musculoskeletal pain, pain headache, migraine, muscle pain, lower back pain, neck pain, dental / maxillofacial pain and visceral pain. 96. The method according to claim 9, wherein the condition mediated with FAAH is an inflammatory condition or an immune disorder. 97. - The method according to claim 96, wherein the inflammatory condition or immune disorder is a gastrointestinal tract. 98. - The method according to claim 96, wherein the inflammatory condition or immune disorder is a condition of the skin. 99. - The method of conformance with rei indication 9, wherein the condition mediated with FAAH is a central nervous system disorder selected from neurotoxicity and / or neurotrauma, embolism, multiple sclerosis, spinal cord injury, a mental disorder, a sleep condition, a movement disorder, nausea and / or emesis, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction. 100. - The method according to claim 94, wherein the condition mediated with FAAH is a metabolic disorder selected from a food condition, a condition related to obesity and complication thereof. 101. The method according to claim 94, wherein the condition mediated with FAAH is a heart disorder selected from hypertension, circulatory shock, reperfusion injury to the myocardium and atherosclerosis. 102. - The method according to claim 94, wherein the condition mediated with FAAH is glaucoma.
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