JP2012527467A - Isoxazolines as fatty acid amide hydrolase inhibitors - Google Patents

Abstract

【選択図】 なしThe invention provides an isoxazoline FAAH inhibitor of formula (I), wherein each of G, R ^a , R ^b , R ^c , and R ^d is as defined herein, or These pharmaceutically acceptable forms are provided. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. The present invention also provides a FAAH-mediated disorder comprising administering to a subject in need of treatment of a FAAH-mediated disorder a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable form thereof. A method of treatment is also provided.
[Chemical 1]

[Selection figure] None

Description

(Cross-reference of related applications)
No. 61 / 179,280, 61 / 179,283, and 61/179, filed May 18, 2009, each of which is incorporated herein by reference in its entirety. The priority of 179,285 is claimed.

(background)
Fatty acid amide hydrolase (FAAH), also called oleamide hydrolase and anandamide amide hydrolase, is a hydrolysis of several important endogenous neuroregulatory fatty acid amides (FAA), including anandamide, oleoylethanolamide and palmitoylethanolamide. Is an integral membrane protein that contributes to and is closely involved in their regulation. Since these FAAs interact with cannabinoid receptors and vanilloid receptors, they are often referred to as “endocannabinoids” or “endovanilloids”. Initial interest in this area has focused on the development of FAAH inhibitors to increase the effects of FAA and reduce pain. Further research has discovered FAAH inhibitors through the interaction of FAA with its own extracellular and intracellular receptors, which can lead to inflammation, metabolic disorders (e.g. obesity-related conditions and cachexia). Debilitating conditions such as quality and anorexia), central nervous system disorders (e.g. neurotoxicity and / or neurotrauma-related disorders, stroke, multiple sclerosis, spinal cord injury, movement disorders such as basal ganglia disorders, muscle Amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, anxiety, depression, mental disorders such as learning and schizophrenia, sleep disorders such as insomnia, nausea and / or vomiting, and drug addiction), heart disease (e.g. , Hypertension, circulatory shock, myocardial reperfusion injury and atherosclerosis) and glaucoma, but can be used to treat a variety of conditions (Pacher et al., “ New targets for drug therapy The Endocannabinoid System as an Emerging Target of Pharmacotherapy, Pharmacological Reviews, (2006) 58: 389-462; Pillarisetti et al., Beyond Pain: Cardiovascular and Metabolic Diseases Fatty acid amides and fatty acid amide hydrolase inhibitors (Pain and Beyond: Fatty Acid Amide Hydrolase Inhibitors in Cardiovascular and Metabolic Diseases) ", Drug Discovery Today, (2009) 597: 1-14).

式中：
(i)R^a、R^b、及びR^cの各々は独立して、H、C_1-10アルキル及びC_1-10ペルハロアルキルから選択され、R^dは、基-L-Zであり、かつZは、C_6-14アリールから選択されるか；
(ii)R^a、R^b、及びR^cの各々は独立して、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから選択され、R^dは、基-L-Zであり、かつZは、3-14員のヘテロシクリル及び5-14員のヘテロアリールから選択されるか；
(iii)R^aとR^dは結合し、C_3-10カルボシクリル(carbocycyl)若しくは3-14員のヘテロシクリル縮合環を形成し、かつR^b及びR^cは、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから独立して選択されるか；又は
(iv)R^cとR^dは結合し、C_3-10カルボシクリル若しくは3-14員のヘテロシクリルスピロ-縮合環を形成し、かつR^a及びR^bは、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから独立して選択され；
Lは、共有結合又は二価のC_1-6炭化水素基であり、ここでLの1、2若しくは3個のメチレン単位は、1個以上の酸素、硫黄又は窒素原子により任意にかつ独立して置換され；
Gは、-CN、-NO₂、-S(=O)R^e、-SO₂R^e、-SO₂NR^fR^e、-PO₂R^e、-PO₂OR^e、-PO₂NR^fR^e、-(C=O)R^e、-(C=O)OR^e、-(C=O)NR^fR^e、-Br、-I、-F、-Cl、-OR^e、-ONR^fR^e、-ONR^f(C=O)R^e、-ONR^fSO₂R^e、-ONR^fPO₂R^e、-ONR^fPO₂OR^e、-SR^e、-OSO₂R^e、-NR^fSO₂R^e、-OPO₂R^e、-OPO₂OR^e、-NR^fPO₂R^e、-NR^fPO₂OR^e、-OPO₂NR^fR^e、-O(C=O)R^e、-O(C=O)OR^e、-NR^fR^e、-NR^f(C=O)R^e,-NR^f(C=O)OR^e、-O(C=O)NR^fR^e、-NR^f(C=NR^f)NR^fR^e、-O(C=NR^f)NR^fR^e、-NR^f(C=NR^f)OR^e、-[N(R^f)₂R^e]⁺X^-から選択され、ここでX^-は、対イオンであり；かつ
各R^eは、C_1-10アルキル、C_2-10アルケニル、C_2-10アルキニル、C_3-10カルボシクリル、C_6-14アリール、3-14員のヘテロシクリル及び5-14員のヘテロアリールから選択され；窒素原子に結合した各R^fは、-H、C_1-10アルキル若しくはアミノ保護基から独立して選択されるか；又は、R^eとR^fは結合し、3-14員のヘテロシクリル環若しくは5-14員のヘテロアリール環を形成している。 (Summary)
The present invention provides isoxazoline FAAH inhibitory compounds of formula (I), or pharmaceutically acceptable forms thereof:

In the formula:
(i) each of R ^a , R ^b , and R ^c is independently selected from H, C _1-10 alkyl, and C _1-10 perhaloalkyl, R ^d is a group -LZ, and Z is , C _6-14 aryl;
(ii) each of R ^a , R ^b , and R ^c is independently selected from —H, C _1-10 alkyl, and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z Is selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl;
(iii) R ^a and R ^d combine to form a C _3-10 carbocycyl or 3-14 membered heterocyclyl fused ring, and R ^b and R ^c are -H, C _1-10 alkyl and Independently selected from C _1-10 perhaloalkyl; or
(iv) R ^c and R ^d combine to form a C _3-10 carbocyclyl or 3-14 membered heterocyclylspiro-fused ring, and R ^a and R ^b are —H, C _1-10 alkyl and C Independently selected from _1-10 perhaloalkyl;
L is a covalent bond or a divalent C _1-6 hydrocarbon group, wherein one, two or three methylene units of L are optionally and independently represented by one or more oxygen, sulfur or nitrogen atoms. Replaced by:
G _{is, -CN, -NO 2, -S (} = O) R e, -SO 2 R e, -SO 2 NR f R e, -PO 2 R e, -PO 2 OR e, -PO 2 NR f R ^e ,-(C = O) R ^e ,-(C = O) OR ^e ,-(C = O) NR ^f R ^e , -Br, -I, -F, -Cl, -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -SR ^e , -OSO ₂ R ^e ,- NR ^f SO ₂ R ^e , -OPO ₂ R ^e , -OPO ₂ OR ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -O (C = NR ^f ) NR ^f R ^e , -NR ^f (C = NR ^f ) OR ^e ,-[N (R ^f ) ₂ R ^e ] ⁺ X ⁻ , wherein X ⁻ is a counter ion; and each R ^e is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl. , C _6-14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each R ^f attached to the nitrogen atom is independently of the —H, C _1-10 alkyl or amino protecting group. Selected Or R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.

  The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.

  The present invention also provides a method for treating a FAAH-mediated disorder in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof. .

  Details of additional embodiments of the invention are set forth in the accompanying Detailed Description and Examples, as described below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

(Definition)
Specific functional group and chemical term definitions are described in more detail below. Chemical elements are identified according to the periodic table of elements on the back cover of the CAS version, Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally found there. As defined. Also, the general principles of organic chemistry, as well as specific functional moieties and reactivities, can be found in Thomas Sorrell's "Organic Chemistry" (University Science Books, Sausalito, 1999); Smith and March, "March. "March's Advanced Organic Chemistry" (5th edition, John Wiley & Sons, New York, 2001); Larock, "Comprehensive Organic Transformations" (VCH Publishers, New York, 1989) As well as in Carruthers, “Some Modern Methods of Organic Synthesis” (3rd edition, Cambridge University Press, Cambridge, 1987).

  Certain compounds of the present invention can contain one or more asymmetric centers and can thus exist in various isomeric forms, such as enantiomers and / or diastereoisomers. The compounds provided herein can be in the form of individual enantiomers, diastereoisomers or geometric isomers, or racemic mixtures and mixtures enriched in one or more stereoisomers. It may be in the form of a mixture of containing stereoisomers. In certain embodiments, the compounds of the invention are enantiomerically pure compounds. In certain other embodiments, a mixture of stereoisomers is provided.

  Furthermore, certain compounds described herein can have one or more double bonds that can exist as cis or trans, or E or Z isomers, unless otherwise specified. The present invention relates to compounds as individual isomers substantially free of other isomers, and as an alternative, mixtures of various isomers, for example racemic mixtures of E / Z isomers or one E Further included are compounds as a mixture enriched in the / Z isomer.

  The terms “enantiomerically enriched”, “enantiomerically pure” and “non-racemic” are used interchangeably herein and are expressed as weight percent of one enantiomer. Refers to a composition that is greater than the amount of one enantiomer in the control mixture of the racemic composition (eg, greater than a 1: 1 weight ratio). For example, an enantiomerically enriched preparation of the (S) -enantiomer refers to more than 50% by weight of (S) -enantiomer relative to the (R) -enantiomer, more preferably at least 75. It means the preparation of compounds by weight, and even more preferably at least 80% by weight. In some embodiments, the enrichment can be much greater than 80% by weight, which is “substantially enantiomerically enriched”, “substantially enantiomerically pure” or A “substantially non-racemic” preparation is provided, which comprises at least 85%, more preferably at least 90%, and even more preferably at least 95% by weight of one enantiomer relative to the other. % Preparation of the composition. In a preferred embodiment, the enantiomerically enriched composition has a higher efficacy with respect to therapeutic utility per unit amount than in the case of a racemic mixture of the composition. Enantiomers can be isolated from the mixture by methods known to those skilled in the art including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or the preferred enantiomers are asymmetrically synthesized. Can be prepared. For example, Jacques et al., “Enantiomers, Racemates and Resolutions” (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron, 33: 2725 (1977); Eliel, EL literature “Stereochemistry of Carbon Compounds” (McGraw-Hill, New York, 1962); and Wilen, SH literature “Tables of Resolving Agents and Optical Resolutions” ) "Page 268, edited by EL Eliel, Univ. Of Notre Dame Press, Notre Dame, IN 1972).

Where a range of values is stated, it is intended to encompass each value and subrange within that range. For example, “C _1-6 alkyl” is C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C Intended to include _5-6 alkyl.

  As used herein, “direct bond” or “covalent bond” refers to a single bond connecting two groups.

  As used herein, `` halo '' and `` halogen '', alone or as part of another group, are fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

As used herein, alone or as part of another group, “alkyl” refers to a monoradical of a straight chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“ C _1-10 alkyl "). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C _1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C _1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C _1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C _1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C _1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C _1-4 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 (“C _1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C ₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C _2-6 alkyl”). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C _4), sec-butyl (C _4), iso - butyl (C _4), n- pentyl (C _5), 3- amyl (C _5), amyl (C _5), neopentyl (C _5), 3- methyl -2-butanyl (C ₅ ), tertiary amyl (C ₅ ), and n-hexyl (C ₆ ). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), and the like. Except as otherwise specified, each example of an alkyl group is independently unsubstituted ("unsubstituted alkyl"), or 1, 2, 3, as described herein, Substituted with 4 or 5 substituents ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C _1-10 alkyl (eg, —CH ₃ ). In certain embodiments, the alkyl group is a substituted C _1-10 alkyl.

“Perhaloalkyl” as defined herein refers to 1-10, wherein all hydrogen atoms are each independently replaced with a halogen selected from, for example, fluoro, bromo, chloro or iodo. An alkyl group having carbon atoms (“C _1-10 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 8 carbon atoms (“C _1-8 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C _1-6 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms (“C _1-4 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms (“C _1-3 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms (“C _1-2 perhaloalkyl”). In some embodiments, all of the hydrogen atoms are each replaced with fluoro. In some embodiments, all hydrogen atoms are each replaced by chloro. Examples of the perhaloalkyl group include —CF ₃ , —CF ₂ CF ₃ , —CF ₂ CF ₂ CF ₃ , —CCl ₃ , —CFCl ₂ , —CF ₂ Cl, and the like.

As used herein, alone or as part of another group, “alkenyl” refers to a straight or branched chain having 2 to 10 carbon atoms and one or more carbon-carbon double bonds. A monoradical of a branched hydrocarbon group (“C _2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C _2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C _2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C _2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C _2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C _2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C _2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C _2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C ₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). Examples of C _2-4 alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ). Examples of the C _2-6 alkenyl group include the C _2-4 alkenyl group, pentenyl (C ₅ ), pentadienyl (C ₅ ), and hexenyl (C ₆ ). Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ), and the like. Except where otherwise specified, each example of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or 1, 2, 3, as described herein, Substituted with 4 or 5 substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C _2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C _2-10 alkenyl.

As used herein, alone or as part of another group, “alkynyl” refers to a straight or branched chain having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds. A monoradical of a hydrocarbon group (“C _2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C _2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C _2-8 alkynyl”). 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 (“C _2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C _2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C _2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C ₂ alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). Examples of C _2-4 alkynyl groups include, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ) and 2-butynyl ( C ₄ ). Examples of the C _2-6 alkenyl group include the C _2-4 alkynyl group, pentynyl (C ₅ ) and hexynyl (C ₆ ). Additional examples of alkynyl include heptynyl (C ₇ ) and octynyl (C ₈ ). Except where otherwise specified, each example of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl"), or 1, 2, 3, as described herein, Substituted with 4 or 5 substituents ("substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C _2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C _2-10 alkynyl.

A “divalent C _1-6 hydrocarbon group” means that one, two or three methylene units (—CH ₂ —) of a hydrocarbon chain are optionally represented by one or more oxygen, sulfur or nitrogen atoms, and A divalent C _1-6 alkyl group, a divalent C _1-6 alkenyl group, or a divalent C _1-6 alkynyl group, independently substituted. In certain embodiments, the divalent C _1-6 hydrocarbon group is a divalent C _1-6 alkyl group. In certain embodiments, the divalent C _1-6 hydrocarbon group is an unsubstituted divalent C _1-6 hydrocarbon group (eg, an unsubstituted divalent C _1-6 alkyl group).

As used herein, alone or as part of another group, “alkoxy” is defined herein as substituted by an oxygen atom such that the point of attachment is an oxygen atom. An alkyl group. In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C _1-10 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 (“C _1-6 alkoxy”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C _1-4 alkoxy”). Examples of C _1-4 alkoxy groups include methoxy (C ₁ ), ethoxy (C ₂ ), propoxy (C ₃ ), isopropoxy (C ₃ ), butoxy (C ₄ ), tert-butoxy (C ₅ ), etc. Is mentioned. Examples of the C _1-6 alkoxy group include the C _1-4 alkoxy group, pentyloxy (C ₅ ), isopentyloxy (C ₅ ), neopentyloxy (C ₅ ), hexyloxy (C ₆ ), and the like. Is mentioned. Further examples of alkoxy groups include heptyloxy (C ₇ ), octyloxy (C ₈ ) and the like. Except as otherwise noted, each example of an alkyl portion of an alkoxy group is independently unsubstituted ("unsubstituted alkoxy") or 1, 2 as described herein. , 3, 4, or 5 substituents (“substituted alkoxy”). In certain embodiments, the alkoxy group is unsubstituted C _2-10 alkoxy (eg, —OCH ₃ ). In certain embodiments, the alkoxy group is a substituted C _2-10 alkoxy (eg, perhaloalkoxy as defined herein).

“Perhaloalkoxy” refers to an alkoxy group in which all of the hydrogen atoms of the alkyl moiety are each independently replaced with a halogen atom selected from fluoro, chloro, bromo and iodo. In certain embodiments, the alkyl moiety has 1 to 10 carbon atoms (“C _1-10 perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 8 carbon atoms (“C _1-8 perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms (“C _1-6 perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms (“C _1-4 perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms (“C _1-3 perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms (“C _1-2 perhaloalkoxy”). In some embodiments, all hydrogen atoms are each replaced by fluoro. In some embodiments, all hydrogen atoms are each replaced by chloro. Examples of perhaloalkoxy groups include, but are not limited to, —OCF ₃ , —OCF ₂ CF ₃ , —OCF ₂ CF ₂ CF ₃ , —OCCl ₃ , —OCFCl ₂ , —OCF ₂ Cl, and the like.

As used herein, “carbocyclyl”, alone or as part of another group, is a non-aromatic having 3 to 10 ring carbon atoms and 0 heteroatoms in a non-aromatic ring system. A radical of an aromatic hydrocarbon group (“C _3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C _3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C _3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C _3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C _5-10 carbocyclyl”). Examples of C _3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C ₃ ), cyclobutyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl. (C ₆ ), cyclohexadienyl (C ₆ ) and the like. Examples of the C _3-8 carbocyclyl group include the C _3-6 carbocyclyl group, as well as cycloheptyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), Bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl and the like. Examples of the C _3-10 carbocyclyl group include the C _3-8 carbocyclyl group, octahydro-1H-indenyl, decahydronaphthalenyl, spiro [4.5] decanyl and the like. As the previous examples show, in some embodiments, the carbocyclyl group is monocyclic (`` monocyclic carbocyclyl ''), or polycyclic (e.g., bicyclic (`` bicyclic carbocyclyl '')) or One of three ring systems (including fused, bridged or spiro ring systems, such as “tricyclic carbocyclyl”) and can be saturated, or one or more carbon-carbon doubles It may contain a bond or a triple bond. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring is fused with one or more aryl or heteroaryl groups such that the point of attachment is on the carbocyclyl ring, as defined above. Unless otherwise specified, each example of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or 1, 2, 3, 4 as described herein. Or substituted with 5 substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C _3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C _3-10 carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms (“C _3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C _3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C _3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C _5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C _5-10 cycloalkyl”). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of the C _3-6 cycloalkyl group include the C _5-6 cycloalkyl group, and cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of the C _3-8 cycloalkyl group include the C _3-6 cycloalkyl group, and cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl"), or 1, 2, as described herein, Substituted with 3, 4, or 5 substituents (“substituted cycloalkyl”). In certain embodiments, the cycloalkyl group is unsubstituted C _3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C _3-10 cycloalkyl.

  As used herein, alone or as part of another group, “heterocyclyl” refers to a ring carbon atom and each heteroatom independently selected from nitrogen, oxygen and sulfur. A 3- to 14-membered non-aromatic ring system radical having one ring heteroatom ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom depending on the valence. A heterocyclyl group may be monocyclic (`` monocyclic heterocyclyl ''), or condensed, such as polycyclic (e.g., bicyclic (`` bicyclic heterocyclyl '') or tricyclic (`` tricyclic heterocyclyl ''). Can be either saturated, bridged or spiro ring systems) and can be saturated or can contain one or more carbon-carbon double bonds or triple bonds. Heterocyclyl polycyclic systems can contain one or more heteroatoms in one or both rings. Also, “heterocyclyl” is a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring. Or a ring system in which a 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, the heterocyclyl group is a 5-10 membered non-aromatic group having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Family ring system ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic group having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Family ring system ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic group having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. Family ring system ("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 membered 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. Examples of 3-membered heterocyclyl containing 1 heteroatom are, but are not limited to, aziridinyl, oxiranyl, thiorenyl. Examples of 4-membered heterocyclyl containing one heteroatom are, but are not limited to, azetidinyl, oxetanyl and thietanyl. Examples of 5-membered heterocyclyls containing one heteroatom are tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. It is not limited. Examples of 5-membered heterocyclyl containing 2 heteroatoms are, but are not limited to, dioxolanyl, oxathiolanyl and dithiolanyl. Examples of 5-membered heterocyclyl containing 3 heteroatoms are, but are not limited to, triazolinyl, oxadiazolinyl, and thiazolidinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom are, but not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms are, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. An example of a 6-membered heterocyclyl group containing two heteroatoms is, but is not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom are, but are not limited to, azepanyl, oxepanyl and thiepanyl. Examples of 8-membered heterocyclyl groups containing one heteroatom are, but not limited to, azocanyl, oxecanyl and thiocanyl. Examples of bicyclic heterocyclyl groups are indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl , Decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl , Chromanyl, chromenyl, 1H-benzo [e] [1,4] diazepinyl, 1,4,5,7-tetrahydropyrano [3,4-b] 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-dihydrofuro [2,3-b] pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo [2,3-b] Pyridinyl, 4,5,6,7-tetrahydrofuro [3,2-c] pyridinyl, 4,5,6,7-tetrahydrothieno [3,2-b] pyridinyl, 1,2,3,4-tetrahydro- Although not limited to 1,6-naphthyridinyl and the like. Except where otherwise specified, each example of a heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or 1, 2, 3, 4, as described herein, Or substituted with 5 substituents ("substituted heterocyclyl"). 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 6-14 ring carbon atoms and 0 heteroatoms provided for an aromatic ring system. A monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system radical (e.g., having 6, 10, or 14 pi electrons shared in a cyclic configuration). “C _6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C ₆ aryl”; eg, phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C ₁₀ aryl”; naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C ₁₄ aryl”; eg, anthracyl). “Aryl” also includes ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the radical or point of attachment is on the aryl ring. Including. Except as otherwise specified, each example of an aryl group is independently unsubstituted ("unsubstituted aryl") or 1, 2, 3, as described herein, Substituted with 4 or 5 substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C _6-14 aryl. In certain embodiments, the aryl group is substituted C _6-14 aryl.

  “Aralkyl” refers to an alkyl group, as defined herein, substituted with an aryl group, as defined herein, which is part of “alkyl” and in which the point of attachment is on the alkyl moiety.

  As used herein, alone or as part of another group, “heteroaryl” refers to a ring carbon atom and an aromatic wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system radicals (e.g., cyclic) having 1 to 4 ring heteroatoms provided in the ring system (Having 6, 10, or 14 pi electrons shared within the configuration) ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom depending on the valence. Heteroaryl polycyclic systems can contain one or more heteroatoms in one or both rings. “Heteroaryl” also refers to a ring system in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the point of attachment is on either the aryl ring or the heteroaryl ring. Or a heteroaryl ring as defined above fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring. For polycyclic heteroaryl groups where one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment is any ring, i.e., a ring having a heteroatom (e.g., 2-indolyl) Or on a ring that does not contain heteroatoms (eg, 5-indolyl). In some embodiments, the heteroaryl group contains 1 to 4 ring heteroatoms provided to a ring carbon atom and an aromatic ring system in which each heteroatom is independently selected from nitrogen, oxygen and sulfur. Having a 5-10 membered aromatic ring system ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group contains 1 to 4 ring heteroatoms provided to a ring carbon atom and an aromatic ring system in which each heteroatom is independently selected from nitrogen, oxygen and sulfur. Having a 5-8 membered aromatic ring system ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group contains 1 to 4 ring heteroatoms provided to a ring carbon atom and an aromatic ring system in which each heteroatom is independently selected from nitrogen, oxygen and sulfur. A 5-6 membered aromatic ring system ("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. Examples of 5-membered heteroaryls containing 1 heteroatom are, but not limited to, pyrrolyl, furanyl and thiophenyl. Examples of 5-membered heteroaryls containing 2 heteroatoms are, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryls containing 3 heteroatoms are, but not limited to, triazolyl, oxadiazolyl, thiadiazolyl. An example of a 5-membered heteroaryl containing 4 heteroatoms is, but is not limited to, tetrazolyl. An example of a 6-membered heteroaryl containing 1 heteroatom is pyridinyl, but is not limited thereto. Examples of 6-membered heteroaryl containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Examples of 6-membered heteroaryls containing 3 or 4 heteroatoms are, but not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl containing 1 heteroatom are, but are not limited to, azepinyl, oxepinyl and thiepinyl. Examples of 5,6-bicyclic heteroaryl are indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxa Zolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl, but are not limited thereto. Examples of 6,6-bicyclic heteroaryl are, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Examples of tricyclic heteroaryl are, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. Unless otherwise specified, each example of a heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”), or 1, 2, as described herein, Substituted with 3, 4, or 5 substituents ("substituted heteroaryl"). 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” refers to an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein, which is part of “alkyl” and in which the point of attachment is on the alkyl moiety.

  As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term `` partially unsaturated '' is intended to include rings having multiple sites of unsaturation, but includes aromatic groups as defined herein (e.g., aryl or heteroaryl moieties). Not intended.

  Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined herein are optionally substituted (e.g. `` substituted '' or `` unsubstituted An alkyl group, a “substituted” or “unsubstituted” alkenyl group, a “substituted” or “unsubstituted” alkynyl group, a “substituted” or “unsubstituted” carbocyclyl group, “substituted” Or “unsubstituted” heterocyclyl group, “substituted” or “unsubstituted” aryl group, or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group (such as a carbon atom or nitrogen atom) is allowed, regardless of whether the term “optionally” precedes it. Substituted with, for example, a substituent that yields a stable compound upon substitution, such as a substituent that yields a compound that does not undergo spontaneous conversion by rearrangement, cyclization, elimination, or other reactions. Means that. Unless otherwise specified, a “substituted” group can have a substituent at one or more substitutable positions in the group, and two or more positions in any given structure are substituted. The substituents are the same or different at each position.

Examples of carbon atom substituents include, but are not limited to:
Halogen (i.e., fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I)), - CN, -NO 2, -N 3, -SO 2 H, -SO 3 H ^{, -OH, -OR aa, -ON (} R bb) 2, -N (R bb) 2, -N (R bb) 3 + X -, -N (OR cc) R bb, -SH, -SR aa , -SSR ^cc , -C (= O) R ^aa , -CO ₂ H, -CHO, -C (OR ^cc ) ₂ , -CO ₂ R ^aa , -OC (= O) R ^aa , -OCO ₂ R ^aa , -C (= O) N (R ^bb ) ₂ , -OC (= O) N (R ^bb ) ₂ , -NR ^bb C (= O) R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C (= O) N (R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -OC (= NR ^bb ) R ^aa , -OC (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -OC (= NR ^bb ) N (R ^bb ) ₂ , -NR ^bb C (= NR ^bb ) N (R ^bb ) ₂ , -C (= O ) NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N (R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S (= O) R ^aa , -OS (= O) R ^aa , -Si (R ^aa ) ₃ , -OSi (R ^aa ) ₃ , -C (= S) N (R ^bb ) ₂ , -C (= O) SR ^aa , -C (= S) SR ^aa , -SC (S) SR ^aa , -P (= O) ₂ R ^aa , -OP (= O) ₂ R ^aa , -P (= O) (R ^aa ) ₂ ,- OP (= O) (R ^aa ) ₂ , -OP (= O) (OR ^cc ) ₂ , -P (= O) ₂ N (R ^bb ) ₂ , -OP (= O) ₂ N (R ^bb ) ₂ , -P (= O) (NR ^bb ) ₂ , -OP (= O) (NR ^bb ) ₂ , -NR ^bb P (= O) (OR ^cc ) ₂ , -NR ^bb P (= O) (NR ^bb ) ₂ , -P (R ^cc ) ₂ , -P (R ^cc ) ₃ , -OP (R ^cc ) ₂ , -OP (R ^cc ) ₃ , -B (OR ^cc ) ₂ , -BR ^aa (OR ^cc ), C _{1 -10} alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;
Or the two geminal hydrogens on the carbon atom are the groups = O, = S, = NN (R ^bb ) ₂ , = NNR ^bb C (= O) R ^aa , = NNR ^bb C (= O) OR ^aa , Replaced by = NNR ^bb S (= O) ₂ R ^aa , = NR ^bb , = NOR ^CC ;
Each example of R ^aa is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 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 is 0, 1, 2, 3, 4, or 5 Independently substituted by an R ^dd group;
Each example of R ^bb is independently hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C (= O) N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , -P (= O ) ₂ R ^aa , -P (= O) (R ^aa ) ₂ , -P (= O) ₂ N (R ^cc ) ₂ , -P (= O) (NR ^cc ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ^cc groups attached to the N atom join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl independently, aryl, and heteroaryl, 0,1,2,3,4, or by five R ^dd group It has been replaced Te;
Each instance of R ^cc is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ^cc groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl or 5-14 membered Forming a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups And;
Each example of R ^dd is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON (R ^ff ) ₂ , -N _{^{(R ff) 2, -N (}} R ff) 3 + X -, -N (OR ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H , -CO ₂ R ^ee , -OC (= O) R ^ee , -OCO ₂ R ^ee , -C (= O) N (R ^ff ) ₂ , -OC (= O) N (R ^ff ) ₂ , -NR ^ff C (= O) R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C (= O) N (R ^ff ) ₂ , -C (= NR ^ff ) OR ^ee , -OC (= NR ^ff ) R ^ee , -OC (= NR ^ff ) OR ^ee , -C (= NR ^ff ) N (R ^ff ) ₂ , -OC (= NR ^ff ) N (R ^ff ) ₂ , -NR ^ff C (= NR ^ff ) N (R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N (R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S (= O) R ^ee , -Si (R ^ee ) ₃ , -OSi (R ^ee ) ₃ , -C (= S) N (R ^ff ) ₂ , -C (= O) SR ^ee , -C (= S) SR ^ee , -SC (= S) SR ^ee , -P (= O) ₂ R ^ee , -P (= O) (R ^ee ) ₂ , -OP (= O) (R ^ee ) ₂ , -OP (= O) (OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member heteroa Is selected from Lumpur, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, 0,1,2,3,4, or 5 amino substituted independently with R ^gg group Or two geminal R ^dd substituents can be joined to form ═O or ═S;
Each example of R ^ee is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 Independently substituted by an R ^gg group;
Each example of R ^ff is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Two R ^ff groups selected from C _6-10 aryl and 5-10 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl Forming an aryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; And; and
Each example of R ^gg is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O)) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1 -6} alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C (= NH ) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1 -6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1 -6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ^gg substituents are attached, Can form O or = S;
Here, X ⁻ is a counter ion.

As used herein, a “counter ion” is a negatively charged group with respect to a positively charged quaternary amine to maintain electrical neutrality. Examples of the counter ion is a halide ion ^{(e.g., F -, Cl -, Br} -, I -), NO 3 -, ClO 4 -, OH -, H 2 PO 4 -, HSO 4 -, a sulfonate ion ( For example, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1- Ions such as sulfonic acid-2-sulfonic acid) and carboxylate ions (for example, ions such as acetic acid, ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid).

Nitrogen atoms can be substituted or unsubstituted depending on the valence and include primary, secondary, tertiary and quaternary nitrogen atoms. Examples of nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C (= O) N ( R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^bb ) R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc ,- C (= S) SR ^cc , -P (= O) ₂ R ^aa , -P (= O) (R ^aa ) ₂ , -P (= O) ₂ N (R ^cc ) ₂ , -P (= O) (NR ^cc ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, And two R ^cc groups attached to the N atom, or a 5-14 membered heteroaryl, to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is 0, 1, 2, 3, 4, or 5 R R ^aa , R ^bb , R ^cc and R ^dd are as defined above, independently substituted by a ^dd group.

In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group. Amino protecting groups are -OH, -OR ^aa , -N (R ^cc ) ₂ , -C (= O) R ^aa , -C (= O) N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^cc ) R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , C _1-10 alkyl (E.g., aralkyl groups), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl groups. , But not limited thereto, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl are represented by 0, 1, 2, 3, 4, or 5 R ^dd groups. Independently substituted, and R ^aa , R ^bb , R ^cc and R ^dd are as defined above. Amino protecting groups are well known in the art and are incorporated herein by reference, TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis", 3rd edition. , John Wiley & Sons, including those detailed in 1999.

For example, amino protecting groups such as amide groups (e.g., -C (= O) R ^aa ) are formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -Pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-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-nitrate Cinnamide, N- acetylmethionine derivative, o- nitrobenzamide and o- (benzoyloxymethyl) including benzamide, but is not limited thereto.

Amino protecting groups such as carbamate groups (e.g. -C (= O) OR ^aa ) are methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo) fluorenyl methyl carbamate. 9- (2,7-dibromo) fluorenylmethyl carbamate, 2,7-di-t-butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] Methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1 -(1-adamantyl) -1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1 , 1-Dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-biphenyl ) Ethyl carbamate (Bpoc), 1- (3,5-di-t-butylphenyl) -1-methylethyl carbamate (t-Bumeoc), 2- (2'- and 4'-pyridyl) ethyl carbamate (Pyoc) 2- (N, N-dicyclohexylcarboxamido) ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc ), Cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz) ), P-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2- (p-toluenesulfonyl) ethylcarbamate, [2 (1,3 dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonio Isopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl) benzyl carbamate, 5-benzoisoxazolyl methyl carbamate, 2- (tri Fluoromethyl) -6-chromonylmethylcarbamate (Tcroc), m-nitrophe Rucarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl (o-nitrophenyl) methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxycarbonylvinylcarbamate, o- (N, N-dimethylcarboxamido) benzylcarbamate 1,1-dimethyl-3- (N, N-dimethylcarboxamido) propyl carbamate, 1,1-dimethylpropynyl carbamate, di (2-pyridyl) methyl carbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbonate Rubamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p- (p'-methoxyphenylazo) benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl Carbamate, 1-methyl-1- (3,5-dimethoxyphenyl) ethylcarbamate, 1-methyl-1- (p-phenylazophenyl) ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1 -(4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium) benzyl carbamate, and 2,4,6- Including but not limited to trimethylbenzyl carbamate.

Amino protecting groups such as sulfonamide groups (e.g., -S (= O) ₂ R ^aa ) are 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-tetramethyl-4-methoxybenzene Sulfonamide (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), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 ', 8'- Dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trimethyl Le Oro methyl sulfonamide, and including phenacyl sulfonamides, but is not limited thereto.

  Other amino protecting groups are phenothiazinyl- (10) -carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1, 1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1 , 3-Dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2- (trimethylsilyl ) Ethoxy] methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro- 2-Oxo-3-pyrrolin-3-yl) amine, quaternary ammonium salt, N-benzylamine, N-di (4-methoxyphenyl) methylamine, N-5-dibenzosuberyl, N-triphenylmethyl Amine (Tr), N-[(4-Methoxyphenyl) diphenylmethyl] amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl) mesityl] methyleneamine, N- (N ′, N′-dimethylaminomethylene) amine, N, N′-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) Nylmethyleneamine, N-cyclohexylideneamine, N- (5,5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl (pentacarbonyl Chromium- or tungsten) carbonyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphine Amide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, penta Chlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenyl Including methyl sulfenamide and 3-nitropyridine sulfenamide (Npys), but is not limited thereto.

  As used herein, a “leaving group” is a molecular fragment that separates with an electron pair in the heterogeneous cleavage of a bond and is understood in the art with respect to what the molecular fragment is an anion or neutral molecule. Is the term. See, for example, Smith, "March Advanced Organic Chemistry", 6th edition (501-502).

  Examples of these and other substituents are described in more detail in the “detailed description”, “exemplary” and “claims”. The present invention is not intended to be limited in any manner by the above list of examples of substituents.

  As used herein, “pharmaceutically acceptable forms thereof” refers to pharmaceutically acceptable salts, hydrates, solvates of the compounds of the invention as defined below and herein, Includes prodrugs, tautomers, isomers, and / or polymorphs.

The term “pharmaceutically acceptable salt” as used herein is within the scope of sound medical judgment, and includes human and lower grades without undue toxicity, irritation, and allergic reactions. A salt that is suitable for use in contact with animal tissue and that corresponds to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. Describe pharmaceutically acceptable salts in detail in a paper (J. Pharmaceutical Sciences, 1977, 66, 1-19) incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of non-toxic pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid Or a salt of an amino group formed using an organic acid such as 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, hydrogen sulfate, borate, butyrate, camphorate, Camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate , Heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate , Methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, Citrate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p -Toluene sulfonate, undecanoate, valerate and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. Non-toxic ammonium cations formed using, quaternary ammonium cations and amine cations.

  In certain embodiments, their pharmaceutically acceptable forms are isomers. As used herein, the term “isomer” includes any and all geometric and stereoisomers. For example, “isomers” are cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereoisomers, (D), as falling within the scope of the invention. -Isomers, (L) -isomers, their racemic mixtures, as well as other mixtures thereof.

  In certain embodiments, their pharmaceutically acceptable forms are tautomers. As used herein, the term “tautomer” refers to at least one formal transfer of a hydrogen atom and at least one change in valence (e.g., to a single bond double bond, to a triple bond single bond). And / or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (ie, reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Examples of tautomerization include: keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to- (different) enamine. Can be mentioned.

  In certain embodiments, their pharmaceutically acceptable forms are hydrates or solvates. The term “hydrate” as used herein refers to a compound that is non-covalently associated with one or more water molecules. Similarly, “solvate” refers to a compound that is non-covalently associated with one or more molecules of an organic solvent.

  In certain embodiments, their pharmaceutically acceptable forms are prodrugs. As used herein, the term “prodrug” refers to a derivative of a parent compound that must be transformed in the body to release the parent compound. In some cases, prodrugs have improved physical and / or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmacologically and / or pharmacokinetically based on properties associated with the parent compound. Advantages of prodrugs include their physical properties, such as enhanced aqueous solubility for parenteral administration at physiological pH, enhanced absorption from the gastrointestinal tract, or enhanced drug stability for long-term storage compared to the parent compound. In the characteristics.

  In certain embodiments, their pharmaceutically acceptable forms are polymorphs. As used herein, “polymorph” refers to a compound having two or more crystal structures resulting from, for example, differences in molecular packing and / or molecular conformation of the compound in the solid state.

SEQ ID NO: SEQ ID NO: Homo sapiens FAAH amino acid sequence:

ここで：
(i)R^a、R^b、及びR^cの各々は独立して、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから選択され、R^dは、基-L-Zであり、かつZは、C_6-14アリールから選択されるか；
(ii)R^a、R^b、及びR^cの各々は独立して、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから選択され、R^dは、基-L-Zであり、かつZは、3-14員のヘテロシクリル及び5-14員のヘテロアリールから選択されるか；
(iii)R^aとR^dは結合し、C_3-10カルボシクリル若しくは3-14員のヘテロシクリル縮合環を形成し、かつR^b及びR^cは、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから独立して選択されるか；又は
(iv)R^cとR^dは結合し、C_3-10カルボシクリル若しくは3-14員のヘテロシクリルスピロ-縮合環を形成し、かつR^a及びR^bは、-H、C_1-10アルキル及びC_1-10ペルハロアルキルから独立して選択され；
Lは、共有結合又は二価のC_1-6炭化水素基であり、ここでLの1、2若しくは3個のメチレン単位は、1個以上の酸素、硫黄又は窒素原子により任意にかつ独立して置換され；
Gは、-CN、-NO₂、-S(=O)R^e、-SO₂R^e、-SO₂NR^fR^e、-PO₂R^e、-PO₂OR^e、-PO₂NR^fR^e、-(C=O)R^e、-(C=O)OR^e、-(C=O)NR^fR^e、-Br、-I、-F、-Cl、-OR^e、-ONR^fR^e、-ONR^f(C=O)R^e、-ONR^fSO₂R^e、-ONR^fPO₂R^e、-ONR^fPO₂OR^e、-SR^e、-OSO₂R^e、-NR^fSO₂R^e、-OPO₂R^e、-OPO₂OR^e、-NR^fPO₂R^e、-NR^fPO₂OR^e、-OPO₂NR^fR^e、-O(C=O)R^e、-O(C=O)OR^e、-NR^fR^e、-NR^f(C=O)R^e,-NR^f(C=O)OR^e、-O(C=O)NR^fR^e、-NR^f(C=NR^f)NR^fR^e、-O(C=NR^f)NR^fR^e、-NR^f(C=NR^f)OR^e、-[N(R^f)₂R^e]⁺X^-から選択され、ここでX^-は、対イオンであり；かつ
各R^eは、C_1-10アルキル、C_2-10アルケニル、C_2-10アルキニル、C_3-10カルボシクリル、C_6-14アリール、3-14員のヘテロシクリル及び5-14員のヘテロアリールから選択され；窒素原子に結合した各R^fは独立して、-H、C_1-10アルキル若しくはアミノ保護基から選択されるか；又は、R^eとR^fは結合し、3-14員のヘテロシクリル環若しくは5-14員のヘテロアリール環を形成している。 (Detailed explanation)
(1. Compound)
The present invention provides isoxazoline FAAH inhibitory compounds of formula (I), or pharmaceutically acceptable forms thereof:

here:
(i) each of R ^a , R ^b , and R ^c is independently selected from —H, C _1-10 alkyl, and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z Is selected from C _6-14 aryl;
(ii) each of R ^a , R ^b , and R ^c is independently selected from —H, C _1-10 alkyl, and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z Is selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl;
(iii) R ^a and R ^d are combined to form a C _3-10 carbocyclyl or 3-14 membered heterocyclyl fused ring, and R ^b and R ^c are -H, C _1-10 alkyl and C _1- Independently selected from ₁₀ perhaloalkyl; or
(iv) R ^c and R ^d combine to form a C _3-10 carbocyclyl or 3-14 membered heterocyclylspiro-fused ring, and R ^a and R ^b are —H, C _1-10 alkyl and C Independently selected from _1-10 perhaloalkyl;
L is a covalent bond or a divalent C _1-6 hydrocarbon group, wherein one, two or three methylene units of L are optionally and independently represented by one or more oxygen, sulfur or nitrogen atoms. Replaced by:
G _{is, -CN, -NO 2, -S (} = O) R e, -SO 2 R e, -SO 2 NR f R e, -PO 2 R e, -PO 2 OR e, -PO 2 NR f R ^e ,-(C = O) R ^e ,-(C = O) OR ^e ,-(C = O) NR ^f R ^e , -Br, -I, -F, -Cl, -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -SR ^e , -OSO ₂ R ^e ,- NR ^f SO ₂ R ^e , -OPO ₂ R ^e , -OPO ₂ OR ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -O (C = NR ^f ) NR ^f R ^e , -NR ^f (C = NR ^f ) OR ^e ,-[N (R ^f ) ₂ R ^e ] ⁺ X ⁻ , wherein X ⁻ is a counter ion; and each R ^e is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl. , C _6-14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each R ^f attached to the nitrogen atom is independently —H, C _1-10 alkyl or an amino protecting group Selected from Or R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.

(Base G)
As previously defined, G _{is, -CN, -NO 2, -S (} = O) R e, -SO 2 R e, -SO 2 NR f R e, -PO 2 R e, -PO 2 OR ^e , -PO ₂ NR ^f R ^e ,-(C = O) R ^e ,-(C = O) OR ^e ,-(C = O) NR ^f R ^e , -Br, -I, -F,- Cl, -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -SR ^e , -OSO ₂ R ^e , -NR ^f SO ₂ R ^e , -OPO ₂ R ^e , -OPO ₂ OR ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e ,- O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -O (C = NR ^f ) NR ^f R ^e , -NR ^f (C = NR ^f ) OR ^e , _{^{- [N (R f) 2}} R e] + X - is selected from wherein X ^- is is a counter ion;
And where R ^e is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, 3-14 membered heterocyclyl and 5-14 membered Each R ^f bonded to the nitrogen atom is independently selected from —H, C _1-10 alkyl or an amino protecting group; or R ^e and R ^f are A 14-membered heterocyclyl ring or a 5-14-membered heteroaryl ring is formed.

In certain embodiments, G is not a leaving group, G as an _{example, -F, -CN, -NO 2,} -S (= O) R e, -SO 2 R e, -SO 2 NR f R ^e , -PO ₂ R ^e , -PO ₂ OR ^e , -PO ₂ NR ^f R ^e ,-(C = O) R ^e ,-(C = O) OR ^e , and-(C = O) NR ^f It is selected from R ^e.

In certain embodiments, G is selected from -CN and -NO _2. In certain embodiments, G is —CN. In certain embodiments, G is —NO ₂ .

In certain embodiments, G is selected from —S (═O) R ^e , —SO ₂ R ^e , and —SO ₂ NR ^f R ^e . In certain embodiments, G is -S (= O) R ^e. In certain embodiments, G is -SO ₂ R ^e. In certain embodiments, G is -SO ₂ NR ^f R ^e.

In certain embodiments, G, -PO ₂ R ^e, is selected from -PO ₂ OR ^e, and -PO ₂ NR ^f R ^e. In certain embodiments, G is -PO ₂ R ^e. In certain embodiments, G is —PO ₂ OR ^e . In certain embodiments, G is -PO ₂ NR ^f R ^e.

In certain embodiments, G is selected from-(C = O) R ^e ,-(C = O) OR ^e , and-(C = O) NR ^f R ^e . In certain embodiments, G is — (C═O) ^Re . In certain embodiments, G is — (C═O) OR ^e . In certain embodiments, G is — (C═O) NR ^f R ^e .

However, in certain embodiments, G is a leaving group, for example, G is -Cl, -Br, -I, -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -SR ^e , -OSO ₂ R ^e , -NR ^f SO ₂ R ^e , -OPO ₂ R ^e ,- OPO ₂ OR ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e ,- NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^{f R e, -O (C = NR} f) NR f R e, -NR f (C = NR f) oR e, and _{^{- [N (R f) 2}} R e] + X - is selected from wherein X ^-Is a counter ion.

  In certain embodiments, G is halogen; that is, selected from -F, -Cl, -Br and -I. In certain embodiments, G is -F. In certain embodiments, G is —Br. In certain embodiments, G is —I. In certain embodiments, G is —Cl. However, in certain embodiments, G is not halogen. For example, in certain embodiments, G is not -Br. In certain embodiments, G is not -I. In certain embodiments, G is not -F. In certain embodiments, G is not -Cl.

In certain embodiments, G is -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO _{^{2 OR e, -OSO 2 R e}} , -OPO 2 R e, -OPO 2 OR e, -OPO 2 NR f R e, -O (C = O) R e, -O (C = O) OR e, ^{-O (C = O) NR f} R e, and -O (C = NR ^f) is selected from NR ^f R ^e. In certain embodiments, G is -OR ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -O (C = O) NR ^f R ^e , and -O (C = NR ^f ) NR ^f R ^{e is} selected. In certain embodiments, G is -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e, is selected from ^{-O (C = O) NR f} R e, and ^{-O (C = NR f) NR} f R e. In certain embodiments, G is —OR ^e . In certain embodiments, G is -ONR ^f R ^e. In certain embodiments, G is —ONR ^f (C═O) R ^e . In certain embodiments, G is -ONR ^f SO ₂ R ^e. In certain embodiments, G is -ONR ^f PO ₂ R ^e. In certain embodiments, G is —ONR ^f PO ₂ OR ^e . In certain embodiments, G is a -OSO ₂ R ^e. In certain embodiments, G is -OPO ₂ R ^e. In certain embodiments, G is —OPO ₂ OR ^e . In certain embodiments, G is -OPO ₂ NR ^f R ^e. In certain embodiments, G is —O (C═O) R ^e . In certain embodiments, G is —O (C═O) OR ^e . In certain embodiments, G is —O (C═O) NR ^f R ^e . In certain embodiments, G is ^{-O (C = NR f) NR} f R e.

In certain embodiments, G is selected from -OR ^e and -SR ^e . In certain embodiments, G is selected from -OR ^e . In certain embodiments, G is -SR ^e .

In certain embodiments, _{^{G, -NR f SO 2 R e,}} -NR f PO 2 R e, -NR f PO 2 OR e, -NR f R e, -NR f (C = O) R e, -NR ^f (C = O) OR ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -NR ^f (C = NR ^f ) OR ^e , and-[N (R ^f ) ₂ R ^e ] ⁺ X ^{− is} selected from where X ⁻ is a counter ion. In certain embodiments, _{^{G, -NR f SO 2 R e,}} -NR f PO 2 R e, -NR f PO 2 OR e, -NR f R e, -NR f (C = O) R e, and it is selected from ^{-NR f (C = O) oR} e. In certain embodiments, _{^{G, -NR f SO 2 R e,}} -NR f R e, is selected from ^{-NR f (C = O) R} e, and ^{-NR f (C = O) OR} e. In certain embodiments, G is -NR ^f SO ₂ R ^e. In certain embodiments, G is -NR ^f PO ₂ R ^e. In certain embodiments, G is —NR ^f PO ₂ OR ^e . In certain embodiments, G is -NR ^f R ^e. In certain embodiments, G is —NR ^f (C═O) R ^e . In certain embodiments, G is —NR ^f (C═O) OR ^e . In certain embodiments, G is ^{-NR f (C = NR f)} NR f R e. In certain embodiments, G is —NR ^f (C═NR ^f ) OR ^e . In certain embodiments, G is _{^{- [N (R f) 2}} R e] + X - a is, where X ^- is a counterion.

Additional embodiments of G included in the description of the groups R ^e and R ^f and further exemplified in the “Tables” and “Examples” are provided below and herein.

(R ^{e of} group G)
G is defined as -S (= O) R ^e , -SO ₂ R ^e , -SO ₂ NR ^f R ^e , -PO ₂ R ^e , -PO ₂ OR ^e , -PO ₂ , as generally defined above. NR ^f R ^e ,-(C = O) R ^e ,-(C = O) OR ^e ,-(C = O) NR ^f R ^e , -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -SR ^e , -OSO ₂ R ^e , -NR ^f SO ₂ R ^e , -OPO ₂ R ^e , -OPO ₂ OR ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^{f) NR f R e, -O} (C = NR f) NR f R e, -NR f (C = NR f) oR e, and _{^{- [N (R f) 2}} R e] + X - is selected from In certain embodiments, wherein X ⁻ is a counter ion, R ^e is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, Selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl.

In certain embodiments, R ^e is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, 3-14 membered heterocyclyl and 5-14. Selected from membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl groups are 0, 1, 2, 3, 4, as defined below and herein. Or is substituted by 5 R ^h groups.

In certain embodiments, R ^e is C _1-10 alkyl. In certain embodiments, R ^e is C _1-6 alkyl. In certain embodiments, R ^e is C _1-6 alkyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C _1-5 alkyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C _1-4 alkyl substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, R ^e is C _1-3 alkyl substituted with 0, 1, 2, or 3 R ^h groups. In certain embodiments, R ^e is C _1-2 alkyl substituted with 0, 1, or 2 R ^h groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Such groups are substituted by 0, 1, 2, 3, 4, or 5 R ^h groups.

In certain embodiments, R ^e is C _1-6 perhaloalkyl. In certain embodiments, R ^e is C _1-5 perhaloalkyl. In certain embodiments, R ^e is C _1-4 perhaloalkyl. In certain embodiments, R ^e is C _1-3 perhaloalkyl. In certain embodiments, R ^e is C _1-2 perhaloalkyl. Examples of R ^e perhaloalkyl _{group, -CF 3, -CF 2 CF 3} , -CF 2 CF 2 CF 3, -CCl 3, -CFCl 2, and -CF ₂ but Cl and the like, are not limited to It is not something.

In certain embodiments, R ^e is C _2-10 alkenyl. In certain embodiments, R ^e is C _2-6 alkenyl. In certain embodiments, R ^e is C _2-6 alkenyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C _2-5 alkenyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C _2-3 alkenyl substituted with 0, 1, 2, or 3 R ^h groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl and hexenyl. Such groups are substituted by 0, 1, 2, 3, 4 or 5 R ^h groups.

In certain embodiments, R ^e is C _2-10 alkynyl. In certain embodiments, R ^e is C _2-6 alkynyl. In certain embodiments, R ^e is C _2-6 alkynyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C _2-5 alkynyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C _2-4 alkynyl substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, R ^e is C _2-3 alkynyl substituted with 0, 1, 2, or 3 R ^h groups. Examples of R ^e alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl and hexynyl, is not limited to, such groups wherein Is substituted by 0, 1, 2, 3, 4, or 5 R ^h groups.

However, in certain embodiments where G is —OR ^e , R ^e is not C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, aralkyl). In certain embodiments where G is —OR ^e , R ^e is not C _2-6 alkenyl (eg, allyl).

In certain embodiments where G is —SR ^e , R ^e is not C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, aralkyl).

G is -NR ^e R ^f, and R ^f is -H or C _1-3 alkyl (e.g. methyl, ethyl, aralkyl) In certain embodiments a, R ^e is not C _1-6 alkyl.

In certain embodiments, R ^e is C _6-14 aryl. In certain embodiments, R ^e is C _6-10 aryl. In certain embodiments, R ^e is C _6-10 aryl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C ₆ aryl (eg, phenyl) substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is C ₁₀ aryl (eg, naphthyl) substituted with 0, 1, 2, 3, 4, or 5 R ^h groups.

In certain embodiments, ^Re is phenyl. In certain embodiments, R ^e is 0, 1, 2, 3, or phenyl substituted by four R ^h groups. In certain embodiments, R ^e is phenyl substituted with 0, 1, 2, or 3 R ^h groups. In certain embodiments, R ^e is 0, 1, or is phenyl substituted by two R ^h groups. In certain embodiments, R ^e is phenyl substituted with 0, or 1 R ^h group. In certain embodiments, ^Re is phenyl that is disubstituted (ie, substituted with two R ^h groups). In certain embodiments, ^Re is phenyl that is monosubstituted (ie, substituted with one R ^h group). In certain embodiments, R ^e is unsubstituted (ie, substituted with 0 R ^h groups) phenyl.

In certain embodiments, ^Re is phenyl substituted with at least one ortho R ^h group. In certain embodiments, R ^e is phenyl substituted with at least one meta R ^h group. In certain embodiments, ^Re is phenyl substituted with at least one para ^Rh group.

ここで、xは、0、1、2、3、4又は5であり、かつR^hは、下記及び本明細書において定義されている。特定の実施態様において、xは、0、1、2、3又は4である。特定の実施態様において、xは、0、1、2又は3である。特定の実施態様において、xは、0、1又は2である。特定の実施態様において、xは、0又は1である。特定の実施態様において、xは3である。特定の実施態様において、R^eは、二置換されたフェニル基である(すなわち、xは2である)。特定の実施態様において、R^eは、一置換されたフェニル基である(すなわち、xは1である)。特定の実施態様において、R^eは、非置換のフェニル基である(すなわち、xは0である)。 In certain embodiments, ^Re is a phenyl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h is defined below and herein. In certain embodiments, x is 0, 1, 2, 3 or 4. In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1. In certain embodiments, x is 3. In certain embodiments, ^Re is a disubstituted phenyl group (ie, x is 2). In certain embodiments, R ^e is a monosubstituted phenyl group (ie, x is 1). In certain embodiments, ^Re is an unsubstituted phenyl group (ie, x is 0).

ここで、R^hは、下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is a substituted or unsubstituted phenyl group of any one of the following formulas:

Here, R ^h is defined below and herein.

ここで、xは0、1、2、3、4又は5であり、かつR^hは、下記及び本明細書において定義されている。特定の実施態様において、xは、0、1、2、3又は4である。特定の実施態様において、xは、0、1、2又は3である。特定の実施態様において、xは、0、1又は2である。特定の実施態様において、xは、0又は1である。特定の実施態様において、R^eは、三置換されたナフチル基である(すなわち、xは3である)。特定の実施態様において、R^eは、二置換されたナフチル基である(すなわち、xは2である)。特定の実施態様において、R^eは、一置換されたナフチル基である(すなわち、xは1である)。特定の実施態様において、R^eは、非置換のナフチル基である(すなわち、xは0である)。 In certain embodiments, ^Re is naphthyl. In certain embodiments, ^Re is a naphthyl group of any one of the following formulas:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h is defined below and herein. In certain embodiments, x is 0, 1, 2, 3 or 4. In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1. In certain embodiments, ^Re is a trisubstituted naphthyl group (ie, x is 3). In certain embodiments, ^Re is a disubstituted naphthyl group (ie, x is 2). In certain embodiments, ^Re is a monosubstituted naphthyl group (ie, x is 1). In certain embodiments, ^Re is an unsubstituted naphthyl group (ie, x is 0).

ここで、R^hは、下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is a substituted or unsubstituted 1-naphthyl group of any one of the following formulas:

Here, R ^h is defined below and herein.

ここで、R^hは、下記及び本明細書において定義されている。 In certain embodiments, ^Re is a substituted or unsubstituted 2-naphthyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

However, in certain embodiments where G is —OR ^e , R ^e is not C ₁₀ aryl (eg, 1-naphthyl, 2-naphthyl).

In certain embodiments, R ^e is a 5-14 membered heteroaryl. In certain embodiments, R ^e is a 5-10 membered heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is 0,1,2,3,4, or five 5-8-membered heteroaryl substituted by R ^h groups. In certain embodiments, R ^e is 0, 1, 2, 3, or 4 5-6 membered heteroaryl substituted by R ^h groups. In certain embodiments, R ^e is 0,1,2,3,4, or five 9-10 membered heteroaryl substituted by R ^h groups.

Examples of R ^e heteroaryl groups include 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, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoo Xazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, These include, but are not limited to, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 R ^h groups. ing.

In certain embodiments, ^Re is 5-membered heteroaryl. In certain embodiments, R ^e is a 5-membered heteroaryl substituted with 0, 1, 2, or 3 R ^h groups. In certain embodiments, R ^e is, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, and heteroaryl selected 5-membered tetrazolyl, wherein Such groups are substituted with 0, 1, 2, or 3 R ^h groups.

ここで、Y^a、Y^b、Y^c及びY^dは独立して、CH、CR^h、O、S、N、又はNR^kから選択され、但しY^a、Y^b、Y^c及びY^dの少なくとも1つは、O、S、N又はNR^kであることを条件とし、かつここでR^h及びR^kは下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is a 5-membered heteroaryl of the formula:

Where Y ^a , Y ^b , Y ^c and Y ^d are independently selected from CH, CR ^h , O, S, N, or NR ^k , provided that Y ^a , Y ^b , Y ^c and Y ^d At least one is subject to O, S, N or NR ^k , where R ^h and R ^k are defined below and herein.

In certain embodiments of the above formula (id), Y ^a is O, S, N or NR ^k and Y ^b , Y ^c and Y ^d are independently CH, CR ^h , NR ^k or Selected from N. In certain embodiments of formula (id) above, Y ^a is O, S, N, or NR ^k and Y ^b , Y ^c, and Y ^d are independently selected from CH or CR ^h . In certain embodiments of the above formula (id), Y ^a is O, S, or NR ^k , Y ^c is N, and Y ^b and Y ^d are independently selected from CH or CR ^h. The

In certain embodiments of the above formula (id), Y ^b is O, S, or NR ^k and Y ^a , Y ^c, and Y ^d are independently selected from CH, CR ^h, or N. In certain embodiments of the above formula (id), Y ^b is O, S, or NR ^k and Y ^a , Y ^c, and Y ^d are independently selected from CH or CR ^h . In certain embodiments of the above formula (id), Y ^b is O, S, or NR ^k , Y ^d is N, and Y ^a and Y ^c are independently selected from CH or CR ^h. The

ここで、xは0、1又は2であり、かつR^h及びR^kは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換の5-員のヘテロアリールである(すなわち、xは0である)。特定の実施態様において、R^eは、置換された5-員のヘテロアリールである(例えば、xは1又は2である)。特定の実施態様において、R^eは、一置換された5-員のヘテロアリールである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換された5-員のヘテロアリールである(すなわち、xは2である)。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a substituted or unsubstituted 5-membered heteroaryl of any one of the following formulae:

Where x is 0, 1 or 2, and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted 5-membered heteroaryl (ie, x is 0). In certain embodiments, ^Re is a substituted 5-membered heteroaryl (eg, x is 1 or 2). In certain embodiments, ^Re is a monosubstituted 5-membered heteroaryl (ie, x is 1). In certain embodiments, ^Re is a disubstituted 5-membered heteroaryl (ie, x is 2). In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1又は2であり、かつR^h及びR^kは下記及び本明細書において定義されている。 However, in certain embodiments where G is —OR ^e , R ^e is not, for example, thiazolyl of the formula:

Where x is 0, 1 or 2, and R ^h and R ^k are defined below and herein.

In certain embodiments, ^Re is 6-membered heteroaryl. In certain embodiments, R ^e is a 6-membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, R ^e is pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyridinyl). Pyramidinyl, 5-pyrimidinyl), 6-membered heteroaryl selected from the group consisting of pyrazinyl, triazinyl and tetrazinyl, wherein such groups are 0, 1, 2, 3 or 4 R ^h Substituted by a group.

ここで、W^a、W^b、W^c、W^d及びW^eは独立して、CH、CR^h、又はNから選択され、但しW^a、W^b、W^c、W^d及びW^eの少なくとも1つはNであることを条件とし、かつここでR^hは下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is a 6-membered heteroaryl group of the formula:

^{Here, W a, W b, W} c, the W ^d and W ^e are independently, CH, CR ^h, or is selected from N, where W ^a, W ^b, at least W ^c, W ^d and W ^e One is contingent on N, and R ^h is defined below and herein.

ここで、xは0、1、2、3又は4であり、かつR^hは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピリンジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピリンジニルである(例えば、xは1、2、3又は4である)。特定の実施態様において、R^eは、一置換されたピリンジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピリンジニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたピリンジニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is pyrindinyl (pyrindinyl) group. In certain embodiments, R ^e is 0, 1, 2, 3, or pyrindinyl group substituted by four R ^h groups. For example, in certain embodiments, R ^e is a pyrindinyl group of the formula:

Where x is 0, 1, 2, 3 or 4 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted pyrindinyl (ie, x is 0). In certain embodiments, R ^e is a pyrindinyl substituted (e.g., x is 1, 2, 3 or 4). In certain embodiments, R ^e is a pyrindinyl monosubstituted (ie, x is 1). In certain embodiments, R ^e is a pyrindinyl which is disubstituted (ie, x is 2). In certain embodiments, R ^e is a pyrindinyl which is trisubstituted (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is, for example, 2-pyrindinyl group of the formula (ie), where W ^a is N, and W ^b, W ^c, the W ^d and W ^e are independently, CH Or CR ^h . In certain embodiments, R ^e is, for example, 3-pyrindinyl group of the formula (ie), where W ^b is N, and W ^a, W ^c, the W ^d and W ^e are independently, CH Or CR ^h . In certain embodiments, R ^e is, for example, a 4-pyrindinyl group of the formula (ie), wherein W ^c is N, and W ^a, W ^b, W ^d and W ^e are independently, CH Or CR ^h .

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted 2-pyridinyl group of any one of the following formulas:

Here, R ^h is defined below and herein.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, ^Re is a substituted or unsubstituted 3-pyridinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted 4-pyridinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、xは0、1、2、又は3であり、かつR^hは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピリダジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピリダジニルである(例えば、xは1、2、又は3である)。特定の実施態様において、R^eは、一置換されたピリダジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピリダジニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたピリダジニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a pyridazinyl group. In certain embodiments, R ^e is a pyridazinyl group substituted with 0, 1, 2, or 3 R ^h groups. For example, in certain embodiments, R ^e is a pyridazinyl group of the formula:

Where x is 0, 1, 2, or 3 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted pyridazinyl (ie, x is 0). In certain embodiments, R ^e is substituted pyridazinyl (eg, x is 1, 2, or 3). In certain embodiments, R ^e is monosubstituted pyridazinyl (ie, x is 1). In certain embodiments, R ^e is disubstituted pyridazinyl (ie, x is 2). In certain embodiments, R ^e is a trisubstituted pyridazinyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is, for example, a 3-pyridazinyl group of the formula (ie), wherein W ^a and W ^b is N, and W ^c, the W ^d and W ^e are independently, CH Or CR ^h . In certain embodiments, R ^e is, for example, a 4-pyridazinyl group of the formula (ie), wherein W ^b and W ^c is N, and W ^a, the W ^d and W ^e are independently, CH Or CR ^h .

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted 3-pyridazinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted 4-pyridazinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、xは0、1、2、又は3であり、かつR^hは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピリミジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピリミジニルである(例えば、xは1、2、又は3である)。特定の実施態様において、R^eは、一置換されたピリミジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピリダジニル(pyridazinyl)である(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたピリミジニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a pyrimidinyl group. In certain embodiments, R ^e is a pyrimidinyl group substituted with 0, 1, 2, or 3 R ^h groups. For example, in certain embodiments, R ^e is a pyrimidinyl group of the formula:

Where x is 0, 1, 2, or 3 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted pyrimidinyl (ie, x is 0). In certain embodiments, R ^e is substituted pyrimidinyl (eg, x is 1, 2, or 3). In certain embodiments, R ^e is monosubstituted pyrimidinyl (ie, x is 1). In certain embodiments, R ^e is a disubstituted pyridazinyl (pyridazinyl) (ie, x is 2). In certain embodiments, R ^e is a trisubstituted pyrimidinyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is, for example, a 2-pyrimidinyl group of the formula (ie), wherein W ^a and W ^e is N, and W ^b, W ^c and W ^d are independently, CH Or CR ^h . In certain embodiments, R ^e is, for example, a 4-pyrimidinyl group of the formula (ie), wherein W ^a and W ^c is N, and W ^b, W ^d and W ^e are independently, CH Or CR ^h . In certain embodiments, R ^e is, for example, a 5-pyrimidinyl group of the formula (ie), wherein W ^b and W ^d is N, and W ^a, the W ^c and W ^e are independently, CH Or CR ^h .

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, ^Re is a substituted or unsubstituted 2-pyrimidinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, ^Re is a substituted or unsubstituted 4-pyrimidinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, ^Re is a substituted or unsubstituted 5-pyrimidinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、xは0、1、2、又は3であり、かつR^hは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピラジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピラジニルである(例えば、xは1、2、又は3である)。特定の実施態様において、R^eは、一置換されたピラジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピラジニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたピラジニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a pyrazinyl group. In certain embodiments, R ^e is a pyrazinyl group substituted with 0, 1, 2, or 3 R ^h groups. For example, in certain embodiments, R ^e is a pyrazinyl group of the formula:

Where x is 0, 1, 2, or 3 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted pyrazinyl (ie, x is 0). In certain embodiments, R ^e is substituted pyrazinyl (eg, x is 1, 2, or 3). In certain embodiments, R ^e is monosubstituted pyrazinyl (ie, x is 1). In certain embodiments, R ^e is a disubstituted pyrazinyl (ie, x is 2). In certain embodiments, R ^e is a trisubstituted pyrazinyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted pyrazinyl group of any one of the following formulas:

Here, R ^h is defined below and herein.

ここで、xは0、1、又は2であり、かつR^hは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピラジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピラジニルである(例えば、xは1、又は2である)。特定の実施態様において、R^eは、一置換されたピラジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピラジニルである(すなわち、xは2である)。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a triazinyl group. In certain embodiments, R ^e is a triazinyl group substituted with 0, 1, or 2 R ^h groups. For example, in certain embodiments, R ^e is a triazinyl group of the formula:

Where x is 0, 1, or 2, and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted pyrazinyl (ie, x is 0). In certain embodiments, R ^e is a substituted pyrazinyl (e.g., x is 1, or 2). In certain embodiments, R ^e is monosubstituted pyrazinyl (ie, x is 1). In certain embodiments, R ^e is a disubstituted pyrazinyl (ie, x is 2). In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted triazinyl group of any one of the following formulae:

Here, R ^h is defined below and herein.

ここで、xは0、又は1であり、かつR^hは下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピラジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピラジニルである(例えば、xは1である)。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is tetrazinyl group. In certain embodiments, R ^e is a tetrazinyl group substituted with 0, or 1 R ^h group. For example, in certain embodiments, R ^e is a tetrazinyl group of the formula:

Where x is 0 or 1, and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted pyrazinyl (ie, x is 0). In certain embodiments, R ^e is a substituted pyrazinyl (e.g., x is 1). In certain embodiments, x is 0 or 1.

ここで、R^hは下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted tetrazinyl group of any one of the following formulas:

Here, R ^h is defined below and herein.

In certain embodiments, R ^e is a 9-membered heteroaryl (e.g., 5,6-bicyclic heteroaryl). In certain embodiments, R ^e is a 5,6 bicyclic heteroaryl substituted by 2, 3, 4 or 5 R ^h groups. In certain embodiments, R ^e is indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, A 5,6-bicyclic heteroaryl selected from benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl, wherein such groups are 0, 1, Substituted by 2, 3, 4 or 5 R ^h groups.

ここで、Y^e、Y^f、Y^g、Yⁱ、Y^j、Y^k及びY^mは独立して、C、CH、CR^h、O、S、N、又はNR^kであり、かつYⁿは、C又はNであり、但しY^e、Y^f、Y^gの少なくとも1つはO、S、N又はNR^kから選択されることを条件とし、ここでR^h及びR^kは、下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is located in the following formula 5,6-bicyclic heteroaryl:

Where Y ^e , Y ^f , Y ^g , Y ⁱ , Y ^j , Y ^k and Y ^m are independently C, CH, CR ^h , O, S, N, or NR ^k and Y ⁿ Is C or N provided that at least one of Y ^e , Y ^f , Y ^g is selected from O, S, N or NR ^k , where R ^h and R ^k are As defined herein.

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換の5,6-二環式ヘテロアリールである(すなわち、xは0である)。特定の実施態様において、R^eは、置換された5,6-二環式ヘテロアリールである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換された5,6-二環式ヘテロアリールである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換された5,6-二環式ヘテロアリールである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換された5,6-二環式ヘテロアリールである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a 5,6-bicyclic heteroaryl group of formula (if), wherein Y ^e is selected from O, S, or NR ^k and Y ⁿ is C And Y ^f , Y ^g , Y ⁱ , Y ^j , Y ^k and Y ^m are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted 5,6-bicyclic heteroaryl (ie, x is 0). In certain embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, x is 1). In certain embodiments, ^Re is a disubstituted 5,6-bicyclic heteroaryl (ie, x is 2). In certain embodiments, R ^e is trisubstituted 5,6-bicyclic heteroaryl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換の5,6-二環式ヘテロアリールである(すなわち、xは0である)。特定の実施態様において、R^eは、置換された5,6-二環式ヘテロアリールである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換された5,6-二環式ヘテロアリールである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換された5,6-二環式ヘテロアリールである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換された5,6-二環式ヘテロアリールである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is 5,6-bicyclic heteroaryl, wherein Y ^e is selected from O, S, or NR ^k ; Y ^g is N; Y ⁿ is C Y ^f is C, CH, or CR ^h or N, and Y ⁱ , Y ^j , Y ^k, and Y ^m are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted 5,6-bicyclic heteroaryl (ie, x is 0). In certain embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, x is 1). In certain embodiments, ^Re is a disubstituted 5,6-bicyclic heteroaryl (ie, x is 2). In certain embodiments, R ^e is trisubstituted 5,6-bicyclic heteroaryl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換の5,6-二環式ヘテロアリールである(すなわち、xは0である)。特定の実施態様において、R^eは、置換された5,6-二環式ヘテロアリールである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換された5,6-二環式ヘテロアリールである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換された5,6-二環式ヘテロアリールである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換された5,6-二環式ヘテロアリールである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is 5,6-bicyclic heteroaryl, wherein Y ^e is NR ^k , S or O; Y ^m is N; Y ⁿ is C And Y ^f , Y ^g , Y ⁱ , Y ^j , and Y ^k are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted 5,6-bicyclic heteroaryl (ie, x is 0). In certain embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, x is 1). In certain embodiments, ^Re is a disubstituted 5,6-bicyclic heteroaryl (ie, x is 2). In certain embodiments, R ^e is trisubstituted 5,6-bicyclic heteroaryl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換の5,6-二環式ヘテロアリールである(すなわち、xは0である)。特定の実施態様において、R^eは、置換された5,6-二環式ヘテロアリールである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換された5,6-二環式ヘテロアリールである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換された5,6-二環式ヘテロアリールである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換された5,6-二環式ヘテロアリールである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is 5,6-bicyclic heteroaryl, wherein Y ^g is O, S, or NR ^k ; Y ^m is N; Y ⁿ is C Yes; and Y ^e , Y ^f , Y ⁱ , Y ^j , and Y ^k are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted 5,6-bicyclic heteroaryl (ie, x is 0). In certain embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, x is 1). In certain embodiments, ^Re is a disubstituted 5,6-bicyclic heteroaryl (ie, x is 2). In certain embodiments, R ^e is trisubstituted 5,6-bicyclic heteroaryl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換の5,6-二環式ヘテロアリールである(すなわち、xは0である)。特定の実施態様において、R^eは、置換された5,6-二環式ヘテロアリールである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換された5,6-二環式ヘテロアリールである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換された5,6-二環式ヘテロアリールである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換された5,6-二環式ヘテロアリールである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is 5,6-bicyclic heteroaryl, wherein Y ^e is selected from N; Y ⁿ is N; and Y ^f , Y ⁱ , Y ^j , Y ^k and Y ^m are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted 5,6-bicyclic heteroaryl (ie, x is 0). In certain embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted 5,6-bicyclic heteroaryl (ie, x is 1). In certain embodiments, ^Re is a disubstituted 5,6-bicyclic heteroaryl (ie, x is 2). In certain embodiments, R ^e is trisubstituted 5,6-bicyclic heteroaryl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is 10-membered heteroaryl (e.g. 6,6-bicyclic heteroaryl). In certain embodiments, R ^e is 6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e is a 6,6-bicyclic heteroaryl selected from naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl, wherein such group is Substituted by 0, 1, 2, 3, 4, or 5 R ^h groups.

ここで、W^f、W^g、W^h、Wⁱ、W^j、W^k、W^m及びWⁿは独立して、C、CH、CR^h又はNから選択され、但しW^f、W^g、W^h、Wⁱ、W^j、W^k、W^m及びWⁿの少なくとも1つは、Nであることを条件とし、かつここでR^hは下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is located in the following formula 6,6-bicyclic heteroaryl:

Where W ^f , W ^g , W ^h , W ⁱ , W ^j , W ^k , W ^m and W ⁿ are independently selected from C, CH, CR ^h or N, provided that W ^f , W ^g , At least one of W ^h , W ⁱ , W ^j , W ^k , W ^m, and W ⁿ is subject to N, where R ^h is defined below and herein.

ここで、xは0、1、2、3、4又は5であり、かつR^hは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のキノリニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたキノリニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたキノリニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたキノリニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたキノリニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is, for example, of formula (ig); a quinolinyl group, wherein W ⁱ is N, and W ^g , W ^h , W ^f , W ^j , W ^k , W ^m and W ⁿ is independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is a quinolinyl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted quinolinyl (ie, x is 0). In certain embodiments, R ^e is substituted quinolinyl (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, R ^e is monosubstituted quinolinyl (ie, x is 1). In certain embodiments, R ^e is disubstituted quinolinyl (ie, x is 2). In certain embodiments, R ^e is a three a substituted quinolinyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1、2、3、4又は5であり、かつR^hは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のイソキノリニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたイソキノリニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたイソキノリニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたイソキノリニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたイソキノリニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is an isoquinolinyl group; eg, a group of formula (ig), where W ^h is N, and W ^f , W ^g , W ⁱ , W ^j , W ^k , W ^m And W ⁿ are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is an isoquinolinyl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted isoquinolinyl (ie, x is 0). In certain embodiments, R ^e is an isoquinolinyl substituted (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, R ^e is monosubstituted isoquinolinyl (ie, x is 1). In certain embodiments, R ^e is disubstituted isoquinolinyl (ie, x is 2). In certain embodiments, R ^e is an isoquinolinyl which is trisubstituted (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

ここで、xは0、1、2、3、4又は5であり、かつR^hは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のキノキサリニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたキノキサリニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたキノキサリニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたキノキサリニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたイソキノリニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a quinoxalinyl group; such as a group of formula (ig), where W ^f and W ⁱ are N, and W ^g , W ^h , W ^j , W ^k , W ^m And W ⁿ are independently C, CH, or CR ^h . For example, in certain embodiments, R ^e is an quinoxalinyl group of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h is defined below and herein. In certain embodiments, R ^e is unsubstituted quinoxalinyl (ie, x is 0). In certain embodiments, R ^e is a quinoxalinyl substituted (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, R ^e is a quinoxalinyl monosubstituted (ie, x is 1). In certain embodiments, R ^e is a quinoxalinyl which is disubstituted (ie, x is 2). In certain embodiments, R ^e is an isoquinolinyl which is trisubstituted (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is 3-14 membered heterocyclyl. In certain embodiments, R ^e is a 3-14 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ^h groups. In certain embodiments, R ^e is 5-10 membered optionally substituted heterocyclyl 0,1,2,3,4 or 5 R ^h groups. In certain embodiments, R ^e is 5-8 membered heterocyclyl substituted by 0,1,2,3,4 or 5 R ^h groups. In certain embodiments, R ^e is a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ^h groups. In certain embodiments, R ^e is 9-10 membered optionally substituted heterocyclyl 0,1,2,3,4 or 5 R ^h groups.

Examples of heterocyclyl R ^e groups include azirdinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5 -Dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxecanyl, thiepanyl, azocanyl, thiepanyl, azocanyl (oxecanyl), thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetra Drobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyl Lydinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1,4] diazepinyl, 1,4, 5,7-tetrahydro-pyrano [3,4-b] 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-dihydrofuro [2,3-b] Pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo [2,3-b] pyridinyl, 4,5,6,7-te And la-hydrofuro [3,2-c] pyridinyl and 4,5,6,7-tetrahydrothieno [3,2-b] pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl However, it is not limited thereto, where such groups are substituted by 0, 1, 2, 3, 4 or 5 R ^h groups.

In certain embodiments, R ^e is been 6-membered heterocyclyl substituted by 0,1, 2,3, 4 or 5 R ^h groups. In certain embodiments, R ^e is, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, selected piperazinyl, morpholinyl, dithianyl, dioxanyl, and Toriajinaniru, heterocyclyl 6-membered, wherein such Such groups are substituted by 0, 1, 2, 3, 4 or 5 R ^h groups.

ここで、W^o、W^p、W^q、W^r、及びW^sは独立して、CH₂、CHR^h、C(R^h)₂、NR^k、O又はSから選択され、かつW^tは、N、CH、CR^hであり、但しW^o、W^p、W^q、W^r、及びW^sの少なくとも1つは、N、NR^k、O又はSから選択され、かつここでR^h及びR^kは、下記及び本明細書において定義されている。 For example, in certain embodiments, ^Re is a 6-membered heterocyclyl having the formula:

Where W ^o , W ^p , W ^q , W ^r and W ^s are independently selected from CH ₂ , CHR ^h , C (R ^h ) ₂ , NR ^k , O or S, and W ^t is , N, CH, CR ^h , wherein at least one of W ^o , W ^p , W ^q , W ^r , and W ^s is selected from N, NR ^k , O, or S, and R ^h and R ^k is defined below and herein.

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピペリジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピペリジニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたピペリジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピペリジニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたピペリジニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is piperidinyl group. In certain embodiments, R ^e is a piperidinyl group substituted by 0, 1, 2, 3, 4 or 5 R ^h groups, for example of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted piperidinyl (ie, x is 0). In certain embodiments, ^Re is substituted piperidinyl (eg, x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted piperidinyl (ie, x is 1). In certain embodiments, R ^e is a disubstituted piperidinyl (ie, x is 2). In certain embodiments, R ^e is a trisubstituted-piperidinyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is, for example, a 1-piperidinyl group of formula (ih), where W ^t is N, and W ^o , W ^p , W ^q , W ^r , and W ^s are independently And selected from CH ₂ , CHR ^h , and C (R ^h ) ₂ . In certain embodiments, R ^e is, for example, a 2-piperidinyl group of formula (ih), where W ^o is NR ^k ; W ^p , W ^q , W ^r , and W ^s are independently CHR ^h , C (R ^h ) ₂ , or CH ₂ ; and W ^t is CH or CR ^h . In certain embodiments, R ^e is, for example, a 3-piperidinyl group of formula (ih), where W ^p is NR ^k ; W ^o , W ^q , W ^r , and W ^s are independently CHR ^h , C (R ^h ) ₂ , or CH ₂ ; and W ^t is CH or CR ^h . In certain embodiments, R ^e is, for example, a 4-piperidinyl group of formula (ih), where W ^q is NR ^k ; W ^o , W ^p , W ^r , and W ^s are independently CHR ^h , C (R ^h ) ₂ , or CH ₂ ; and W ^t is CH or CR ^h .

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のピペラジニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたピペラジニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたピペラジニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたピペラジニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたピペラジニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a piperazinyl group. In certain embodiments, R ^e is a piperazinyl group substituted by 0, 1, 2, 3, or 4 R ^h groups, for example of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is an unsubstituted piperazinyl (ie, x is 0). In certain embodiments, R ^e is substituted piperazinyl (eg, x is 1, 2, 3, 4 or 5). In certain embodiments, ^Re is a monosubstituted piperazinyl (ie, x is 1). In certain embodiments, R ^e is a disubstituted piperazinyl (ie, x is 2). In certain embodiments, R ^e is a three-substituted piperazinyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is, for example, a 1-piperazinyl group of formula (ih), where W ^t is N, W ^q is NR ^k , and W ^o , W ^p , W ^r , And W ^s are independently selected from CH ₂ , CHR ^h , C (R ^h ) ₂ . In certain embodiments, R ^e is, for example, a 2-piperazinyl group of formula (ih), where W ^o and W ^r are independently NR ^k and W ^p , W ^q , W ^r and W ^s is independently CHR ^h , C (R ^h ) ₂ , CH ₂ ; and W ^t is CH or CR ^h .

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のモルホリニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたモルホリニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたモルホリニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたモルホリニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたモルホリニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is morpholinyl group. In certain embodiments, R ^e is a morpholinyl group substituted by 0, 1, 2, 3, or 4 R ^h groups, for example of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted morpholinyl (ie, x is 0). In certain embodiments, ^Re is substituted morpholinyl (eg, x is 1, 2, 3, 4 or 5). In certain embodiments, R ^e is monosubstituted morpholinyl (ie, x is 1). In certain embodiments, R ^e is disubstituted morpholinyl (ie, x is 2). In certain embodiments, R ^e is morpholinyl which is trisubstituted (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is a morpholinyl group of formula (ih), where W ^t is N, W ^q is O, and W ^o , W ^p , W ^r , and W ^s are Independently, it is selected from CH ₂ , CHR ^h , and C (R ^h ) ₂ .

ここで、xは0、1、2、3、4又は5であり、かつR^h及びR^kは、下記及び本明細書において定義されている。特定の実施態様において、R^eは、非置換のジオキサニルである(すなわち、xは0である)。特定の実施態様において、R^eは、置換されたジオキサニルである(例えば、xは1、2、3、4又は5である)。特定の実施態様において、R^eは、一置換されたジオキサニルである(すなわち、xは1である)。特定の実施態様において、R^eは、二置換されたジオキサニルである(すなわち、xは2である)。特定の実施態様において、R^eは、三置換されたジオキサニルである(すなわち、xは3である)。特定の実施態様において、xは0、1、2又は3である。特定の実施態様において、xは0、1又は2である。特定の実施態様において、xは0又は1である。 In certain embodiments, R ^e is a dioxanyl group. In certain embodiments, R ^e is a dioxanyl group substituted by 0, 1, 2, 3, or 4 R ^h groups, for example of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ^h and R ^k are defined below and herein. In certain embodiments, R ^e is unsubstituted dioxanyl (ie, x is 0). In certain embodiments, R ^e is a dioxanyl substituted (e.g., x is 1, 2, 3, 4 or 5). In certain embodiments, R ^e is a dioxanyl monosubstituted (ie, x is 1). In certain embodiments, R ^e is a dioxanyl which is disubstituted (ie, x is 2). In certain embodiments, R ^e is trisubstituted dioxanyl (ie, x is 3). In certain embodiments, x is 0, 1, 2, or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R ^e is, for example, a dioxanyl group of formula (ih), where W ^o and W ^r are O, and W ^p , W ^q , W ^r , and W ^s are independently , CHR ^h , C (R ^h ) ₂ , or CH ₂ ; and W ^t is CH or CR ^h .

Other 6-membered heterocyclyl R ^e groups encompassed by formula (ih) are monosaccharide sugars such as ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, iodose. And pyranosides selected from galactose and talose.

In certain embodiments, R ^e is C _3-10 carbocyclyl. In certain embodiments, R ^e is C _3-10 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ^h groups. In certain embodiments, R ^e is C _5-8 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ^h groups. In certain embodiments, R ^e is C _5-6 carbocyclyl substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, R ^e is C _9-10 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ^h groups.

Examples of R ^e C _3-10 carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, and cycloheptadienyl. Where such groups are substituted by 0, 1, 2, 3, 4, or 5 R ^h groups.

(R ^{f of} group G)
G is defined as -SO ₂ NR ^f R ^e , -PO ₂ NR ^f R ^e ,-(C = O) NR ^f R ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -NR ^f SO ₂ R ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -O (C = NR ^f ) NR ^f R ^e , -NR ^f (C = NR ^f ) OR ^e , and-[N (R ^f ) ₂ R ^{e] +} X ^- is selected from wherein X ^- is in certain embodiments a counterion, each R ^f which is bonded to the nitrogen atom independently, -H or C _1-10 alkyl, or amino Either selected from protecting groups or R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring.

In certain embodiments, R ^f is H or a C _1-10 alkyl group.

In certain embodiments, R ^f is H.

In certain embodiments, R ^f is a C _1-10 alkyl group. In certain embodiments, R ^f is C _1-10 alkyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. Examples of R ^f alkyl groups include, but are not limited to, methyl, ethyl, propyl, allyl, and benzyl. In certain embodiments, R ^f is unsubstituted methyl, ie —CH ₃ . In certain embodiments, R ^f is unsubstituted ethyl, ie —CH ₂ CH ₃ .

In certain embodiments, R ^f is an amino protecting group. For example, in certain embodiments, R ^f is -OH, -OR ⁱ , -N (R ^k ) ₂ , -C (= O) R ⁱ , -C (= O) N (R ^k ) ₂ , -CO ₂ R ⁱ , -SO ₂ R ⁱ , -C (= NR ^k ) R ⁱ , -C (= NR ^k ) OR ^j , -C (= NR ^k ) N (R ^k ) ₂ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , -SO ₂ OR ⁱ , -SOR ⁱ , -C (= S) N (R ^k ) ₂ , -C (= O) SR ⁱ , -C (= S) SR ⁱ C _1-10 alkyl (eg aralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups Where R ⁱ , R ^k , R ^m are defined below and herein.

However, in certain embodiments where G is —NR ^e R ^f and R ^f is —H or C _1-3 alkyl, R ^e is not C _1-6 alkyl or thiazolyl.

Further, in certain embodiments where G is —OC (═O) NR ^f R ^e , R ^e and R ^f are not both —CH ₃ .

Alternatively, in certain embodiments, R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring; for example, G is —SO ₂ NR ^f R ^e , -PO ₂ NR ^f R ^e ,-(C = O) NR ^f R ^e , -ONR ^f R ^e , -OPO ₂ NR ^f R ^e , -NR ^f R ^e , -O (C = O) NR ^f R ^{e , -NR f (C = NR f} ) NR f R e, -O (C = NR f) NR f R e, and _{^{- [N (R f) 2}} R e] + X - a, where in X ^- Is a counter ion. In certain embodiments, when R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, the heterocyclyl ring or heteroaryl ring is defined below and herein. Substituted by 0, 1, 2, 3, 4, or 5 R ^h groups as defined in

In certain embodiments, R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring. In certain embodiments, R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 5-10 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 5-8 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 5-6 membered heterocyclyl ring substituted with 0, 1, 2 or 3 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 9-10 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups.

In certain embodiments, R ^e and R ^f are combined and aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, dihydropyridinyl, thianyl. , Piperazinyl, morpholinyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, indolinyl, isoindolinyl, tetrahydrobenzothienyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, Forms a heterocyclyl group, selected from indolinyl, and phthalimidyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 R ^h groups.

ここで、xは0、1、2、又は3であり、かつR^h及びR^kは、下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e and R ^f combine to form a 5-membered heterocyclyl ring selected from the following groups:

Where x is 0, 1, 2, or 3 and R ^h and R ^k are defined below and herein.

ここで、xは0、1、2、又は3であり、かつR^h及びR^kは、下記及び本明細書において定義されている。 In certain embodiments, R ^e and R ^f combine to form a 6-membered heterocyclyl ring selected from the following groups:

Where x is 0, 1, 2, or 3 and R ^h and R ^k are defined below and herein.

However, in certain embodiments where G is —NR ^e R ^f , R ^e and R ^f do not combine to form a pyrrolidinyl, piperidinyl or azepanyl ring.

In certain embodiments, R ^e and R ^f are joined to form a 5-14 membered heteroaryl ring. In certain embodiments, R ^e and R ^f are joined to form a 5-14 membered heteroaryl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 5-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 5-8 membered heteroaryl ring substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 5-6 membered heteroaryl ring substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, R ^e and R ^f are joined to form a 9-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups.

ここで、xは0、1、又は2であり、かつR^h及びR^kは、下記及び本明細書において定義されている。 In certain embodiments, R ^e and R ^f combine to form a 5-membered heteroaryl ring selected from:

Where x is 0, 1, or 2, and R ^h and R ^k are defined below and herein.

ここで、xは0又は1であり、かつR^hは、下記及び本明細書において定義されている。 However, in certain embodiments where G is —NR ^f R ^e , R ^e and R ^f do not combine to form a 1,2,4-triazolyl ring of the formula:

Where x is 0 or 1 and R ^h is defined below and herein.

ここで、xは0、1、2、又は3であり、かつR^h及びR^kは、下記及び本明細書において定義されている。 In certain embodiments, R ^e and R ^f are joined to form a 9-membered heteroaryl (“5,6-bicyclic heteroaryl”) ring, selected from:

Where x is 0, 1, 2, or 3 and R ^h and R ^k are defined below and herein.

(Substituent of group G)
(Embodiment of R ^h)
As used above and herein, each instance of R ^h is independently halogen (fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I)), -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ⁱ , -ON (R ^k ) ₂ , -N (R ^k ) ₂ , -N (R ^k ) _{^{3 + X -, -N (OR}} j) R k, -SH, -SR i, -SSR j, -C (= O) R i, -CO 2 H, -CHO, -CO 2 R i, -OC (= O) R ⁱ , -OCO ₂ R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -NR ^k C (= O) N (R ^k ) ₂ , -C (= NR ^k ) R ⁱ , -C (= NR ^k ) OR ⁱ , -OC (= NR ^k ) R ⁱ , -OC (= NR ^k ) OR ⁱ , -C (= NR ^k ) N (R ^k ) ₂ , -OC (= NR ^k ) N (R ^k ) ₂ , -NR ^k C (= NR ^k ) N (R ^k ) ₂ , -C (= O) NR ^k SO ₂ R ⁱ , -NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , -SO ₂ OR ⁱ , -OSO ₂ R ⁱ , -S (= O) R ⁱ , -OS (= O) R ⁱ , -Si (R ⁱ ) ₃ , -OS ⁱ (R ⁱ ) ₃ , -C (= S) N (R ^k ) ₂ , -C (= O) SR ⁱ , -C (= S) SR ⁱ , -SC (S) SR ⁱ , -P (= O) ₂ R ⁱ , -OP (= O) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -OP (= O) (R ⁱ ) ₂ , -OP (= O) (OR ^j ) ₂ , -P (= O) ₂ N (R ^k ) ₂ , -OP (= O) ₂ N (R ^k ) ₂ , -P (= O) (NR ^k ) ₂ , -OP (= O) (NR ^k ) ₂ , -NR ^k P (= O) (OR ^j ) ₂ , -NR ^k P (= O) (NR ^k ) ₂ , -P (R ^j ) ₂ , -P (R ^j ) ₃ , -OP (R ^j ) ₂ , -OP (R ^j ) ₃ , -B (OR ^j ) ₂ , -BR ⁱ (OR ^j ) , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 member Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups. ;
Each example of R ⁱ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4 or Substituted by 5 R ^m groups;
Each example of R ^k is independently hydrogen, -OH, -OR ⁱ , -N (R ^j ) ₂ , -CN, -C (= O) R ⁱ , -C (= O) N (R ^j ) ₂ , -CO ₂ R ⁱ , -SO ₂ R ⁱ , -C (= NR ^j ) OR ⁱ , -C (= NR ^j ) N (R ^j ) ₂ , -SO ₂ N (R ^j ) ₂ , -SO ₂ R ^j , -SO ₂ OR ^j , -SOR ⁱ , -C (= S) N (R ^j ) ₂ , -C (= O) SR ^j , -C (= S) SR ^j , -P (= O ) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -P (= O) ₂ N (R ^j ) ₂ , -P (= O) (NR ^j ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ^j groups attached to an N atom join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl And each of the heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups;
Each instance of R ^j is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ^j groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl Forming an aryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups;
Each example of R ^m is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H _{, -SO 3 H, -OH, -OR} o, -ON (R n) 2, -N (R n) 2, -N (R n) 3 + X -, -N (OR o) R n, - ^{SH, -SR o, -SSR o,} -C (= O) R o, -CO 2 H, -CO 2 R o, -OC (= O) R o, -OCO 2 R o, -C (= O ) N (R ⁿ ) ₂ , -OC (= O) N (R ⁿ ) ₂ , -NR ⁿ C (= O) R ^o , -NR ⁿ CO ₂ R ^o , -NR ⁿ C (= O) N ( R ⁿ ) ₂ , -C (= NR ⁿ ) OR ^o , -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) OR ^o , -C (= NR ⁿ ) N (R ⁿ ) ₂ ,- ^{OC (= NR n) n (} R n) 2, -NR n C (= NR n) n (R n) 2, -NR n SO 2 R o, -SO 2 n (R n) 2, -SO 2 R ^o , -SO ₂ OR ^o , -OSO ₂ R ^o , -S (= O) R ^o , -Si (R ^o ) ₃ , -OSi (R ^o ) ₃ , -C (= S) N (R ⁿ _{) 2, -C (= O)} SR o, -C (= S) SR o, -SC (= S) SR o, -P (= O) 2 R o, -P (= O) (R o) ₂ , -OP (= O) (R ^o ) ₂ , -OP (= O) (OR ^o ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14 membered f It is selected from Roariru, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted 0,1,2,3,4, or by five R ^p group Or two geminal R ^m substituents can be joined to form ═O or ═S;
Each example of R ^o is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ^p groups;
Each example of R ⁿ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Selected from C _6-10 aryl, and 5-10 membered heteroaryl, or two R ⁿ groups bonded to the N atom are bonded together to form a 3-14 membered heterocyclyl or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^p groups Is; and
Each example of R ^p is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H , -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, --NH (C _1-6 alkyl) ₂ X, --NH ₂ (C _1-6 alkyl) X, --NH ₃ X, --N (OC _1-6 alkyl) (C _1-6 alkyl), --N (OH ) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (= O) (C _1-6 alkyl),- CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ ,- C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _{1- 6} alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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} (C 1-6 alkyl), - OC (NH) NH 2, - NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N (C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl,- Si (C _1-6 alkyl) 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) SC 1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) ( OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, 3-14 membered heterocyclyl, or a 5-14 membered heteroaryl; or two geminal R ^p substituent bonded, = O Wakashi It can form the = S;
Here, X ⁻ is a counter ion. ).

In certain embodiments, R ^h is fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -OH, -OR i, - _{^{SR i, -SO 2 H, -SO}} 3 H, -N (R k) 2, -N (R k) 3 + X -, -C (= O) R i, -CO 2 H, -CHO, - CO ₂ R ⁱ , -OC (= O) R ⁱ , -OCO ₂ R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -NR ^k C (= O) N (R ^k ) ₂ , -C (= NR ^k ) R ⁱ , -C (= NR ^k ) OR ⁱ , -OC (= NR ^k ) R ⁱ , -OC (= NR ^k ) OR ⁱ , -C (= NR ^k ) N (R ^k ) ₂ , -OC (= NR ^k ) N (R ^k ) ₂ , -NR ^k C (= NR ^k ) N (R ^k ) ₂ , -C (= O) NR ^k SO ₂ R ⁱ , -NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , -SO ₂ OR ⁱ , -OSO ₂ R ⁱ , -S (= O) R ⁱ , -OS (= O) R ⁱ , -C (= S) N (R ^k ) ₂ , -C (= O) SR ⁱ , -C (= S) SR ⁱ , -SC (S) SR ⁱ , -P (= O) ₂ R ⁱ , -OP (= O) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -OP (= O) (R ⁱ ) ₂ , -OP (= O) (OR ^j ) ₂ , -P (= O) ₂ N (R ^k ) ₂ , -OP (= O) ₂ N (R ^k ) ₂ , -P (= O) (NR ^k ) ₂ , -OP (= O) (NR ^k ) ₂ , -NR ^k P (= O) (OR ^j ) ₂ , -NR ^k P (= O) (NR ^k ) ₂ , -B (OR ^j ) ₂ , -BR ⁱ (OR ^j ), C _1-10 alkyl, -C _1-10 Selected from perhaloalkyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is Independently substituted by 0, 1, 2, 3, 4 or 5 R ^m groups; and wherein X ⁻ is a counter ion.

In certain embodiments, R ^h is fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -OH, -OR i, - ^{SR i, -N (R k)} 2, -N (R k) 3 + X -, -C (= O) R i, -CO 2 R i, -CO 2 H, -OC (= O) R i , -OCO ₂ R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -NR ^k C (= O) N (R ^k ) ₂ , -C (= O) NR ^k SO ₂ R ⁱ , -NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , C _1-10 alkyl, C ₆ aryl, and 5-6 membered heteroaryl, wherein each of alkyl, aryl, and heteroaryl is independently 0, 1, 2, 3, Or is substituted by four R ^m groups; and where X ⁻ is a counter ion.

In certain embodiments, R ^h is —OR ⁱ , eg, selected from —OCH ₃ , —OCF ₃ , —OCH ₂ CH ₃ , —OCH ₂ CF ₃ , —OiPr, and —OnBu.

In certain embodiments, R ^h is —SR ⁱ , eg, selected from —SCH ₃ .

In certain embodiments, R ^h is, for example, -NH ₂ and -NH ₃ ⁺ X ^- is selected from, -N (R ^k) _2, or _{^{-N (R k) 3 + X}} - is.

In certain embodiments, R ^h is —C (═O) R ⁱ , eg, selected from —C (═O) CH ₃ .

In certain embodiments, R ^h is —CO ₂ R ⁱ , eg, selected from —CO ₂ CH ₃ .

In certain embodiments, R ^h is, for example, -C (= O) NHOH, -C (= O) NH 2, -C (= O) NHCH 3, -C (= O) N (CH 3) 2, _{-C (= O) NHCH 2 CH} 3, -C (= O) NHCH 2 CF 3, -C (= O) NH (CH 2) 1-6 NH 3 + X -, -C (= O) NHCH 2 Selected from C (= O) OCH ₃ , -C (= O) NHCH ₂ C (= O) OH, and -C (= O) NHCH ₂ CH ₂ OH, -C (= O) N (R ^k ₂ )

In certain embodiments, R ^h is —OC (═O) R ⁱ , eg, selected from —OC (═O) CH ₃ .

In certain embodiments, R ^h is, for example, selected from --OCO ₂ CH _3, a -OCO ₂ R ^i.

In certain embodiments, R ^h is —OC (═O) N (R ^k ) ₂ , eg, selected from —OC (═O) NH ₂ .

In certain embodiments, R ^h is —NR ^k C (═O) R ⁱ , eg, selected from —NHC (═O) CH ₃ .

In certain embodiments, R ^h is —NR ^k CO ₂ R ⁱ , selected from, for example, —NHC (═O) OCH ₃ and —NHC (═O) OtBu.

In certain embodiments, R ^h is —NR ^k C (═O) N (R ^k ) ₂ , eg, selected from NHC (═O) NH ₂ .

In certain embodiments, R ^h is, for example, -C (= O) NHSO ₂ CH ₃ , -C (= O) NHSO ₂ CH ₂ CH ₃ , -C (= O) NHSO ₂ C ₅ H ₉ , and- C (= O) is selected from the NHS0 ₂ iBu, a ^{-C (= O) NR k SO} 2 R i.

In certain embodiments, R ^h is, for example, is selected from -NHSO ₂ CH _3, a -NR ^k SO ₂ R ^i.

In certain embodiments, R ^h is —SO ₂ N (R ^k ) ₂ , eg, selected from —SO ₂ NH ₂ , —SO ₂ N (CH ₃ ) ₂ .

In certain embodiments, R ^h is —SO ₂ R ⁱ , selected from, for example, —SO ₂ CH ₃ , —SO ₂ CH ₂ CH ₃ , —SO ₂ C ₅ H ₉ , and —SO ₂ iBu. .

In certain embodiments, R ^h is, for example, —CH ₃ , —CH ₂ CH ₃ , —iPr, —nBu, —CF ₃ , —CH ₂ CH ₂ CO ₂ Me, —CH ₂ CH ₂ CO ₂ H, and C _1-10 alkyl selected from —CH ₂ CH ₂ CO ₂ NH ₂ .

In certain embodiments, R ^h is selected from —C (═O) R ⁱ , —CO ₂ H, and —SO ₂ R ⁱ . In certain embodiments, R ^h is —C (═O) R ⁱ . In certain embodiments, R ^h is —SO ₂ R ⁱ . In certain embodiments, R ^h is —CO ₂ H or —SO ₂ CH ₃ . In certain embodiments, R ^h is —CO ₂ H. In certain embodiments, R ^h is —SO ₂ CH ₃ .

In certain embodiments, each instance of R ^h is independently fluoro (-F), bromo (-Br), chloro (-Cl), iodine _{(-I), - NH 2,} -NH 3 + X - , -CN, -NO ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ C ₅ H ₉ , -SO ₂ iBu, -SO ₂ NH ₂ , -SO ₂ N (CH ₃ ) ₂ , -C (= O) NHSO ₂ CH ₃ , -C (= O) NHSO ₂ CH ₂ CH ₃ , -C (= O) NHSO ₂ C ₅ H ₉ , -C (= O) NHSO ₂ iBu, -C (= O) CH ₃ , -CO ₂ H, -CO ₂ CH ₃ , -OC (= O) CH ₃ , -OCO ₂ CH ₃ , -C (= O) NHOH, -C (= O) NH ₂ , -C (= O) NHCH ₃ , C (= O) N (CH ₃ ) ₂ , -C (= O) NHCH ₂ CH ₃ , -C (= O) NHCH ₂ CF ₃ , -C (= O) NH ^{_{(CH 2) 1-6 NH 3 +}} X -, -OC (O) NH 2, -NHC (= O) CH 3, -NHC (= O) OCH 3, -NHC (= O) OtBu, -NHC ( _{= O) NH 2, -NHSO 2} CH 3, -CH 3, -CH 2 CH 3, -iPr, -nBu, -CF 3, -OH, -OCH 3, -SCH 3, -OCF 3, -OCH 2 CH ₃ , -OCH ₂ CF ₃ , -OiPr, -OnBu, -CH ₂ CH ₂ CO ₂ Me, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ NH ₂ , -C (= O) NHCH ₂ C (= O) OCH ₃ , -C (= O) NHCH ₂ C (= O) OH, -C (= O) NHCH ₂ CH ₂ OH, substituted by 0, 1, or 2 R ^m groups and C ₆ aryl,及0,1, or are selected from two 5-6 membered heteroaryl substituted by R ^m groups; and, wherein X ^- is a counterion.

In certain embodiments, R ^h is C ₆ aryl (eg, phenyl) substituted with 0, 1, or 2 R ^m groups. In certain embodiments, R ^h is C ₆ aryl (eg, phenyl) substituted with one R ^m group, and R ^m is —CO ₂ H, —CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , and —C (═O) NH ₂ .

In certain embodiments, R ^h is a 5-6 membered heteroaryl substituted with 0, 1, or 2 R ^m groups. In certain embodiments, R ^h is 5-membered heteroaryl substituted with 0, 1, or 2 R ^m groups. Examples of 5-membered heteroaryl R ^h groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl Rather, here such groups are substituted by 0 or 1 R ^m groups. In certain embodiments, the R ^h 5-membered heteroaryl group is selected from pyrazolyl and oxadiazolyl, wherein such group is substituted with 0 or 1 R ^m group.

(Embodiment of R ⁱ⁾
In certain embodiments, each example of R ⁱ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 Selected from membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein each of alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is unsubstituted.

In certain embodiments, R ⁱ is unsubstituted C _1-10 alkyl. In certain embodiments, R ⁱ is C _1-10 perhaloalkyl. In certain embodiments, R ⁱ is unsubstituted C _2-10 alkenyl. In certain embodiments, R ⁱ is unsubstituted C _2-10 alkynyl. In certain embodiments, R ⁱ is unsubstituted C _3-10 carbocyclyl. In certain embodiments, R ⁱ is unsubstituted 3-14 membered heterocyclyl. In certain embodiments, R ⁱ is unsubstituted C _6-14 aryl. In certain embodiments, R ⁱ is unsubstituted 5-14 membered heteroaryl.

(Embodiment of R ^m)
In certain embodiments, each instance of R ^m is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -SO _{2 H, -SO 3 H, -OH} , -OR o, -ON (R n) 2, -N (R n) 2, -N (R n) 3 + X -, -N (OR o) R n , -SH, -SR ^o , -SSR ^o , -C (= O) R ^o , -CO ₂ H, -CO ₂ R ^o , -OC (= O) R ^o , -OCO ₂ R ^o , -C ( = O) N (R ⁿ ) ₂ , -OC (= O) N (R ⁿ ) ₂ , -NR ⁿ C (= O) R ^o , -NR ⁿ CO ₂ R ^o , -NR ⁿ C (= O) N (R ⁿ ) ₂ , -C (= NR ⁿ ) OR ^o , -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) OR ^o , -C (= NR ⁿ ) N (R ⁿ ) ₂ , -OC (= NR ⁿ ) N (R ⁿ ) ₂ , -NR ⁿ C (= NR ⁿ ) N (R ⁿ ) ₂ , -NR ⁿ SO ₂ ^Ro , -SO ₂ N (R ⁿ ) ₂ ,- _{^{SO 2 R o, -SO 2 OR}} o, -OSO 2 R o, -S (= O) R o, -C (= S) n (R n) 2, -C (= O) SR o, -C ^{(= S) SR o, -SC} (= S) SR o, -P (= O) 2 R o, -P (= O) (R o) 2, -OP (= O) (R o) 2, -OP (= O) (OR ^o ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14 membered hetero Selected from aryl, where Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted 0,1,2,3,4, or by five R ^p groups.

In certain embodiments, each instance of R ^m is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -SO _{2 H, -SO 3 H, -OH} , -OR o, -ON (R n) 2, -N (R n) 2, -N (R n) 3 + X -, -N (OR o) R n , -SH, -SR ^o , -SSR ^o , -C (= O) R ^o , -CO ₂ H, -CO ₂ R ^o , -OC (= O) R ^o , -OCO ₂ R ^o , -C ( = O) N (R ⁿ ) ₂ , -OC (= O) N (R ⁿ ) ₂ , -NR ⁿ C (= O) R ^o , -NR ⁿ CO ₂ R ^o , -NR ⁿ C (= O) N (R ⁿ ) ₂ , -C (= NR ⁿ ) OR ^o , -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) OR ^o , -C (= NR ⁿ ) N (R ⁿ ) ₂ , -OC (= NR ⁿ ) N (R ⁿ ) ₂ , -NR ⁿ C (= NR ⁿ ) N (R ⁿ ) ₂ , -NR ⁿ SO ₂ ^Ro , -SO ₂ N (R ⁿ ) ₂ ,- _{^{SO 2 R o, -SO 2 OR}} o, -OSO 2 R o, -S (= O) R o, -C (= S) n (R n) 2, -C (= O) SR o, -C ^{(= S) SR o, -SC} (= S) SR o, -P (= O) 2 R o, -P (= O) (R o) 2, -OP (= O) (R o) 2, -OP (= O) (OR ^o ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14 membered hetero Selected from aryl.

In certain embodiments, R ^m is fluoro (-F), bromo (-Br), chloro (-Cl), and iodo _{(-I), - NH 2,} -NH 3 + X -, -CN, - NO ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ C ₅ H ₉ , -SO ₂ iBu, -SO ₂ NH ₂ , -SO ₂ N (CH ₃ ) ₂ , -C (= O) NHSO ₂ CH ₃ , -C (= O) NHSO ₂ CH ₂ CH ₃ , -C (= O) NHSO ₂ C ₅ H ₉ , -C (= O) NHSO ₂ iBu, -C (= O) CH ₃ , -CO ₂ H, -CO ₂ CH ₃ , -OC (= O) CH ₃ , -OCO ₂ CH ₃ , -C (= O) NHOH, -C (= O) NH ₂ , -C (= O ) NHCH ₃ , -C (= O) N (CH ₃ ) ₂ , -C (= O) NHCH ₂ CH ₃ , -C (= O) NHCH ₂ CF ₃ , -C (= O) NH (CH ₂ ) _{^{1-6 NH 3 + X -, -OC}} (= O) NH 2, -NHC (= O) CH 3, -NHC (= O) 0CH 3, -NHC (= O) OtBu, -NHC (= O) _{NH 2, -NHSO 2 CH 3,} -CH 3, -CH 2 CH 3, -iPr, -nBu, -CF 3, -OH, -OCH 3, -OCF 3, -OCH 2 CH 3, -OCH 2 CF ₃ , -OiPr, -OnBu, -CH ₂ CH ₂ CO ₂ Me, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ NH ₂ , -C (= O) NHCH ₂ C (= O) OCH ₃ , selected from —C (═O) NHCH ₂ C (═O) OH and —C (═O) NHCH ₂ CH ₂ OH.

( ^Rk embodiment)
As used above and herein, each instance of R ^k is independently -H, -OH, -OR ⁱ , -N (R ^k ) ₂ , -C (= O) R ⁱ ,- C (= O) N (R ^k ) ₂ , -CO ₂ R ⁱ , -SO ₂ R ⁱ , -C (= NR ^k ) R ⁱ , -C (= NR ^k ) OR ⁱ , -C (= NR ^k ) N (R ^k ) ₂ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , -SO ₂ OR ⁱ , -SOR ⁱ , -C (= S) N (R ^k ) ₂ , -C ( = O) SR ⁱ , -C (= S) SR ⁱ , C _1-10 alkyl (e.g. aralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl groups, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently 0, 1, 2 , 3, 4, or 5 R ^m groups, where R ⁱ , R ^k , R ^m are as defined above and herein.

In certain embodiments, each example of R ^k is independently from —H, —C (═O) R ⁱ , —C (═O) OR ⁱ , —SO ₂ R ⁱ , or C _1-6 alkyl. Selected. In certain embodiments, each example of R ^k is independently selected from —H or C _1-6 alkyl. In certain embodiments, each instance of R ^k is independently selected from —H and —CH ₃ . In certain embodiments, each instance of R ^k is independently selected from -H. In certain embodiments, each instance of R ^k is independently selected from —CH ₃ .

(Groups R ^a , R ^b , and R ^c )
As defined generally above, when R ^d is a group -LZ, each of R ^a , R ^b , and R ^c is independently -H, C _1-10 alkyl, and C _1-10 perhaloalkyl. Selected from.

In certain embodiments, each of R ^a , R ^b , and R ^c is independently selected from —H, C _1-6 alkyl, and C _1-6 perhaloalkyl. In certain embodiments, each of R ^a , R ^b , and R ^c is independently selected from —H, C _1-3 alkyl, and C _1-3 perhaloalkyl. In certain embodiments, each of R ^a , R ^b , and R ^c is independently selected from —H, —CH ₃ , —CH ₂ CH ₃ , and —CF ₃ . In certain embodiments, each of R ^a , R ^b , and R ^c is independently selected from —H, —CH ₃ , and —CF ₃ .

In certain embodiments, R ^a and R ^b are H and R ^c is selected from C _1-3 alkyl and C _1-3 perhaloalkyl. In certain embodiments, R ^a and R ^b are H and R ^c is selected from —CH ₃ and —CF ₃ . In certain embodiments, R ^a and R ^b are H and R ^c is —CH ₃ . In certain embodiments, R ^a and R ^b are H and R ^c is —CF ₃ .

In certain embodiments, R ^b and R ^c are H, and R ^a is selected from C _1-3 alkyl and C _1-3 perhaloalkyl. In certain embodiments, R ^b and R ^c are H, and R ^a is selected from —CH ₃ and —CF ₃ . In certain embodiments, R ^b and R ^c are H and R ^a is —CH ₃ . In certain embodiments, R ^b and R ^c are H and R ^a is —CF ₃ .

In certain embodiments, each of R ^a , R ^b , and R ^c is independently selected from H, —CH ₃ , and —CF ₃ . In certain embodiments, each of R ^a , R ^b , and R ^c is independently selected from H or —CH ₃ . In certain embodiments, each of R ^a , R ^b , and R ^c is independently H.

( ^Rd )
In certain embodiments, as defined generally above, R ^d is a group -LZ;
Where L is a covalent bond or a divalent C _1-6 hydrocarbon group, wherein 1, 2 or 3 methylene units of L are optionally and independently selected from one or more oxygen, sulfur or Replaced with a nitrogen atom, and
Z is selected from C _6-10 aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl.

(R ^d group L)
As generally defined above, L is a covalent bond or a divalent C _1-6 hydrocarbon group, wherein 1, 2 or 3 methylene units of L are optionally and independently 1 Replaced with one or more oxygen, sulfur or nitrogen atoms.

  In certain embodiments, L is a covalent bond.

In certain embodiments, L is one or more oxygen (-O-), sulfur (-S-) or nitrogen (e.g.,- A divalent C _1-6 hydrocarbon group replaced by an NR ^1- ) atom.

In certain embodiments, L is a divalent C _{1- 6} hydrocarbon group.

In certain embodiments, L is a divalent C _1- , wherein 1, 2 or 3 methylene units of L are optionally and independently replaced with one or more sulfur (-S-) atoms. ₆ hydrocarbon group.

In certain embodiments, L is a divalent C _{1, wherein one} , two or three methylene units of L are optionally and independently replaced with one or more nitrogen (—NR ¹ —) atoms. _-6 hydrocarbon group. However, in certain embodiments, when L is a divalent C _1-6 hydrocarbon group containing 1, 2 or 3 nitrogen atoms, L is an “unsubstituted” divalent C _1-6 carbon group. L is not a group —CH ₂ NR ¹ —, which is a hydrogen group and R ¹ is H, C _1-6 alkyl or an amino protecting group.

In certain embodiments, L is a divalent C _1-6 hydrocarbon group in which one methylene unit of L is optionally and independently replaced with an oxygen, sulfur or nitrogen atom. In certain embodiments, L is a divalent C _1-6 hydrocarbon group, wherein one methylene unit of L is optionally and independently replaced with an oxygen atom. In certain embodiments, L is a divalent C _1-6 hydrocarbon group in which one methylene unit of L is optionally and independently replaced with a sulfur atom. In certain embodiments, L is a divalent C _1-6 hydrocarbon group in which one methylene unit of L is optionally and independently replaced with a nitrogen atom.

In certain embodiments of L, the divalent C _1-6 hydrocarbon group is an unsubstituted divalent C _1-6 hydrocarbon group. In certain embodiments of L, the divalent C _1-6 hydrocarbon group contains one oxygen, sulfur or nitrogen atom. In certain embodiments, the divalent C _1-6 hydrocarbon group is an unsubstituted divalent C _1-6 hydrocarbon group (eg, an unsubstituted divalent C _1-6 alkyl group).

For example, in certain embodiments, L is an unsubstituted divalent C _1-6 alkyl group in which 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 in which one methylene unit of L is replaced with an oxygen atom. In certain embodiments, L is unsubstituted divalent C _1-6 alkyl, wherein one methylene unit of L is replaced with a sulfur atom. In certain embodiments, L is an unsubstituted divalent C _1-6 alkyl group in which one methylene unit of L is replaced with a nitrogen atom. However, in certain embodiments, when L is an unsubstituted divalent C _1-6 alkyl group, L is a group —CH ₂ where R ¹ is H, C _1-6 alkyl, or an amino protecting group. NR ^1- Not.

In certain embodiments, L is a group in which one methylene unit of L is replaced with an oxygen, sulfur, or nitrogen atom, for example, L is oxygen (-O-), sulfur (-S-), or nitrogen (e.g., -NR ^A divalent C ₁ hydrocarbon group selected from ^1- ). In certain embodiments, L is oxygen (—O—). In certain embodiments, L is sulfur (—S—). In certain embodiments, L is nitrogen (eg, —NR ¹ —).

In certain embodiments, L is-(C (R ¹⁰ ) ₂ ) _m -,-(C (R ¹¹ ) ₂ ) _m -O- (C (R ¹² ) ₂ ) _n -,-(C (R ¹¹ ) ₂ ) _m -S- (C (R ¹² ) ₂ ) _n- or-(C (R ¹¹ ) ₂ ) _m -NR ^1- (C (R ¹² ) ₂ ) _n- Where m and n are independently 0, 1, 2, 3, 4, 5 or 6, and each instance of R ¹⁰ , R ¹¹ and R ¹² is independently H, halogen or C Selected from _1-6 alkyl. In certain embodiments, each of R ¹⁰ , R ¹¹ and R ¹² is —H.

In certain embodiments, L is — (C (R ¹⁰ ) ₂ ) _m —. In certain embodiments, L _{is, -CH 2 -, - CH 2} CH 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 Selected from CH ₂ — and —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ .

In certain embodiments, L is — (C (R ¹¹ ) ₂ ) _m —O— (C (R ¹² ) ₂ ) _n —. In certain embodiments, L _{is, -O -, - CH 2 O} -, - OCH 2 -, - OCH 2 CH 2 -, - OCH 2 CH 2 -, - OCH 2 CH 2 CH 2 -, - CH 2 Selected from CH ₂ CH ₂ O—, —CH ₂ OCH ₂ CH ₂ —, and —CH ₂ CH ₂ OCH ₂ —.

In certain embodiments, L is — (C (R ¹¹ ) ₂ ) _m —S— (C (R ¹² ) ₂ ) _n —. In certain embodiments, L is -S-, -CH ₂ S-, -SCH _2- , -SCH ₂ CH _2- , -CH ₂ CH ₂ S-, -SCH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ CH ₂ S—, —CH ₂ SCH ₂ CH ₂ —, and —CH ₂ CH ₂ SCH ₂ — are selected.

In certain embodiments, L is — (C (R ¹¹ ) ₂ ) _m —NR ¹ — (C (R ¹² ) ₂ ) _n —. In certain embodiments, L is -NR ^1- , -CH ₂ NR ^1- , -NR ¹ CH _2- , -NR ¹ CH ₂ CH _2- , -CH ₂ CH ₂ NR ^1- , -NR ¹ CH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ CH ₂ NR ^1- , -CH ₂ NR ¹ CH ₂ CH _2- , and -CH ₂ CH ₂ NR ¹ CH _2- , where R ¹ is Selected from H, C _1-6 alkyl or amino protecting groups.

In certain embodiments, R ¹ is selected from H or C _1-6 alkyl. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is —CH ₃ .

(Specific embodiments wherein the group Z of R ^d is aryl)
In certain embodiments, Z is C _6-14 aryl, as generally defined above.

In certain embodiments, Z is C _6-14 aryl. In certain embodiments, Z is C _6-14 aryl. In certain embodiments, Z is C _6-14 aryl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In certain embodiments, Z is C ₆ aryl (eg, phenyl) substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In certain embodiments, Z is C ₁₀ aryl (eg, naphthyl) substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups.

In certain embodiments, Z is phenyl. In certain embodiments, Z is phenyl substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups. In certain embodiments, Z is phenyl substituted with 0, 1, 2, or 3 R ¹⁵ groups. In certain embodiments, Z is phenyl substituted with 0, 1, or 2 R ¹⁵ groups. In certain embodiments, Z is phenyl substituted with 0, or 1 R ¹⁵ group. In certain embodiments, Z is phenyl that is disubstituted (ie, substituted with two R ¹⁵ groups). In certain embodiments, Z is phenyl that is monosubstituted (ie, substituted with one R ¹⁵ group). In certain embodiments, Z is phenyl (ie, substituted with 0 R ¹⁵ groups).

In certain embodiments, Z is phenyl substituted with at least one ortho R ¹⁵ group. In certain embodiments, Z is phenyl substituted with at least one meta R ¹⁵ group. In certain embodiments, Z is phenyl substituted with at least one para R ¹⁵ group.

In certain embodiments, Z is a monosubstituted phenyl substituted with one ortho R ¹⁵ group. In certain embodiments, Z is monosubstituted phenyl substituted with one meta R ¹⁵ group. In certain embodiments, Z is a mono-substituted substituted with one para R ¹⁵ group.

In certain embodiments, Z is a disubstituted phenyl substituted with an ortho R ¹⁵ group and a meta R ¹⁵ group. In certain embodiments, Z is a disubstituted phenyl substituted with an ortho R ¹⁵ group and a para R ¹⁵ group. In certain embodiments, Z is a disubstituted phenyl substituted with a meta R ¹⁵ group and a para R ¹⁵ group. In certain embodiments, Z is a disubstituted phenyl substituted with two meta R ¹⁵ groups.

ここで、zは、0、1、2、3、4、又は5であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、zは、0、1、2、3、又は4である。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは、0又は1である。特定の実施態様において、zは3である。特定の実施態様において、Zは、二置換されたフェニル基である(すなわちzは2である)。特定の実施態様において、Zは、一置換されたフェニル基である(すなわちzは1である)。特定の実施態様において、Zは、非置換のフェニル基である(すなわちzは0である)。 In certain embodiments, Z is a phenyl group of the formula:

Here, z is 0, 1, 2, 3, 4, or 5, and R ¹⁵ is defined below and herein. In certain embodiments, z is 0, 1, 2, 3, or 4. In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1. In certain embodiments, z is 3. In certain embodiments, Z is a disubstituted phenyl group (ie, z is 2). In certain embodiments, Z is a monosubstituted phenyl group (ie, z is 1). In certain embodiments, Z is an unsubstituted phenyl group (ie, z is 0).

ここで、R¹⁵は、下記及び本明細書において定義されている。 For example, in certain embodiments, Z is a substituted or unsubstituted phenyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、zは、0、1、2、3、4、又は5であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、zは、0、1、2、3、又は4である。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは、0又は1である。特定の実施態様において、Zは、三置換されたナフチル基である(すなわちzは3である)。特定の実施態様において、Zは、二置換されたナフチル基である(すなわちzは2である)。特定の実施態様において、Zは、一置換されたナフチル基である(すなわちzは1である)。特定の実施態様において、Zは、非置換のナフチル基である(すなわちzは0である)。 In certain embodiments, Z is naphthyl. In certain embodiments, Z is a naphthyl group of any one of the following formulas:

Here, z is 0, 1, 2, 3, 4, or 5, and R ¹⁵ is defined below and herein. In certain embodiments, z is 0, 1, 2, 3, or 4. In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1. In certain embodiments, Z is a trisubstituted naphthyl group (ie, z is 3). In certain embodiments, Z is a disubstituted naphthyl group (ie, z is 2). In certain embodiments, Z is a monosubstituted naphthyl group (ie, z is 1). In certain embodiments, Z is an unsubstituted naphthyl group (ie, z is 0).

ここで、R¹⁵は、下記及び本明細書において定義されている。 For example, in certain embodiments, Z is a substituted or unsubstituted 1-naphthyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a substituted or unsubstituted 2-naphthyl group of any one of the following formulae:

Here, R ¹⁵ is defined below and herein.

(Specific embodiments wherein the group Z of R ^d is heterocyclyl or heteroaryl)
As defined generally above, in certain embodiments, Z is selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl.

In certain embodiments, Z is a 5-14 membered heteroaryl. In certain embodiments, Z is a 5-10 membered heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In certain embodiments, Z is a 5-8 membered heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In certain embodiments, Z is a 5-6 membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups. In certain embodiments, Z is a 9-10 membered heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups.

Examples of Z heteroaryl groups include 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, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoo Sazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, Examples include, but are not limited to, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, where such groups are substituted by 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. ing.

In certain embodiments, Z is a 5-membered heteroaryl substituted with 0, 1, 2, or 3 R ¹⁵ 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 Such groups are substituted by 0, 1, 2, or 3 R ¹⁵ groups.

ここで、Y¹、Y²、Y³及びY⁴は独立して、CH、CR¹⁵、O、S、N、又はNR¹⁸から選択され、但しY¹、Y²、Y³及びY⁴の少なくとも1つは、O、S、N、又はNR¹⁸から選択され、かつここでR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。 For example, in certain embodiments, Z is a 5-membered heteroaryl of the formula:

Where Y ¹ , Y ² , Y ³ and Y ⁴ are independently selected from CH, CR ¹⁵ , O, S, N or NR ¹⁸ provided that Y ¹ , Y ² , Y ³ and Y ⁴ At least one is selected from O, S, N, or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are defined below and herein.

In certain embodiments of the above formula (ii-d), Y ¹ is O, S, or NR ¹⁸ and Y ² , Y ³ , and Y ⁴ are independently CH, CR ¹⁵ , or N Selected from. In certain embodiments of formula (ii-d) above, Y ¹ is O, S, or NR ¹⁸ and Y ² , Y ³ , and Y ⁴ are independently selected from CH or CR ¹⁵ The In certain embodiments of formula (ii-d) above, Y ¹ is O, S, or NR ¹⁸ , Y ³ is N, and Y ² and Y ⁴ are independently CH or CR ¹⁵ Selected from. In certain embodiments of formula (ii-d) above, Y ¹ is S, Y ³ is N, and Y ² and Y ⁴ are CH or CR ¹⁵ . In certain embodiments of formula (ii-d) above, Y ¹ is S, Y ³ is N, Y ² is CR ¹⁵ and Y ⁴ is CH. In certain embodiments of formula (ii-d) above, Y ¹ is S and Y ² , Y ³ and Y ⁴ are CH or CR ¹⁵ .

In certain embodiments of formula (ii-d) above, Y ² is O, S, or NR ¹⁸ and Y ¹ , Y ³ and Y ⁴ are independently selected from CH, CR ¹⁵ or N Is done. In certain embodiments of formula (ii-d) above, Y ² is O, S or NR ¹⁸ and Y ¹ , Y ³ and Y ⁴ are independently selected from CH or CR ¹⁵ . In certain embodiments of formula (ii-d) above, Y ² is O, S, or NR ¹⁸ , Y ⁴ is N, and Y ¹ and Y ³ are independently CH or CR ¹⁵ Selected from.

ここで、R¹⁵及びR¹⁸は、下記及び本明細書において定義されており、かつzは、0、1又は2である。ここでzは、0、1又は2であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換の5-員のヘテロアリールである(すなわち、zは0である)。特定の実施態様において、Zは、置換された5-員のヘテロアリールである(例えば、zは1又は2である)。特定の実施態様において、Zは、一置換された5-員のヘテロアリールである(すなわち、zは1である)。特定の実施態様において、Zは、二置換された5-員のヘテロアリールである(すなわち、zは2である)。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは、0又は1である。 In certain embodiments, Z is a 5-membered heteroaryl of any one of the following formulas:

Here, R ¹⁵ and R ¹⁸ are defined below and herein, and z is 0, 1 or 2. Where z is 0, 1 or 2 and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted 5-membered heteroaryl (ie, z is 0). In certain embodiments, Z is a substituted 5-membered heteroaryl (eg, z is 1 or 2). In certain embodiments, Z is a monosubstituted 5-membered heteroaryl (ie, z is 1). In certain embodiments, Z is a disubstituted 5-membered heteroaryl (ie, z is 2). In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 6-membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ^h groups. In certain embodiments, Z is 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 and tetrazinyl, which is a 6-membered heteroaryl, wherein such groups are 0, 1, 2, 3 or 4 R ¹⁵ groups Is replaced by

ここで、W¹、W²、W³、W⁴及びW⁵は独立して、CH、CR¹⁵又はNから選択され、但しW¹、W²、W³、W⁴及びW⁵の少なくとも1つはNであることを条件とし、かつここでR¹⁵は、下記及び本明細書において定義されている。 For example, in certain embodiments, R ^e is a 6-membered heteroaryl group of the formula:

Here, W ¹ , W ² , W ³ , W ⁴ and W ⁵ are independently selected from CH, CR ¹⁵ or N, provided that at least one of W ¹ , W ² , W ³ , W ⁴ and W ⁵ Provided that N is N, and R ¹⁵ is defined below and herein.

ここで、zは、0、1、2、3又は4であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピリンジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピリンジニルである(例えば、zは、1、2、3又は4である)。特定の実施態様において、Zは、一置換されたピリンジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピリンジニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたピリンジニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは、0又は1である。 In certain embodiments, Z is a pyrindinyl group. In certain embodiments, Z is a pyrindinyl group substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups. For example, in certain embodiments, Z is a pyrindinyl group of the formula:

Where z is 0, 1, 2, 3 or 4, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted pyrindinyl (ie, z is 0). In certain embodiments, Z is substituted pyrindinyl (eg, z is 1, 2, 3 or 4). In certain embodiments, Z is a monosubstituted pyrindinyl (ie, z is 1). In certain embodiments, Z is disubstituted pyrindinyl (ie, z is 2). In certain embodiments, Z is a trisubstituted pyrindinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is, for example, a 2-pyridinyl group of formula (ii-e), where W ¹ is N, and W ² , W ³ , W ⁴ and W ⁵ are independently CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 3-pyridinyl group of formula (ii-e), where W ² is N, and W ¹ , W ³ , W ⁴ and W ⁵ are independently CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 4-pyrindinyl group of formula (ii-e), where W ³ is N, and W ¹ , W ² , W ⁴ and W ⁵ are independently CH or CR ¹⁵ .

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, R ^e is a substituted or unsubstituted 2-pyridinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a substituted or unsubstituted 3-pyridinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a substituted or unsubstituted 4-pyridinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、zは、0、1、2又は3であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピリダジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピリダジニルである(例えば、zは、1、2又は3である)。特定の実施態様において、Zは、一置換されたピリダジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピリダジニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたピリダジニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a pyridazinyl group. In certain embodiments, Z is a pyridazinyl group substituted with 0, 1, 2 or 3 R ¹⁵ groups. For example, in certain embodiments, Z is a pyridazinyl group of the following formula:

Where z is 0, 1, 2 or 3, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted pyridazinyl (ie, z is 0). In certain embodiments, Z is substituted pyridazinyl (eg, z is 1, 2 or 3). In certain embodiments, Z is a monosubstituted pyridazinyl (ie, z is 1). In certain embodiments, Z is disubstituted pyridazinyl (ie, z is 2). In certain embodiments, Z is trisubstituted pyridazinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is, for example, a 3-pyridazinyl group of formula (ii-e), where W ¹ and W ² are N, and W ³ , W ⁴ and W ⁵ are independently CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 4-pyridazinyl group of formula (ii-e), where W ² and W ³ are N, and W ¹ , W ⁴ and W ⁵ are independently CH or CR ^h .

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a substituted or unsubstituted 3-pyridazinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a substituted or unsubstituted 4-pyridazinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、zは、0、1、2又は3であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピリミジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピリミジニルである(例えば、zは、1、2又は3である)。特定の実施態様において、Zは、一置換されたピリミジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピリダジニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたピリミジニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a pyrimidinyl group. In certain embodiments, Z is a pyrimidinyl group substituted with 0, 1, 2 or 3 R ¹⁵ groups. For example, in certain embodiments, Z is a pyrimidinyl group of the formula:

Where z is 0, 1, 2 or 3, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted pyrimidinyl (ie, z is 0). In certain embodiments, Z is substituted pyrimidinyl (eg, z is 1, 2 or 3). In certain embodiments, Z is a monosubstituted pyrimidinyl (ie, z is 1). In certain embodiments, Z is disubstituted pyridazinyl (ie, z is 2). In certain embodiments, Z is trisubstituted pyrimidinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is, for example, a 2-pyrimidinyl group of formula (ii-e), where W ¹ and W ⁵ are N, and W ² , W ³ , and W ⁴ are independently CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 4-pyrimidinyl group of formula (ii-e), where W ¹ and W ³ are N, and W ² , W ⁴ and W ⁵ are independently CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 5-pyrimidinyl group of formula (ii-e), where W ² and W ⁴ are N, and W ¹ , W ³ , and W ⁵ are independently CH or CR ¹⁵ .

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a 2-pyrimidinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, R ^e is either one 4-pyrimidinyl group of the formula:

Here, R ¹⁵ is defined below and herein.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a 5-pyrimidinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、zは、0、1、2又は3であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピラジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピラジニルである(例えば、zは、1、2又は3である)。特定の実施態様において、Zは、一置換されたピラジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピラジニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたピラジニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a pyrazinyl group. In certain embodiments, Z is a pyrazinyl group substituted with 0, 1, 2 or 3 R ¹⁵ groups. For example, in certain embodiments, Z is a pyrazinyl group of the formula:

Where z is 0, 1, 2 or 3, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted pyrazinyl (ie, z is 0). In certain embodiments, Z is substituted pyrazinyl (eg, z is 1, 2 or 3). In certain embodiments, Z is monosubstituted pyrazinyl (ie, z is 1). In certain embodiments, Z is disubstituted pyrazinyl (ie, z is 2). In certain embodiments, Z is trisubstituted pyrazinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a pyrazinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、zは、0、1、又は2であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピラジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピラジニルである(例えば、zは、1又は2である)。特定の実施態様において、Zは、一置換されたピラジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピラジニルである(すなわち、zは2である)。特定の実施態様において、zは、0、1、又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a triazinyl group. In certain embodiments, Z is a triazinyl group substituted with 0, 1, or 2 R ¹⁵ groups. For example, in certain embodiments, Z is a triazinyl group of the formula:

Here, z is 0, 1 or 2, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted pyrazinyl (ie, z is 0). In certain embodiments, Z is substituted pyrazinyl (eg, z is 1 or 2). In certain embodiments, Z is monosubstituted pyrazinyl (ie, z is 1). In certain embodiments, Z is disubstituted pyrazinyl (ie, z is 2). In certain embodiments, z is 0, 1, or 2. In certain embodiments, z is 0 or 1.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a substituted or unsubstituted triazinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

ここで、zは、0、又は1であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピラジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピラジニルである(例えば、zは、1である)。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a tetrazinyl group. In certain embodiments, Z is a tetrazinyl group substituted with 0, or 1 R ¹⁵ group. For example, in certain embodiments, Z is a tetrazinyl group of the formula:

Here, z is 0 or 1, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted pyrazinyl (ie, z is 0). In certain embodiments, Z is substituted pyrazinyl (eg, z is 1). In certain embodiments, z is 0 or 1.

ここで、R¹⁵は、下記及び本明細書において定義されている。 In certain embodiments, Z is a tetrazinyl group of any one of the following formulas:

Here, R ¹⁵ is defined below and herein.

In certain embodiments, Z is a 9-membered heteroaryl (eg, 5,6-bicyclic heteroaryl). In certain embodiments, Z is 5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzo 5,6-bicyclic heteroaryl, selected from oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl, wherein such groups are 0, 1, 2 , 3, 4 or 5 R ¹⁵ groups.

ここで、Y⁵、Y⁶、Y⁷、Y⁹、Y¹⁰、Y¹¹及びY¹²は独立して、C、CH、CR¹⁵、O、S、N、又はNR¹⁸であり、かつY¹³は、C又はNであり、但しY⁵、Y⁶、Y⁷の少なくとも1つは、O、S、N又はNR¹⁸から選択されることを条件とし、かつR¹⁵及びR¹⁸は、本明細書において定義されている通りである。 For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl of the formula:

Where Y ⁵ , Y ⁶ , Y ⁷ , Y ⁹ , Y ¹⁰ , Y ¹¹ and Y ¹² are independently C, CH, CR ¹⁵ , O, S, N, or NR ¹⁸ and Y ¹³ Is C or N, provided that at least one of Y ⁵ , Y ⁶ , Y ⁷ is selected from O, S, N or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are as defined herein. As defined in the book.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換の5,6-二環式ヘテロアリールである(すなわち、zは0である)。特定の実施態様において、Zは、置換された5,6-二環式ヘテロアリールである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換された5,6-二環式ヘテロアリールである(すなわち、zは1である)。特定の実施態様において、Zは、二置換された5,6-二環式ヘテロアリールである(すなわち、zは2である)。特定の実施態様において、Zは、三置換された5,6-二環式ヘテロアリールである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a 5,6-bicyclic heteroaryl group of formula (ii-f), wherein Y ⁵ is selected from O, S, or NR ¹⁸ and Y ¹³ is C And Y ⁶ , Y ⁷ , Y ⁹ , Y ¹⁰ , Y ¹¹ and Y ¹² are independently C, CH, or CR ¹⁵ . For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryl (ie, z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換の5,6-二環式ヘテロアリールである(すなわち、zは0である)。特定の実施態様において、Zは、置換された5,6-二環式ヘテロアリールである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換された5,6-二環式ヘテロアリールである(すなわち、zは1である)。特定の実施態様において、Zは、二置換された5,6-二環式ヘテロアリールである(すなわち、zは2である)。特定の実施態様において、Zは、三置換された5,6-二環式ヘテロアリールである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ⁵ is selected from O, S, or NR ¹⁸ ; Y ⁷ is N; Y ¹³ is C Yes; Y ⁶ is C, CH or CR ¹⁵ or N, and Y ⁹ , Y ¹⁰ , Y ¹¹ and Y ¹² are independently C, CH or CR ¹⁵ . For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryl (ie, z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換の5,6-二環式ヘテロアリールである(すなわち、zは0である)。特定の実施態様において、Zは、置換された5,6-二環式ヘテロアリールである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換された5,6-二環式ヘテロアリールである(すなわち、zは1である)。特定の実施態様において、Zは、二置換された5,6-二環式ヘテロアリールである(すなわち、zは2である)。特定の実施態様において、Zは、三置換された5,6-二環式ヘテロアリールである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ⁵ is NR ^k , S or O; Y ¹² is N; Y ¹³ is C And Y ⁶ , Y ⁷ , Y ⁹ , Y ¹⁰ , and Y ¹¹ are each independently C, CH, or CR ¹⁵ ; For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryl (ie, z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換の5,6-二環式ヘテロアリールである(すなわち、zは0である)。特定の実施態様において、Zは、置換された5,6-二環式ヘテロアリールである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換された5,6-二環式ヘテロアリールである(すなわち、zは1である)。特定の実施態様において、Zは、二置換された5,6-二環式ヘテロアリールである(すなわち、zは2である)。特定の実施態様において、Zは、三置換された5,6-二環式ヘテロアリールである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ⁷ is O, S, or NR ^k ; Y ¹² is N; Y ¹³ is C And Y ⁵ , Y ⁶ , Y ⁹ , Y ¹⁰ and Y ¹¹ are independently C, CH, or CR ¹⁵ ; For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryl (ie, z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換の5,6-二環式ヘテロアリールである(すなわち、zは0である)。特定の実施態様において、Zは、置換された5,6-二環式ヘテロアリールである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換された5,6-二環式ヘテロアリールである(すなわち、zは1である)。特定の実施態様において、Zは、二置換された5,6-二環式ヘテロアリールである(すなわち、zは2である)。特定の実施態様において、Zは、三置換された5,6-二環式ヘテロアリールである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ⁵ is selected from O, S, or NR ¹⁸ ; Y ¹³ is N; and Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ and Y ¹⁰ are independently C, CH, or CR ¹⁵ . For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted 5,6-bicyclic heteroaryl (ie, z is 0). In certain embodiments, Z is a substituted 5,6-bicyclic heteroaryl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (ie, z is 1). In certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (ie, z is 2). In certain embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is 10-membered heteroaryl (eg, 6,6-bicyclic heteroaryl). In certain embodiments, Z is 6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is a 6,6-bicyclic heteroaryl selected from naphthyridyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl, wherein such group is 0 , 1, 2, 3, 4 or 5 R ¹⁵ groups.

ここで、W⁶、W⁷、W⁸、W⁹、W¹⁰、W¹¹、W¹²及びW¹³は独立して、C、CH、CR¹⁵又はNから選択され、但しW⁶、W⁷、W⁸、W⁹、W¹⁰、W¹¹、W¹²及びW¹³の少なくとも1つは、Nであることを条件とし、かつここでR¹⁵は、下記及び本明細書において定義されている。 For example, in certain embodiments, Z is a 6,6-bicyclic heteroaryl of the formula:

Here, W ⁶ , W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² and W ¹³ are independently selected from C, CH, CR ¹⁵ or N, provided that W ⁶ , W ⁷ , At least one of W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ^12, and W ¹³ is subject to N, and R ¹⁵ is defined below and herein.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のキノリニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたキノリニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたキノリニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたキノリニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたキノリニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a quinolinyl group; eg, a group of formula (ii-g), wherein W ⁹ is N and W ⁶ , W ⁷ , W ⁸ , W ¹⁰ , W ¹¹ , W ¹² and W ¹³ are independently C, CH, or CR ¹⁵ . For example, in certain embodiments, Z is a quinolinyl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted quinolinyl (ie, z is 0). In certain embodiments, Z is substituted quinolinyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted quinolinyl (ie, z is 1). In certain embodiments, Z is disubstituted quinolinyl (ie, z is 2). In certain embodiments, Z is trisubstituted quinolinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のイソキノリニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたイソキノリニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたイソキノリニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたイソキノリニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたイソキノリニルである(すなわち、zは3である)。特定の実施態様において、特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is an isoquinolinyl group; such as a group of formula (ii-g), where W ⁸ is N and W ⁶ , W ⁷ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² and W ¹³ are independently C, CH, or CR ¹⁵ . For example, in certain embodiments, Z is an isoquinolinyl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted isoquinolinyl (ie, z is 0). In certain embodiments, Z is substituted isoquinolinyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted isoquinolinyl (ie, z is 1). In certain embodiments, Z is disubstituted isoquinolinyl (ie, z is 2). In certain embodiments, Z is trisubstituted isoquinolinyl (ie, z is 3). In certain embodiments, in certain embodiments, z is 0, 1, 2, or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のキノキサリニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたキノキサリニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたキノキサリニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたキノキサリニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたキノキサリニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a quinoxalinyl group; such as a group of formula (ii-g), where W ⁶ and W ⁹ are N, and W ⁷ , W ⁸ , W ¹⁰ , W ¹¹ , W ¹² and W ¹³ are independently C, CH, or CR ¹⁵ . For example, in certain embodiments, Z is a quinoxalinyl group of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted quinoxalinyl (ie, z is 0). In certain embodiments, Z is substituted quinoxalinyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted quinoxalinyl (ie, z is 1). In certain embodiments, Z is a disubstituted quinoxalinyl (ie, z is 2). In certain embodiments, Z is a trisubstituted quinoxalinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, 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 R ¹⁵ groups. In certain embodiments, Z is a 5-10 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is a 5-8 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is a 9-10 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

Examples of heterocyclyl Z groups include aziridinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl , Oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxcanyl, oxcanyl , Isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothie , Tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl , Decahydro-1,8-naphthyridinyl, octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1,4] diazepinyl, 1,4,5, 7-tetrahydro-pyrano [3,4-b] 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-dihydrofuro [2,3-b] pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo [2,3-b] pyridinyl, 4,5,6,7-tetra-hydrofuro [3 , 2-c] pyridinyl, and 4,5,6,7-tetrahydrothieno [3,2-b] pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl. However, where such groups are substituted by 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

In certain embodiments, Z is a 6-membered heterocyclyl. In certain embodiments, Z is a 6-membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, and triazinanyl, where The group is substituted by 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

ここで、W¹⁴、W¹⁵、W¹⁶、W¹⁷、W¹⁸は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、NR¹⁸、O又はSであり、かつW¹⁹は、N、CH又はCR¹⁵であり、但しW¹⁴、W¹⁵、W¹⁶、W¹⁷、W¹⁸及びW¹⁹の少なくとも1つは、N、NR¹⁸、O又はSであることを条件とし、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。 For example, in certain embodiments, Z is a 6-membered heterocyclyl having the formula:

Here, W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ , W ¹⁸ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , NR ¹⁸ , O or S, and W ¹⁹ is N CH ¹⁴ or CR ^{15 provided} that at least one of W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ , W ¹⁸ and W ¹⁹ is N, NR ¹⁸ , O or S, and R ¹⁵ And R ¹⁸ are defined below and herein.

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピペリジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピペリジニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたピペリジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピペリジニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたピペリジニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a piperidinyl group. In certain embodiments, Z is a piperidinyl group substituted with, for example, 0, 1, 2, 3, 4 or 5 R ¹⁵ groups of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted piperidinyl (ie, z is 0). In certain embodiments, Z is substituted piperidinyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted piperidinyl (ie, z is 1). In certain embodiments, Z is a disubstituted piperidinyl (ie, z is 2). In certain embodiments, Z is a trisubstituted piperidinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is, for example, a 1-piperidinyl group of formula (ii-h), where W ¹⁹ is N, and W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ , and W ¹⁸ are Independently, it is selected from CH ₂ , CHR ¹⁵ and C (R ¹⁵ ) ₂ . In certain embodiments, Z is, for example, a 2-piperidinyl group of formula (ii-h), where W ¹⁴ is NR ¹⁸ ; W ¹⁵ , W ¹⁶ , W ¹⁷ , and W ¹⁸ are independently , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ ; and W ¹⁹ is CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 3-piperidinyl group of formula (ii-h), where W ¹⁵ is NR ¹⁸ ; W ¹⁴ , W ¹⁶ , W ¹⁷ and W ¹⁸ are independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ ; and W ¹⁹ is CH or CR ¹⁵ . In certain embodiments, Z is, for example, a 4-piperidinyl group of formula (ii-h), where W ¹⁶ is NR ¹⁸ ; W ¹⁴ , W ¹⁵ , W ¹⁷ and W ¹⁸ are independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ ; and W ¹⁹ is CH or CR ¹⁵ .

ここで、xは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のピペラジニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたピペラジニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたピペラジニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたピペラジニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたピペラジニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a piperazinyl group. In certain embodiments, Z is a piperazinyl group substituted with, for example, 0, 1, 2, 3, 4 or 5 R ¹⁵ groups of the formula:

Where x is 0, 1, 2, 3, 4 or 5 and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted piperazinyl (ie, z is 0). In certain embodiments, Z is substituted piperazinyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is a monosubstituted piperazinyl (ie, z is 1). In certain embodiments, Z is a disubstituted piperazinyl (ie, z is 2). In certain embodiments, Z is a trisubstituted piperazinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is, for example, a piperazinyl group of formula (ii-h), where W ¹⁹ is N, W ¹⁶ is NR ¹⁸ and W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ and W ¹⁸ are independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ . In certain embodiments, Z is a piperazinyl group, where W ¹⁹ is CH or CR ¹⁵ , W ¹⁴ and W ¹⁷ are independently NR ¹⁸ , and W ¹⁵ , W ¹⁶ , and W ¹⁸ is independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ .

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のモルホリニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたモルホリニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたモルホリニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたモルホリニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたモルホリニルである(すなわち、zは3である)。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a morpholinyl group substituted with, for example, 0, 1, 2, 3, 4 or 5 R ¹⁵ groups of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ are defined below and herein. In certain embodiments, Z is unsubstituted morpholinyl (ie, z is 0). In certain embodiments, Z is substituted morpholinyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is monosubstituted morpholinyl (ie, z is 1). In certain embodiments, Z is disubstituted morpholinyl (ie, z is 2). In certain embodiments, Z is trisubstituted morpholinyl (ie, z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a morpholinyl group; such as a group of formula (ii-h), wherein W ¹⁹ is N, W ¹⁶ is O, and W ¹⁴ , W ¹⁵ , W ¹⁶ , And W ¹⁷ are independently selected from CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ . In certain embodiments, Z is a morpholinyl group, wherein W ¹⁹ is CH or CR ¹⁵ , W ¹⁴ and W ¹⁷ are independently selected from O and NR ¹⁸ and W ¹⁵ , W ¹⁶ and W ¹⁸ are independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ .

ここで、zは、0、1、2、3、4又は5であり、かつR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Zは、非置換のジオキサニルである(すなわち、zは0である)。特定の実施態様において、Zは、置換されたジオキサニルである(例えば、zは、1、2、3、4又は5である)。特定の実施態様において、Zは、一置換されたジオキサニルである(すなわち、zは1である)。特定の実施態様において、Zは、二置換されたジオキサニルである(すなわち、zは2である)。特定の実施態様において、Zは、三置換されたジオキサニルである(すなわち、zは3である)。特定の実施態様において、特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは0又は1である。 In certain embodiments, Z is a dioxanyl group. In certain embodiments, Z is a dioxanyl group substituted with, for example, 0, 1, 2, 3, or 4 R ¹⁵ groups of the formula:

Where z is 0, 1, 2, 3, 4 or 5, and R ¹⁵ is defined below and herein. In certain embodiments, Z is unsubstituted dioxanyl (ie, z is 0). In certain embodiments, Z is substituted dioxanyl (eg, z is 1, 2, 3, 4 or 5). In certain embodiments, Z is monosubstituted dioxanyl (ie, z is 1). In certain embodiments, Z is disubstituted dioxanyl (ie, z is 2). In certain embodiments, Z is trisubstituted dioxanyl (ie, z is 3). In certain embodiments, in certain embodiments, z is 0, 1, 2, or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is, for example, a dioxanyl group of formula (ii-h), where W ¹⁴ and W ¹⁷ are O, and W ¹⁵ , W ¹⁶ , and W ¹⁸ are independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ ; and W ¹⁹ is CH or CR ¹⁵ . In certain embodiments, Z is a dioxanyl group, wherein W ¹⁹ is CH or CR ¹⁵ , W ¹⁴ and W ¹⁶ are independently selected from O, and W ¹⁵ , W ¹⁷ , and W ¹⁸ is independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ . In certain embodiments, Z is a dioxanyl group, wherein W ¹⁹ is CH or CR ¹⁵ , W ¹⁵ and W ¹⁷ are independently selected from O, and W ¹⁴ , W ¹⁶ , and W ¹⁸ is independently CHR ¹⁵ , C (R ¹⁵ ) ₂ , or CH ₂ .

In certain embodiments, Z is C _3-10 carbocyclyl. In certain embodiments, Z is C _3-10 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is C _5-8 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is C _5-6 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups. In certain embodiments, Z is C _9-10 carbocyclyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

(Embodiment in which R ^a and R ^d are combined (condensed))
As defined generally above, in certain embodiments, R ^a and R ^d are joined to form a C _3-10 carbocyclyl or 3-14 membered heterocyclyl fused ring, and R ^b and R ^c are independently And selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl.

In certain embodiments, each of R ^b and R ^c is independently selected from —H, C _1-6 alkyl, and C _1-6 perhaloalkyl. In certain embodiments, each of R ^b and R ^c is independently selected from —H, C _1-3 alkyl and C _1-3 perhaloalkyl. In certain embodiments, each of R ^b and R ^c is independently selected from —H, C ₁ alkyl, and C ₁ perhaloalkyl. In certain embodiments, each of R ^b and R ^c is independently selected from —H, —CH ₃ , and —CF ₃ . In certain embodiments, each of R ^b and R ^c is independently selected from —H and —CH ₃ . In certain embodiments, each of R ^b and R ^c is independently selected from —H and —CF ₃ . In certain embodiments, R ^b and R ^c are both —H.

ここで、W²⁰、W²¹、W²²、及びW²³は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、R¹⁵及びR¹⁸は、下記及び本明細書において定義されており、sは、0、1又は2であり、かつ点線は環縮合を示す。 In certain embodiments, R ^a and R ^d are joined to form a C _5-7 carbocyclyl or 5-7 membered heterocyclyl fused ring. In certain embodiments, R ^a and R ^d combine to form a C _5-7 carbocyclyl or 5-7 membered heterocyclyl fused ring of the formula:

Here, W ²⁰ , W ²¹ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are S is 0, 1 or 2, and the dotted line indicates a ring condensation.

In certain embodiments, R ^a and R ^d are joined to form a C _5-7 carbocyclyl fused ring. For example, in certain embodiments of formula (ii-j), W ²⁰ , W ²¹ , W ²² and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . Examples of C _5-7 carbocyclyl groups that can be formed by combining R ^a and R ^d include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, where such groups include: Substituted by 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

In certain embodiments, R ^a and R ^d are joined to form a 5-7 membered heterocyclyl fused ring. For example, in certain embodiments of formula (ii-j), W ²⁰ is NR ¹⁸ and W ²¹ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) _2. It is. In certain embodiments of formula (ii-j), W ²¹ is NR ¹⁸ and W ²⁰ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . is there. In certain embodiments of formula (ii-j), W ²² is NR ¹⁸ and W ²⁰ , W ²¹ , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . is there. Examples of 5-7 membered heterocyclyl groups that R ^a and R ^d can combine to form include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and azepanyl. Such groups are substituted by 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

ここで、W²⁰、W²¹、及びW²²は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、R¹⁵及びR¹⁸は、下記及び本明細書において定義されており、かつ点線は環縮合を示す。 In certain embodiments, where s is 0, R ^a and R ^d are joined to form a C ₅ carbocyclyl or 5-membered heterocyclyl fused ring as follows:

Here, W ²⁰ , W ²¹ , and W ²² are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are defined below and herein. The dotted line indicates ring condensation.

In certain embodiments of formula (ii-k), R ^a and R ^d combine to form a C ₅ carbocyclyl fused ring (ie, cyclopentyl), for example, where W ²⁰ , W ²¹ , and W ²² are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ .

In certain embodiments of formula (ii-k), R ^a and R ^d combine to form a 5-membered heterocyclyl fused ring (eg, pyrrolidinyl), eg, where W ²¹ is NR ¹⁸ and W ²⁰ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ . In certain embodiments of formula (ii-k), R ^a and R ^d combine to form a 5-membered heterocyclyl fused ring (eg, pyrrolidinyl), eg, where W ²⁰ is NR ¹⁸ and W ²¹ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ .

ここで、W²⁰、W²¹、W²²及びW²³は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、R¹⁵及びR¹⁸は、下記及び本明細書において定義されており、かつ点線は環縮合を示す。 In certain embodiments where s is 1, R ^a and R ^d are joined to form a C ₆ carbocyclyl or 6-membered heterocyclyl fused ring of the formula:

Where W ²⁰ , W ²¹ , W ²² and W ²³ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are And the dotted line indicates a ring condensation.

In certain embodiments of formula (ii-m), R ^a and R ^d combine to form a C ₆ carbocyclyl fused ring (ie, cyclohexyl), eg, where W ²⁰ , W ²¹ , W ²² , and W ²³ is independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

In certain embodiments of formula (ii-m), R ^a and R ^d combine to form a 6-membered heterocyclyl fused ring (eg, piperidinyl), eg, where W ²¹ is NR ¹⁸ and W ²⁰ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ . In certain embodiments of formula (ii-m), R ^a and R ^d combine to form a 6-membered heterocyclyl fused ring (eg, piperidinyl), eg, where W ²⁰ is NR ¹⁸ and W ²¹ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

ここで、W²⁰、W²¹、W²²及びW²³は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、R¹⁵及びR¹⁸は、下記及び本明細書において定義されており、かつ点線は環縮合を示す。 In certain embodiments where s is 2, R ^a and R ^d are joined to form a C ₇ carbocyclyl or 7-membered heterocyclyl ring:

Where W ²⁰ , W ²¹ , W ²² and W ²³ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are And the dotted line indicates a ring condensation.

In certain embodiments of formula (ii-n), R ^a and R ^d combine to form a C ₇ carbocyclyl ring (ie, cycloheptyl), eg, where W ²⁰ , W ²¹ , W ²² , and W ²³ is independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

In certain embodiments of formula (ii-n), R ^a and R ^d combine to form a 7-membered heterocyclyl ring (eg, azepanyl), eg, where W ²¹ is NR ¹⁸ and W ²⁰ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments of formula (ii-n), R ^a and R ^d combine to form a 7-membered heterocyclyl ring (eg, azepanyl), eg, where W ²² is NR ¹⁸ and W ²⁰ , W ²¹ , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

Embodiment in which R ^c and R ^d are combined (spiro-condensed)
In certain embodiments, as generally defined above, R ^c and R ^d are joined to form a C _3-10 carbocyclyl or 3-14 membered heterocyclylspiro-fused ring, and R ^a and R ^b are Independently selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl.

In certain embodiments, each of R ^a and R ^b is independently selected from —H, C _1-6 alkyl, and C _1-6 perhaloalkyl. In certain embodiments, each of R ^a and R ^b is independently selected from —H, C _1-3 alkyl, and C _1-3 perhaloalkyl. In certain embodiments, each of R ^a and R ^b is independently selected from —H, C ₁ alkyl, and C ₁ perhaloalkyl. In certain embodiments, each of R ^a and R ^b is independently selected from —H, —CH ₃ and —CF ₃ . In certain embodiments, each of R ^a and R ^b is independently selected from —H and —CH ₃ . In certain embodiments, each of R ^a and R ^b is independently selected from —H and —CF ₃ . In certain embodiments, R ^a and R ^b are both —H.

In certain embodiments, R ^c and R ^d are combined and C _5-7 carbocyclyl, 5-7 membered heterocyclyl, 5,6-bicyclic carbocyclyl, 6,6-bicyclic carbocyclyl, 5,6- Bicyclic heterocyclyl or 6,6-bicyclic heterocyclylspiro-fused rings are formed.

ここで、W²⁴、W²⁵、W²⁶、W²⁷、W²⁸及びW²⁹は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、任意にここでW²⁵及びW²⁶は、縮合したC₆アリール環又は縮合した6-員のヘテロアリール環により置換され；t及びvは独立して、0又は1であり；かつ、R¹⁵及びR¹⁸は、下記及び本明細書において定義される通りである。特定の実施態様において、tは0であり、かつvは0である。特定の実施態様において、tは0であり、かつvは1である。特定の実施態様において、tは1であり、かつvは0である。特定の実施態様において、tは1であり、かつvは1である。 For example, in certain embodiments, R ^c and R ^d are combined and C _5-7 carbocyclyl, 5-7 membered heterocyclyl, 5,6-bicyclic carbocyclyl, or 5,6-bicyclic heterocyclylspiro of the formula: -Form a condensed ring:

Where W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , optionally where W ²⁵ And W ²⁶ are substituted by a fused C ₆ aryl ring or a fused 6-membered heteroaryl ring; t and v are independently 0 or 1, and R ¹⁵ and R ¹⁸ are As defined herein. In certain embodiments, t is 0 and v is 0. In certain embodiments, t is 0 and v is 1. In certain embodiments, t is 1 and v is 0. In certain embodiments, t is 1 and v is 1.

In certain embodiments, R ^c and R ^d are joined to form a C _5-7 carbocyclyl spiro-fused ring. For example, in certain embodiments of formula (iii-a), W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) _2. It is. Examples of C _5-7 carbocyclyl groups that can be formed by combining R ^c and R ^d include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl. Is substituted by 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

In certain embodiments, R ^c and R ^d are joined to form a 5-7 membered heterocyclylspiro-fused ring. For example, in certain embodiments of formula (iii-a), W ²⁵ is NR ¹⁸ and W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ₂ ) In certain embodiments of formula (iii-a), W ²⁶ is NR ¹⁸ and W ²⁴ , W ²⁵ , W ²⁷ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . In certain embodiments of formula (iii-a), W ²⁷ is NR ¹⁸ and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . Examples of 5-7 membered heterocyclyl groups that can be formed by combining R ^c and R ^d include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and azepanyl, Here such groups are substituted by 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

ここで、W²⁵、W²⁶、W²⁷、及びW²⁸は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている通りである。 In certain embodiments where t is 0 and v is 0, R ^c and R ^d are joined to form a C ₅ carbocyclyl or 5-membered heterocyclylspiro-fused ring of the formula:

Here, W ²⁵ , W ²⁶ , W ²⁷ , and W ²⁸ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are As defined in the specification.

In certain embodiments, R ^c and R ^d are joined to form a C ₅ carbocyclyl spiro-fused ring (eg, cyclopentyl); eg, a ring of formula (iii-b), wherein W ²⁵ is NR ¹⁸ and W ²⁶ , W ²⁷ , and W ²⁸ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

In certain embodiments, R ^c and R ^d are joined to form a 5-membered heterocyclylspiro-fused ring; for example, a ring of formula (iii-b), wherein W ²⁶ is NR ¹⁸ ; W ²⁵ , W ²⁷ , and W ²⁸ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

ここで、W²⁵、W²⁶、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている通りである。 In certain embodiments where t is 0 and v is 1, R ^c and R ^d are joined to form a C ₆ carbocyclyl or 6-membered heterocyclylspiro-fused ring of the formula:

Where W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ are As defined below and herein.

In certain embodiments, R ^c and R ^d are joined to form a C ₆ carbocyclyl-spiro-fused ring (eg, cyclohexyl); eg, a ring of formula (iii-c), wherein W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

In certain embodiments, R ^c and R ^d are joined to form a 5-membered heterocyclylspiro-fused ring; eg, a ring of formula (iii-c), wherein W ²⁶ is NR ¹⁸ And W ²⁵ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments, R ^c and R ^d combine to form a 5-membered heterocyclylspiro-fused ring of formula (iii-c), wherein W ²⁷ is NR ¹⁸ and W ²⁵ , W ²⁶ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

ここで、W²⁴、W²⁵、W²⁶、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている通りである。 In certain embodiments where t is 1 and v is 1, R ^c and R ^d are combined to form a C ₇ carbocyclyl or 7-membered heterocyclyl spiro-fused ring of the formula:

Where W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , and R ¹⁵ and R ¹⁸ is as defined below and herein.

In certain embodiments, R ^c and R ^d are joined to form a C ₇ carbocyclylspiro-fused ring (eg, cycloheptyl); eg, a ring of formula (iii-d), wherein W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

In certain embodiments, R ^c and R ^d are joined to form a 7-membered heterocyclylspiro-fused ring; eg, a ring of formula (iii-d), wherein W ²⁵ is NR ¹⁸ ; And W ²⁴ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments, R ^c and R ^d are combined, W ²⁶ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , Or form a 7-membered heterocyclylspiro-fused ring that is C (R ¹⁵ ) ₂ . In certain embodiments, R ^c and R ^d are combined, W ²⁷ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , Or form a 7-membered heterocyclylspiro-fused ring that is C (R ¹⁵ ) ₂ .

In certain embodiments, R ^c and R ^d are joined to form a 5,6-bicyclic carbocyclyl spiro-fused ring or a 5,6-bicyclic heterocyclyl spiro-fused ring. For example, in certain embodiments of formula (iii-a), t and v are both 0 and W ²⁵ and W ²⁶ are substituted by a fused C ₆ aryl ring or a fused 6-membered heteroaryl ring; W ²⁷ is CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , and NR ¹⁸ , and W ²⁸ is CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments of formula (iii-a), R ^c and R ^d are attached, for example, t and v are both 0 and W ²⁵ and W ²⁶ are fused C ₆ aryl rings or fused 6- 5,6-bicyclic carbocyclyl spiro-fused ring substituted by a member heteroaryl ring and W ²⁷ and W ²⁸ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ Form. In certain embodiments, W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring.

ここで、W²⁷及びW²⁸は独立して、CH₂、CHR¹⁵、及びC(R¹⁵)₂であり、zは、0、1、2、3又は4であり；かつ、R¹⁵は、下記及び本明細書において定義されている通りである。特定の実施態様において、W²⁷及びW²⁸は両方ともCH₂基である。特定の実施態様において、zは、0、1、2、3又は4である。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは2である。特定の実施態様において、zは1である。特定の実施態様において、zは0である。 For example, in certain embodiments where both t and v are 0 and W ²⁵ and W ²⁶ are substituted by a fused C ₆ aryl ring, R ^c and R ^d are attached and A bicyclic carbocyclyl spiro-fused ring is formed:

Where W ²⁷ and W ²⁸ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ , z is 0, 1, 2, 3 or 4; and R ¹⁵ is As defined below and herein. In certain embodiments, W ²⁷ and W ²⁸ are both CH ₂ groups. In certain embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 2. In certain embodiments, z is 1. In certain embodiments, z is 0.

In certain embodiments, R ^c and R ^d are joined to form a 6,6-bicyclic carbocyclyl spiro-fused ring or a 6,6-bicyclic heterocyclyl spiro-fused ring. For example, in certain embodiments of formula (iii-a), t is 0 and v is 1, and W ²⁵ and W ²⁶ are substituted by a fused C ₆ aryl ring or a fused 6-membered heteroaryl ring. And W ²⁷ and W ²⁸ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , and NR ¹⁸ , and W ²⁹ is CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . . In certain embodiments of formula (iii-a), R ^c and R ^d are attached, for example, t is 0 and v is 1, and W ²⁵ and W ²⁶ are fused C ₆ aryl rings or fused 6,6-bicyclic carbocyclyl substituted by a 6-membered heteroaryl ring and W ²⁷ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ Spiro-fused rings are formed. In certain embodiments, W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring.

ここで、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、及びC(R¹⁵)₂であり、zは、0、1、2、3又は4であり、かつ、R¹⁵は、下記及び本明細書において定義されている通りである。特定の実施態様において、W²⁷、W²⁸、及びW²⁹は各々CH₂基である。特定の実施態様において、zは、0、1、2、3又は4である。特定の実施態様において、zは、0、1、2又は3である。特定の実施態様において、zは、0、1又は2である。特定の実施態様において、zは2である。特定の実施態様において、zは1である。特定の実施態様において、zは0である。 For example, in certain embodiments where t is 0 and v is 1 and W ²⁵ and W ²⁶ are substituted by a fused C ₆ aryl ring, R ^c and R ^d are attached and A 6-bicyclic carbocyclyl spiro-fused ring is formed:

Where W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ , z is 0, 1, 2, 3, or 4, and R ¹⁵ is as defined below and herein. In certain embodiments, W ²⁷ , W ²⁸ , and W ²⁹ are each a CH ₂ group. In certain embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 2. In certain embodiments, z is 1. In certain embodiments, z is 0.

ここで、W³⁰、W³¹、W³²、W³³、及びW³⁶は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり；かつ、W³⁴及びW³⁵は独立して、CH又はCR¹⁵であり、かつR¹⁵及びR¹⁸は、下記及び本明細書において定義されている通りである。 In another embodiment, R ^c and R ^d are joined to form a bridged carbocyclyl or bridged heterocyclylspiro-fused ring of the formula:

Where W ³⁰ , W ³¹ , W ³² , W ³³ , and W ³⁶ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ ; and W ³⁴ and W ³⁵ are Independently, CH or CR ¹⁵ and R ¹⁵ and R ¹⁸ are as defined below and herein.

In certain embodiments of formula (iii-f), W ³⁰ , W ³¹ , W ³² , W ³³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ ; W ³⁶ is NR ¹⁸ And W ³⁴ and W ³⁵ are independently CH or CR ¹⁵ . In certain embodiments of formula (iii-f), W ³⁰ , W ³¹ , W ³² , W ³³ , and W ³⁶ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ ; and , W ³⁴ and W ³⁵ are independently CH or CR ¹⁵ . In certain embodiments of formula (iii-f), W ³⁴ and W ³⁵ are CH.

(R ¹⁵ )
As used herein, each instance of R ¹⁵ is independently halogen (i.e., fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I)), -CN,- _{NO 2, -N 3, -SO 2} H, -SO 3 H, -OH, -OR 16, -ON (R 18) 2, -N (R 18) 2, -N (R 18) 3 + X - , -N (OR ¹⁷ ) R ¹⁸ , -SH, -SR ¹⁶ , -SSR ¹⁷ , -C (= O) R ¹⁶ , -CO ₂ H, -CHO, -CO ₂ R ¹⁶ , -OC (= O) R ¹⁶ , -OCO ₂ R ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -OC (= O) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= O) R ¹⁶ , -NR ¹⁸ CO ₂ R ¹⁶ , -NR ¹⁸ C (= O) N (R ¹⁸ ) ₂ , -C (= NR ¹⁸ ) R ¹⁶ , -C (= NR ¹⁸ ) OR ¹⁶ , -OC (= NR ¹⁸ ) R ¹⁶ ,- OC (= NR ¹⁸ ) OR ¹⁶ , -C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -OC (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -C (= O) NR ¹⁸ SO ₂ R ¹⁶ , -NR ¹⁸ SO ₂ R ¹⁶ , -SO ₂ N (R ¹⁸ ) ₂ , -SO ₂ R ¹⁶ , -SO ₂ OR ¹⁶ , -OSO ₂ R ¹⁶ , -S (= O) R ¹⁶ , -OS (= O) R ¹⁶ , -Si (R ¹⁶ ) ₃ , -OSi (R ¹⁶ ) ₃ , -C (= S) N (R ¹⁸ ) ₂ ,- C (= O) SR ¹⁶ , -C (= S) SR ¹⁶ , -SC (S) SR ¹⁶ , -P (= O) ₂ R ¹⁶ , -OP (= O) ₂ R ¹⁶ , -P (= O _{^{) (R 16) 2, -OP}} (= O) (R 16) 2, -OP (= O) (OR 17) 2 _{-P (= O) 2 N (} R 18) 2, -OP (= O) 2 N (R 18) 2, -P (= O) (NR 18) 2, -OP (= O) (NR 18) ₂ , -NR ¹⁸ P (= O) (OR ¹⁷ ) ₂ , -NR ¹⁸ P (= O) (NR ¹⁸ ) ₂ , -P (R ¹⁷ ) ₂ , -P (R ¹⁷ ) ₃ , -OP (R _{^{17) 2, -OP (R 17}} ) 3, -B (OR 17) 2, -BR 16 (OR 17), C 1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2- Selected from ₁₀ alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and hetero Each of the aryls is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups; or two adjacent R ¹⁵ groups are group —O (C (R ² ₂ ) substituted by _1-2x O-, wherein each R ² is independently -H, C _1-6 alkyl or halogen;
Each instance of R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ¹⁹ groups;
Each example of R ¹⁸ is independently hydrogen, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -CN, -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁷ , -SO ₂ OR ¹⁷ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁷ , -C (= S) SR ¹⁷ , -P (= O ) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -P (= O) ₂ N (R ¹⁷ ) ₂ , -P (= O) (NR ¹⁷ ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ¹⁷ groups attached to the N atom join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl , and heteroaryl each aryl is independently 0, 1, 2, 3, or five R ¹⁹ groups Is more substituted;
Each instance of R ¹⁷ is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ¹⁷ groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl Forms an aryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups ;
Each example of R ¹⁹ is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ²⁰ , -ON (R ²¹ ) ₂ , -N _{^{(R 21) 2, -N (}} R 21) 3 + X -, -N (OR 20) R 21, -SH, -SR 20, -SSR 20, -C (= O) R 20, -CO 2 H , -CO ₂ R ²⁰ , -OC (= O) R ²⁰ , -OCO ₂ R ²⁰ , -C (= O) N (R ²¹ ) ₂ , -OC (= O) N (R ²¹ ) ₂ , -NR ²¹ C (= O) R ^2O , -NR ²¹ CO ₂ R ²⁰ , -NR ²¹ C (= O) N (R ²¹ ) ₂ , -C (= NR ²¹ ) OR ²⁰ , -OC (= NR ²¹ ) R ²⁰ , -OC (= NR ²¹ ) OR ²⁰ , -C (= NR ²¹ ) N (R ²¹ ) ₂ , -OC (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ C (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ SO ₂ R ²⁰ , -SO ₂ N (R ²¹ ) ₂ , -SO ₂ R ²⁰ , -SO ₂ OR ²⁰ , -OSO ₂ R ²⁰ , -S (= O) R ²⁰ , -Si (R ²⁰ ) ₃ , -OSi (R ²⁰ ) ₃ , -C (= S) N (R ²¹ ) ₂ , -C (= O) SR ²⁰ , -C (= S) SR ²⁰ , -SC (= S) SR ²⁰ , -P (= O) ₂ R ²⁰ , -P (= O) (R ²⁰ ) ₂ , -OP (= O) (R ²⁰ ) ₂ , -OP (= O) (OR ²⁰ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member of hetero ants Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups. Or two geminal R ¹⁹ substituents can be joined to form ═O or ═S;
Each example of R ²⁰ is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ²² groups;
Each example of R ²¹ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Two R ²¹ groups selected from C _6-10 aryl and 5-10 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl Forming a ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups; And
Each example of R ²² is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH ( C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1- 6} alkyl), - NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), - NHC (= O) NH 2, -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1- 6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1- 6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ²² substituents are attached and = O or = S can be formed;
Here, X ⁻ is a counter ion.

In certain embodiments, each instance of R ¹⁵ is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -OR ¹⁶ , -C (= O ) N (R ¹⁸ ) ₂ , -SO ₂ N (R ¹⁸ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-14 aryl, and Selected from 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups Is done.

In certain embodiments, R ¹⁵ is independently from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —OR ¹⁶ , and C _1-10 perhaloalkyl. Selected. In certain embodiments, R ¹⁵ is independently selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), and —OR ¹⁶ . In certain embodiments, R ¹⁵ is independently selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), and C _1-10 perhaloalkyl.

In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

In certain embodiments, R ¹⁵ is —OR ¹⁶ . In certain embodiments, R ¹⁶ is from C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-10 aryl, and 5-6 membered heteroaryl. Selected, wherein each of alkyl, alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups.

In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _1-10 alkyl. In certain embodiments, R ¹⁵ 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 C _1-4 alkyl. In certain embodiments, R ¹⁵ 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, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is —CH ₃ .

In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _1-10 perhaloalkyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _1-6 perhaloalkyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _1-4 perhaloalkyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _1-2 perhaloalkyl. In certain embodiments, R ¹⁵ is -OR ¹⁶ and R ¹⁶ is -CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , -CCl ₃ , -CFCl ₂ , or -CF ₂ Cl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is —CF ₃ .

In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _2-10 alkenyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _2-6 alkenyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _2-4 alkenyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from —CH ₂ CHCH ₂ (ie, allyl).

In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _2-10 alkynyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _2-6 alkynyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from C _2-4 alkynyl. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from —CH ₂ CCH (ie, propargyl).

In certain embodiments, R ¹⁵ is --OR ¹⁶ and R ¹⁶ is selected from C ₆ aryl (eg, phenyl) substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. The In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is phenyl substituted with 0, 1, or 2 R ¹⁹ groups. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is phenyl substituted with one R ¹⁹ group. In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is phenyl substituted with 0 R ¹⁹ groups (ie, —C ₆ H ₅ ).

In certain embodiments, R ¹⁵ is -OR ¹⁶ and R ¹⁶ is selected from 5-6 membered heteroaryl substituted by 0, 1, 2, 3, or 4 R ¹⁹ groups. The In certain embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is selected from 6-membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In certain embodiments, R ¹⁵ is -OR ¹⁶ and R ¹⁶ is a pyridinyl (e.g., 2-pyridinyl, 3-pyridine) substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. Pyridinyl, 4-pyridinyl). In certain embodiments, R ¹⁵ is --OR ¹⁶ and R ¹⁶ is pyrimidinyl substituted with 0, 1, 2, or 3 R ¹⁹ groups (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl).

In certain embodiments, R ¹⁵ is —C (═O) N (R ¹⁸ ) ₂ .

In certain embodiments, R ¹⁵ is —SO ₂ N (R ¹⁸ ) ₂ .

In certain embodiments, R ¹⁵ is C _1-10 perhaloalkyl. In certain embodiments, R ¹⁵ is C _1-6 perhaloalkyl. In certain embodiments, R ¹⁵ is C _1-4 perhaloalkyl. In certain embodiments, R ¹⁵ is C _1-2 perhaloalkyl. In certain embodiments, R ¹⁵ is selected from —CF ₃ , —CF ₂ CF ₃ , —CF ₂ CF ₂ CF ₃ , —CCl ₃ , —CFCl ₂ , and —CF ₂ Cl. In certain embodiments, R ¹⁵ is selected from —CF ₃ .

In certain embodiments, R ¹⁵ is C _1-10 alkyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups. In certain embodiments, R ¹⁵ is C _1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups. R ¹⁵ is C _1-4 alkyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups. In certain embodiments, the R ¹⁵ alkyl group is unsubstituted (0 R ¹⁹ groups). In certain embodiments, R ¹⁵ is —CH ₃ , —Et, —iPr, —nBu, —n-pentyl.

In certain embodiments, R ¹⁵ is C _2-10 alkenyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups. In certain embodiments, R ¹⁵ is C _2-6 alkenyl substituted with 0, 1, 2, 3 or 4 R ¹⁹ groups. In certain embodiments, R ¹⁵ is C _2-4 alkenyl substituted with 0, 1, 2 or 3 R ¹⁹ groups. In certain embodiments, the R ¹⁵ alkenyl group is unsubstituted (0 R ¹⁹ groups). In certain embodiments, R ¹⁵ is —CH ₂ CHCH ₂ (ie, allyl).

In certain embodiments, R ¹⁵ is C _2-10 alkynyl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups. In certain embodiments, R ¹⁵ is C _2-6 alkynyl substituted with 0, 1, 2, or 3 R ¹⁹ groups. In certain embodiments, R ¹⁵ is C _2-4 alkynyl substituted with 0, 1 or 2 R ¹⁹ groups. In certain embodiments, the R ¹⁵ alkynyl group is unsubstituted (0 R ¹⁹ groups). In certain embodiments, R ¹⁵ is —CH ₂ CCH (ie, propargyl).

In certain embodiments, R ¹⁵ is C _6-14 aryl. In certain embodiments, R ¹⁵ is selected from C ₆ aryl (eg, phenyl) substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In certain embodiments, R ¹⁵ is unsubstituted phenyl. In certain embodiments, R ¹⁵ is monosubstituted phenyl (ie, substituted with one R ¹⁹ group).

In certain embodiments, R ¹⁵ is a 5-14 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups. In certain embodiments, R ¹⁵ is a 5-6 membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In certain embodiments, R ¹⁵ is a 6-membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In certain embodiments, R ¹⁵ is pyridinyl (eg, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In certain embodiments, R ¹⁵ is pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2, or 3 R ¹⁹ groups. In certain embodiments, the R ¹⁵ heteroaryl group is unsubstituted (0 R ¹⁹ groups).

(R ¹⁸ )
In certain embodiments, each instance of R ¹⁸ is independently -H, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁶ , -SO ₂ OR ¹⁶ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁶ , -C (= S) SR ¹⁶ , C _1-10 alkyl (eg aralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, And a 5-14 membered heteroaryl group, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or Substituted by 5 R ¹⁹ groups, wherein R ¹⁶ , R ¹⁷ , R ¹⁹ are as defined above and herein.

In certain embodiments, each instance of R ¹⁷ is independently from —H, —C (═O) R ¹⁶ , —C (═O) OR ¹⁶ , —SO ₂ R ¹⁶ , or C _1-6 alkyl. Selected. In certain embodiments, each example of R ¹⁷ is independently selected from —H or C _1-6 alkyl. In certain embodiments, each instance of R ¹⁷ is independently selected from —H and —CH ₃ . In certain embodiments, each instance of R ¹⁷ is independently selected from —H. In certain embodiments, each instance of R ¹⁷ is independently selected from —CH ₃ .

ここで、G、R^a、R^b、R^c、及びR^dは、本明細書に定義されている通りである。 Additional embodiments of compounds of formula (I)
As generally defined above, the present invention provides compounds of formula (I), or pharmaceutically acceptable forms thereof:

Here, G, R ^a , R ^b , R ^c , and R ^d are as defined in this specification.

ここで、G及びZは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gは、ハロゲン(例えば-Br、-Cl、-I)ではない。 In one embodiment where R ^a , R ^b , R ^c are each H and R ^d is a group Z, the present invention provides a compound of formula (II), or a pharmaceutically acceptable form thereof:

Here, G and Z are as defined in this specification. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、R^e及びZは、本明細書に定義されている通りである。 In certain embodiments where, for example, L is a covalent bond, R ^a , R ^b , R ^c are each H and G is a group —OR ^e , the present invention provides a compound of formula (II-a): Or a pharmaceutically acceptable form thereof:

Here, ^Re and Z are as defined in this specification.

ここで、G、L、R^a、R^b、R^c、R¹⁵、及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、zは2であり、かつR¹⁵は、メタ及びパラ位にある。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば-Br、-Cl、-I)ではない。特定の実施態様において、R¹⁵は、-OR¹⁶、及びC_1-10ペルハロアルキルから選択される。 In certain embodiments where Z is a phenyl ring, the present invention provides compounds of formula (II-b), or a pharmaceutically acceptable form thereof:

Here, G, L, R ^a , R ^b , R ^c , R ¹⁵ , and z are as defined herein. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, z is 2 and R ¹⁵ is in the meta and para positions. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

ここで、G、L、R^a、R^b、R^c、R¹⁵、及びzは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし、特定の実施態様において、Gはハロゲン(例えば-Br、-Cl、-I)ではない。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。 For example, in certain embodiments where z is 1 and R ¹⁵ is para, a compound of formula (II-c), or a pharmaceutically acceptable form thereof, is provided:

Here, G, L, R ^a , R ^b , R ^c , R ¹⁵ , and z are as defined herein. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

ここで、G、L、R^a、R^b、R^c、R¹⁵、及びzは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば-Br、-Cl、-I)ではない。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。 For example, in certain embodiments where z is 2 and one R ¹⁵ is meta and one R ¹⁵ is para, a compound of formula (II-c), or a pharmaceutically acceptable salt thereof Provide possible forms:

Here, G, L, R ^a , R ^b , R ^c , R ¹⁵ , and z are as defined herein. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

ここで、L、R^a、R^b、R^c、R¹⁵、R^e、及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、Lは共有結合である。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。 For example, in certain embodiments where Z is a phenyl ring and G is a group —OR ^e , the present invention provides a compound of formula (II-d), or a pharmaceutically acceptable form thereof:

Here, L, R ^a , R ^b , R ^c , R ¹⁵ , R ^e , and z are as defined in this specification. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, L is a covalent bond. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

ここで、L、R^a、R^b、R^c、R¹⁵、R^h、x及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、Lは共有結合である。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。 Z is a phenyl ring, G is a group -OR ^e, and in certain embodiments R ^e is a phenyl ring, the invention provides compounds of formula (II-e), or acceptable their pharmaceutically Provide the form to obtain:

Here, L, R ^a , R ^b , R ^c , R ¹⁵ , R ^h , x and z are as defined in this specification. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, L is a covalent bond. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

ここで、Y^a、Y^b、Y^c、Y^d、L、R^a、R^b、R^c、R¹⁵、及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、Lは共有結合である。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。 In certain embodiments where Z is a phenyl ring, G is a group -OR ^e and R ^e is a 5-membered heteroaryl ring, the present invention provides compounds of formula (II-f), or Provides a pharmaceutically acceptable form of:

Here, Y ^a , Y ^b , Y ^c , Y ^d , L, R ^a , R ^b , R ^c , R ¹⁵ , and z are as defined in this specification. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, L is a covalent bond. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

ここで、W^a、W^b、W^c、W^d、W^e、L、R^a、R^b、R^c、R¹⁵及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。特定の実施態様において、Lは共有結合である。特定の実施態様において、W^bはNであり、かつW^a、W^c、W^d及びW^eは、CH又はCR^hから選択される。特定の実施態様において、特定の実施態様において、W^bはNであり、W^cはCR^hであり、かつW^a、W^c、W^d及びW^eは、各々CHである。特定の実施態様において、W^b及びW^dはNであり、かつW^a、W^c、W^d及びW^eは、CH又はCR^hから選択される。 In certain embodiments where Z is a phenyl ring, G is a group -OR ^e and R ^e is a 6-membered heteroaryl ring, the present invention provides compounds of formula (II-g), or Provides a pharmaceutically acceptable form of:

^{Here, W a, W b, W} c, W d, W e, L, R a, R b, R c, R 15 and z are as defined herein. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In certain embodiments, L is a covalent bond. In certain embodiments, W ^b is N, and W ^a, W ^c, W ^d and W ^e is selected from CH or CR ^h. In certain embodiments, In certain embodiments, W ^b is N, W ^c is CR ^h, and W ^a, W ^c, W ^d and W ^e are each CH. In certain embodiments, W ^b and W ^d is N, and W ^a, W ^c, W ^d and W ^e is selected from CH or CR ^h.

ここで、Y^e、Y^f、Y^g、Yⁱ、Y^j、Y^k、Y^m、Yⁿ、L、R^a、R^b、R^c、R¹⁵及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。特定の実施態様において、Lは共有結合である。 In certain embodiments where Z is a phenyl ring, G is a group -OR ^e and R ^e is a 9-membered heteroaryl ring, the present invention provides compounds of formula (II-h), or Provides a pharmaceutically acceptable form of:

Here, Y ^e , Y ^f , Y ^g , Y ⁱ , Y ^j , Y ^k , Y ^m , Y ⁿ , L, R ^a , R ^b , R ^c , R ¹⁵ and z are defined herein. That's right. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In certain embodiments, L is a covalent bond.

ここで、W^f、W^g、W^h、Wⁱ、W^j、W^k、W^m、Wⁿ、L、R^a、R^b、R^c、R¹⁵及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。特定の実施態様において、Lは共有結合である。 Z is a phenyl ring, G is a group -OR ^e, and in certain embodiments R ^e is 10-membered heteroaryl ring, the present invention provides a compound of formula (II-i), or they Provides a pharmaceutically acceptable form of:

Where W ^f , W ^g , W ^h , W ⁱ , W ^j , W ^k , W ^m , W ⁿ , L, R ^a , R ^b , R ^c , R ¹⁵ and z are defined herein. That's right. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In certain embodiments, L is a covalent bond.

ここで、L、R^a、R^b、R^c、R^e、R^f、R¹⁵及びzは、本明細書に定義されている通りである。例えば、特定の実施態様において、zは1であり、かつR¹⁵はオルト位にある。特定の実施態様において、zは1であり、かつR¹⁵はメタ位にある。特定の実施態様において、zは1であり、かつR¹⁵はパラ位にある。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。特定の実施態様において、Lは共有結合である。特定の実施態様において、R^eとR^fは結合し、3-10員のヘテロシクリル環を形成する。特定の実施態様において、R^eとR^fは結合し、5-14員のヘテロアリール環を形成する。 In certain embodiments where Z is a phenyl ring and G is a group —NR ^e R ^f , the present invention provides a compound of formula (II-j), or a pharmaceutically acceptable form thereof:

Here, L, R ^a , R ^b , R ^c , R ^e , R ^f , R ¹⁵ and z are as defined in this specification. For example, in certain embodiments, z is 1 and R ¹⁵ is in the ortho position. In certain embodiments, z is 1 and R ¹⁵ is in the meta position. In certain embodiments, z is 1 and R ¹⁵ is in the para position. In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In certain embodiments, L is a covalent bond. In certain embodiments, R ^e and R ^f are joined to form a 3-10 membered heterocyclyl ring. In certain embodiments, R ^e and R ^f are joined to form a 5-14 membered heteroaryl ring.

ここで、Y¹、Y²、Y³、Y⁴、G、L、R^a、R^b及びR^cは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、Y¹はSであり、Y²はCR¹⁵であり、Y³はNであり、かつY⁴はCH又はCR¹⁵であり、ここでR¹⁵は、下記及び本明細書において定義されている。特定の実施態様において、Y⁴はCHである。特定の実施態様において、Y²上に存在する置換基は、C₆アリール(例えば、フェニル)である。 In certain embodiments of formula (II) wherein Z is a 5-membered heteroaryl ring, the present invention provides compounds of formula (III-a), or pharmaceutically acceptable forms thereof:

Here, Y ¹ , Y ² , Y ³ , Y ⁴ , G, L, R ^a , R ^b and R ^c are as defined in this specification. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, Y ¹ is S, Y ² is CR ¹⁵ , Y ³ is N, and Y ⁴ is CH or CR ¹⁵ , where R ¹⁵ is as described below and herein. Defined in In certain embodiments, Y ⁴ is CH. In certain embodiments, the substituent present on Y ² is C ₆ aryl (eg, phenyl).

ここで、W¹、W²、W³、W⁴、G、L、R^a、R^b及びR^cは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、6-員のヘテロアリール環は、ピリジニル(例えば、2-ピリジニル、3-ピリジニル、4-ピリジニル)又はピリミジニル(例えば、2-ピリミジニル、4-ピリミジニル、5-ピリミジニル)である。 In certain embodiments of formula (II) wherein Z is a 6-membered heteroaryl ring, the invention provides compounds of formula (III-b), or a pharmaceutically acceptable form thereof:

Here, W ¹ , W ² , W ³ , W ⁴ , G, L, R ^a , R ^b and R ^c are as defined in this specification. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -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). .

ここで、Y⁵、Y⁶、Y⁷、Y⁹、Y¹⁰、Y¹¹、Y¹²、Y¹³、G、L、R^a、R^b及びR^cは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments where Z is a 9-membered heteroaryl ring, the invention provides compounds of formula (III-c), or a pharmaceutically acceptable form thereof:

Where Y ⁵ , Y ⁶ , Y ⁷ , Y ⁹ , Y ¹⁰ , Y ¹¹ , Y ¹² , Y ¹³ , G, L, R ^a , R ^b and R ^c are as defined herein. It is. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、W⁶、W⁷、W⁸、W⁹、W¹⁰、W¹¹、W¹²、W¹³、G、L、R^a、R^b及びR^cは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments where Z is a 10-membered heteroaryl ring, the invention provides compounds of formula (III-e), or a pharmaceutically acceptable form thereof:

Where W ⁶ , W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² , W ¹³ , G, L, R ^a , R ^b and R ^c are as defined herein. It is. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、W¹⁴、W¹⁵、W¹⁶、W¹⁷、W¹⁸、W¹⁹、G、L、R^a、R^b及びR^cは、本明細書に定義されている通りである。特定の実施態様において、Lは共有結合である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments where Z is a 6-membered heterocyclyl, the invention provides compounds of formula (III-f), or a pharmaceutically acceptable form thereof:

Here, W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ , W ¹⁸ , W ¹⁹ , G, L, R ^a , R ^b and R ^c are as defined in this specification. In certain embodiments, L is a covalent bond. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、sは0、1、又は2であり、かつW²⁰、W²¹、W²²、W²³、G、R^c、R^d、R¹⁵及びR¹⁸は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In another embodiment where R ^a and R ^d combine to form a C _3-10 carbocyclyl or 3-14 membered heterocyclyl, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable form thereof: Offer to:

Where s is 0, 1, or 2 and W ²⁰ , W ²¹ , W ²² , W ²³ , G, R ^c , R ^d , R ¹⁵ and R ¹⁸ are defined above and herein. That's right. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、W²⁰、W²¹、及びW²²は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments where s is 0, the present invention provides compounds of formula (IV-a), or pharmaceutically acceptable forms thereof:

Here, G, R ^b , R ^c , W ²⁰ , W ²¹ , and W ²² are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、R¹⁸、及びR¹⁵は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments, where s is 0, W ²¹ is NR ¹⁸ and W ²⁰ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ The invention provides compounds of formula (IV-b), or pharmaceutically acceptable forms thereof:

Here, G, R ^b , R ^c , R ¹⁸ , and R ¹⁵ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、W²⁰、W²¹、W²²及びW²³は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments where s is 1, the present invention provides compounds of formula (IV-c), or a pharmaceutically acceptable form thereof:

Here, G, R ^b , R ^c , W ²⁰ , W ²¹ , W ²² and W ²³ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、R¹⁸、及びR¹⁵は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments, where s is 1, W ²¹ is NR ¹⁸ , and W ²⁰ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ The invention provides compounds of formula (IV-d), or pharmaceutically acceptable forms thereof:

Here, G, R ^b , R ^c , R ¹⁸ , and R ¹⁵ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、R¹⁸、及びR¹⁵は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments, where s is 1, W ²² is NR ¹⁸ , and W ²⁰ , W ²¹ , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ The present invention provides compounds of formula (IV-e), or pharmaceutically acceptable forms thereof:

Here, G, R ^b , R ^c , R ¹⁸ , and R ¹⁵ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、W²⁰、W²¹、W²²、及びW²³は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments where s is 2, the present invention provides compounds of formula (IV-f), or a pharmaceutically acceptable form thereof:

Here, G, R ^b , R ^c , W ²⁰ , W ²¹ , W ²² , and W ²³ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^b、R^c、R¹⁸、及びR¹⁵は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 In certain embodiments, where s is 2, W ²² is NR ¹⁸ , and W ²⁰ , W ²¹ , and W ²³ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ The present invention provides compounds of formula (IV-g), or pharmaceutically acceptable forms thereof:

Here, G, R ^b , R ^c , R ¹⁸ , and R ¹⁵ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、W²⁴、W²⁶、W²⁷、W²⁸、及びW³⁰は独立して、CH₂、CHR¹⁵、C(R¹⁵)₂、又はNR¹⁸であり、任意にここでW²⁵及びW²⁶は、縮合C₆アリール環又は縮合6-員のヘテロアリール環により置換され；t及びvは独立して、0又は1であり；ここで、G、R^a、R^b、R¹⁵及びR¹⁸は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、tは0であり、かつvは0である。特定の実施態様において、tは0であり、かつvは1である。特定の実施態様において、tは1であり、かつvは0である。特定の実施態様において、tは1であり、かつvは1である。 In yet another embodiment where R ^c and R ^d are combined to form a C _3-10 carbocyclyl or 3-14 membered heterocyclyl ring, the present invention provides a compound of formula (V), or a pharmaceutically acceptable salt thereof. Provide the form to obtain:

Where W ²⁴ , W ²⁶ , W ²⁷ , W ²⁸ , and W ³⁰ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , optionally where W ²⁵ and W ²⁶ is substituted by a fused C ₆ aryl ring or a fused 6-membered heteroaryl ring; t and v are independently 0 or 1; where G, R ^a , R ^b , R ¹⁵ and R ¹⁸ is as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, t is 0 and v is 0. In certain embodiments, t is 0 and v is 1. In certain embodiments, t is 1 and v is 0. In certain embodiments, t is 1 and v is 1.

ここで、G、R^a、R^b、W²⁵、W²⁶、W²⁷、及びW²⁸は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、W²⁷はNR¹⁸であり、かつW²⁵、W²⁶、及びW²⁸は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。特定の実施態様において、W²⁵、W²⁶、W²⁷、及びW²⁸は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。 In certain embodiments where t is 0 and v is 0, the present invention provides compounds of formula (Va), or a pharmaceutically acceptable form thereof:

Here, G, R ^a , R ^b , W ²⁵ , W ²⁶ , W ²⁷ , and W ²⁸ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, W ²⁷ is NR ¹⁸ and W ²⁵ , W ²⁶ , and W ²⁸ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments, W ²⁵ , W ²⁶ , W ²⁷ , and W ²⁸ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

ここで、G、R^a、R^b、R¹⁵、及びR¹⁸は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 t is 0, v is 0, W ²⁷ is NR ¹⁸ , and W ²⁵ , W ²⁶ , and W ²⁸ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments, the present invention provides compounds of formula (Vb), or pharmaceutically acceptable forms thereof:

Here, G, R ^a , R ^b , R ¹⁵ , and R ¹⁸ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^a、R^b、W²⁵、W²⁶、W²⁷、W²⁸、及びW²⁹は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、W²⁶はNR¹⁸であり、かつW²⁵、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。特定の実施態様において、W²⁷はNR¹⁸であり、かつW²⁵、W²⁶、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。特定の実施態様において、W²⁵、W²⁶、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。 In certain embodiments where t is 0 and v is 1, the present invention provides compounds of formula (Vc), or pharmaceutically acceptable forms thereof:

Here, G, R ^a , R ^b , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, W ²⁶ is NR ¹⁸ and W ²⁵ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments, W ²⁷ is NR ¹⁸ and W ²⁵ , W ²⁶ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . In certain embodiments, W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

ここで、G、R^a、R^b、R¹⁵、及びR¹⁸は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 t is 0, v is 1, W ²⁷ is NR ¹⁸ , and W ²⁵ , W ²⁶ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ). _In certain embodiments being ₂ , the present invention provides compounds of formula (Vd), or pharmaceutically acceptable forms thereof:

Here, G, R ^a , R ^b , R ¹⁵ , and R ¹⁸ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^a、R^b、W²⁴、W²⁵、W²⁶、W²⁷、W²⁸、及びW²⁹は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、W²⁵はNR¹⁸であり、かつW²⁴、W²⁶、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。特定の実施態様において、W²⁶はNR¹⁸であり、かつW²⁴、W²⁵、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。特定の実施態様において、W²⁷はNR¹⁸であり、かつW²⁴、W²⁵、W²⁶、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。特定の実施態様において、W²⁴、W²⁵、W²⁶、W²⁷、W²⁸、及びW²⁹は独立して、CH₂、CHR¹⁵、又はC(R¹⁵)₂である。 In certain embodiments where t is 1 and v is 1, the present invention provides compounds of formula (Ve), or a pharmaceutically acceptable form thereof:

Here, G, R ^a , R ^b , W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, W ²⁵ is NR ¹⁸ and W ²⁴ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . . In certain embodiments, W ²⁶ is NR ¹⁸ and W ²⁴ , W ²⁵ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . . In certain embodiments, W ²⁷ is NR ¹⁸ and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ . . In certain embodiments, W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C (R ¹⁵ ) ₂ .

ここで、G、R^a、R^b、R¹⁵、及びR¹⁸は、上記及び本明細書に定義されている通りである。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。 t is 1, v is 1, W ²⁷ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ , and W ²⁹ are independently CH ₂ , CHR ¹⁵ , or C ( In certain embodiments of R ¹⁵ ) ₂ , the present invention provides compounds of formula (Vf), or a pharmaceutically acceptable form thereof:

Here, G, R ^a , R ^b , R ¹⁵ , and R ¹⁸ are as defined above and herein. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I).

ここで、G、R^a、R^b、及びR¹⁵は、上記及び本明細書に定義されている通りである。特定の実施態様において、R^a及びR^bは-Hである。特定の実施態様において、zは1である。特定の実施態様において、Gは-OR^eである。特定の実施態様において、Gは-Brである。しかし特定の実施態様において、Gはハロゲン(例えば、-Br、-Cl、-I)ではない。特定の実施態様において、R¹⁵は、-OR¹⁶及びC_1-10ペルハロアルキルから選択される。 t is 0, v is 0, W ²⁷ and W ²⁸ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵ ) ₂ , and W ²⁵ and W ²⁶ are fused C ₆ aryl rings In certain embodiments substituted by R ^c and R ^d combine to form a 5,6-bicyclic carbocyclyl spiro-fused ring of formula (Vg):

Here, G, R ^a , R ^b , and R ¹⁵ are as defined above and herein. In certain embodiments, R ^a and R ^b are —H. In certain embodiments, z is 1. In certain embodiments, G is —OR ^e . In certain embodiments, G is —Br. However, in certain embodiments, G is not a halogen (eg, -Br, -Cl, -I). In certain embodiments, R ¹⁵ is selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

(Exemplary compounds of the invention)
Exemplary compounds of formulas (I) and (II), and their subgenera, are shown in Tables 1a-1m below and are described in more detail in Examples 1-253 provided herein. The compound was assayed as an inhibitor of human FAAH using the method detailed in Example 351.

In certain embodiments, the compound is any one of the compounds provided in Table 1a, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1b, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1c, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1d, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1e, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1f, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1g, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1h, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1i, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1j, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1k, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 11 or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 1m, or a pharmaceutically acceptable form thereof:

  Further exemplary compounds of formula (I), (II), (III), and subgenera thereof are shown in Tables 2a to 2e below and also in Examples 254-284 provided herein. This will be described in detail. The compound was assayed as an inhibitor of human FAAH using the method detailed in Example 351.

In certain embodiments, the compound is any one of the compounds provided in Table 2a, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 2b, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 2c, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 2d, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 2e, or a pharmaceutically acceptable form thereof:

  Additional exemplary compounds of formulas (I), (IV) and (V), and their subgenera are shown in Tables 3a to 3d below and also in Examples 285-350 provided herein. This will be described in detail. The compound was assayed as an inhibitor of human FAAH using the method detailed in Example 351.

In certain embodiments, the compound is any one of the compounds provided in Table 3a, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 3b, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 3c, or a pharmaceutically acceptable form thereof:

In certain embodiments, the compound is any one of the compounds provided in Table 3d, or a pharmaceutically acceptable form thereof:

However, in certain embodiments of formulas (I) and (II), or subgroups thereof, any one of the following compounds is specifically excluded:

In certain embodiments of formulas (I), (II), and (III), or a subgenus thereof, any one of the following compounds wherein R ¹⁸ is defined herein is specifically excluded: Has been:

In certain embodiments of formulas (I), (IV) and (V), or subgenera thereof, R ¹⁸ is defined herein and R ¹⁵ is —OCH ₃ , —CN, —CO ₂ Any one of the following compounds that are H, —CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ is specifically excluded:

(II. Pharmaceutical composition)
In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, as well as a pharmaceutically acceptable excipient.

  Pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid media, dispersion or suspending aids, surfactants, isotonic agents, enhancement agents suitable for the particular dosage form desired. Examples include stickers or emulsifiers, preservatives, solid binders, lubricants, and the like. General considerations in the formulation and / or manufacture of pharmaceutical compositions include, for example, Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing, Easton, Pa., 1980) and Remington: It can be found in Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005).

  The pharmaceutical compositions described herein can be manufactured by any method known in the art of pharmacology. In general, the preparative methods include the step of bringing into association the active ingredient with the carrier and / or one or more other accessory ingredients and then, as necessary and / or desirable, the product in the desired single dosage unit or multiple doses. Forming and / or packing into dosage units.

  The pharmaceutical composition can be manufactured, packaged and / or sold in bulk as a single unit dose and / or as multiple single unit doses. As used herein, a “unit dose” is an individual amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient administered to the subject and / or a convenient fraction of the dose, eg, one half or one third of the dose.

  The relative amounts of the active ingredient, pharmaceutically acceptable carrier and / or any additional ingredients in the pharmaceutical composition of the present invention will depend on the individuality, size and / or condition of the subject being treated, and may further vary depending on the composition. Varies depending on the route by which the product is administered. By way of example, the composition can comprise from about 0.1% to about 100% (w / w) active ingredient.

  Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders. , Preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents and perfumes may also be present in the composition.

  Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium lactate phosphate, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol. , Sodium chloride, dry starch, corn starch, powdered sugar, and the like, and combinations thereof.

  Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge bodies, cations Exchange resin, calcium carbonate, silicate, sodium carbonate, crosslinked poly (vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, crosslinked sodium carboxymethylcellulose (croscarmellose), methylcellulose , Pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium magnesium silicate (vee gum), lauryl Sodium acid, such as quaternary ammonium compounds, and combinations thereof.

  Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g. acacia gum, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat , Cholesterol, wax and lecithin), colloidal clay (e.g. bentonite [aluminum silicate] and bee gum [aluminum magnesium silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, Triacetin monostearate, ethylene glycol distearate, glyceryl monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxypolymethylene, (Acrylic acid, acrylic acid polymer and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g. sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan) Monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], tristearic acid Sorbitan [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene ester (for example, polyoxyethylene monostearate [ Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and saltol), sucrose fatty acid ester, polyethylene glycol fatty acid ester (eg Cremophor), polyoxyethylene ether (eg polyoxyethylene lauryl) Ether [Brij 30]), poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68 Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, doxate sodium, and the like, and / or combinations thereof.

  Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugar (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., Acacia gum, sodium alginate, Irish moss extract, panwar gum, gati gum, Isapol husk mucus, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate , Poly (vinyl-pyrrolidone), magnesium magnesium silicate (vee gum) and larch arabogalactan), alginate, polyethylene oxide Polyethylene glycol, inorganic calcium salts, silicate, polymethacrylate, waxes, water, alcohols, and / or combinations thereof.

  Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives and other preservatives.

  Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, ascorbine Examples include sodium acid, sodium bisulfite, sodium metabisulfite and sodium sulfite.

  Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates such as sodium edetate, disodium edetate, trisodium edetate, disodium calcium edetate and dipotassium edetate. Citric acid and its salts and hydrates (e.g. citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, And tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imide Examples include urea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

  Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate and sorbic acid.

  Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, 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), ether sodium lauryl sulfate (SLES) , Sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methyl paraben, Germall 115, Germaben II, Neolone, Kathon and Euxyl It is done. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

  Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium grubionate, calcium glucoceptate, calcium gluconate, D-glucone Acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic Potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, Sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof.

  Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate , Sodium lauryl sulfate, and the like, and combinations thereof.

  Exemplary oils include tonsil oil, apricot oil, avocado oil, babas oil, bergamot oil, blackcurrant seed oil, lurichichi oil, cadet oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil , Cocoa butter oil, palm oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, cucumber oil, grape seed oil, hazelnut oil, hyssop oil, myristic Isopropyl acid, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, lysh akbaba oil, macadamia nut oil, mallow oil, mango seed oil, meadow foam oil, mink oil, nutmeg oil, olive oil, orange oil, orange luffy oil , Palm oil, palm kernel oil, peach kernel oil, pea Oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasanqua oil, saberly oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil , Sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil and malt oil. Exemplary oils include butyl stearate, caprylic acid triglyceride, capric acid triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil and combinations thereof. But not limited to.

  Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, inert diluents widely used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (e.g. cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydroflur Furyl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof can be included. Oral compositions can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents in addition to the inert diluent. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizers such as cremophor, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer and combinations thereof.

  Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, US Pharmacopeia (USP) listing, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the manufacture of injectables.

  Sterile injectable formulations may be sterilized, for example, by filtration through a bacteria capture filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. can do.

  In order to prolong the effect of the drug, it is often desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug is accomplished by dissolving or suspending the drug in an oil vehicle.

  Compositions for rectal or vaginal administration are generally a conjugate of the invention and a cocoa that is solid at ambient temperature but liquid at body temperature, so that it dissolves in the rectum or vaginal cavity and releases the active ingredient. Suppositories that can be manufactured by mixing with a suitable non-irritating excipient or carrier such as butter, polyethylene glycol or suppository wax.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In the solid dosage form, the active ingredient is at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) starch, lactose, sucrose, glucose, Fillers or extenders such as mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia gum, c) humectants such as glycerol, d) agar, calcium carbonate Potato, tapioca starch, alginic acid, certain disintegrants such as silicates and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) e.g. cetyl alcohol and mono Humectants such as glycerol stearate, h) Absorbents such as Olin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lubricants such as sodium lauryl sulfate, as well as mixed with mixtures thereof. In the case of capsules, tablets and pills, the dosage forms can contain buffering agents.

  Similar types of solid compositions can be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They can optionally contain opacifiers and can have a composition that releases only the active ingredient preferentially in a specific part of the intestinal tract, or in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols.

  The active ingredient can be in the form of a microcapsule containing one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent such as sucrose, lactose or starch. The dosage form can typically include additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can contain buffering agents. They can optionally contain opacifiers and can have a composition that releases only the active ingredient preferentially in a specific part of the intestinal tract, or 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 the compounds of the present invention include ointments, plasters, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Can be mentioned. In general, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and / or any needed preservatives and / or buffers as may be required. The present invention also contemplates the use of transdermal patches that often have the added benefit of providing controlled delivery of the active ingredient to the body. Such dosage forms can be made, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by providing a rate controlling membrane and / or by dispersing the active ingredient in the polymer matrix and / or gel.

  Suitable devices for use in delivering the intradermal pharmaceutical compositions described herein include US Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; Short needle devices such as those described in US Pat. Nos. 5,141,496; and 5,417,662. Intradermal compositions can be administered by devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication No. 99/34850, and functional equivalents thereof. Liquid jet injectors and / or jet injection devices that deliver liquid vaccines to the dermis through needles that penetrate the stratum corneum and generate a jet that reaches the dermis are preferred. Jet injection devices include, for example, U.S. Patent 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; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT International Publications 97/37705 and 97 / It is described in 13537. A ballistic powder / particle delivery device that uses compressed gas to accelerate the powdered vaccine from the outer skin layer to the dermis is preferred. Alternatively or additionally, conventional syringes can be used for the classic Manto method of intradermal administration.

  Formulations suitable for topical administration include oil-in-water and / or water-in-oil emulsions such as liniments, lotions, creams, ointments and / or muds, and / or liquids and / or suspensions, etc. Non-liquid and / or semi-liquid preparations. Topically administrable formulations can contain, for example, from about 1% to about 10% (w / w) active ingredient, but the concentration of active ingredient is as high as the solubility limit of the active ingredient in the solvent May be. Formulations for topical administration can further include one or more of the additional ingredients described herein.

  The pharmaceutical composition of the present invention can be produced, packed and / or sold in a formulation suitable for pulmonary administration via the oral cavity. The 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 about 1 to about 6 nanometers. The composition conveniently uses a device with a dry powder reservoir capable of directing a propellant stream to disperse the powder and / or dissolves and / or dissolves in a low boiling propellant in a closed container. In the form of a dry powder for administration using a self-propelled solvent / powder dispensing container such as a device containing the suspended active ingredient. The powder includes particles in which at least 98% by weight of the particles have a diameter greater than 0.5 nanometers and at least 95% by weight of the particles have a diameter of less than 7 nanometers. Alternatively, at least 95% by weight of the particles have a diameter greater than 1 nanometer and at least 90% by volume of the particles have a diameter less than 6 nanometers. Dry powder compositions can include a solid fine powder diluent such as sugar and are conveniently provided in a unit dosage form.

  Low boiling propellants generally include liquid propellants having a boiling point below 65 ° F. (18.3 ° C.) at atmospheric pressure. In general, the propellant can make up 50-99.9% (w / w) of the composition and the active ingredient can make up 0.1-20% (w / w) of the composition. The propellant further comprises another component such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size isotope with the particle containing the active component). be able to.

  A pharmaceutical composition of the present invention formulated for pulmonary delivery can provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be manufactured, packaged and / or sold as sterile aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, conveniently in any spray and / or mist. Can be administered using a crystallization device. The formulation further includes one or more additional ingredients including but not limited to flavoring agents such as sodium saccharin, volatile oils, buffering agents, surfactants, and / or preservatives such as methyl hydroxybenzoate. be able to. The droplets provided by this route of administration can have an average diameter in the range of about 0.1 to about 200 nanometers.

  The formulations described herein that are useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle size of about 0.2 to 500 micrometers. The formulation is administered by rapid inhalation through a nasal passage from a powder container held near the nostril.

  Formulations suitable for nasal administration can contain, for example, from about 0.1% (w / w) to about 100% (w / w) of the active ingredient, including one or more additional ingredients as described herein. Can do. The pharmaceutical composition of the present invention can be produced, packaged and / or sold in a formulation suitable for oral administration. The formulation can take the form of, for example, tablets and / or lozenges manufactured using conventional methods, for example, containing 0.1-20% (w / w) of the active ingredient with the remainder being orally dissolved And / or degradable compositions, and optionally one or more of the additional ingredients described herein. Alternatively, formulations suitable for buccal administration can include powders and / or aerosolized and / or atomized solutions and / or suspensions containing the active ingredients. The powdered, aerosolized, and / or aerosolized formulation, when dispersed, can have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers, as described herein. One or more additional components may further be included.

  The pharmaceutical composition of the present invention can be manufactured, packed and / or sold in a formulation suitable for ocular administration. Such formulations may take the form of, for example, eye drops comprising a 0.1 / 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier. The eye drops may further comprise a buffering agent, salt, and / or one or more additional components described herein. Other ophthalmically administrable formulations that are useful include those that comprise the active ingredient in microcrystalline form and / or in a liposome preparation. Ear drops and / or eye drops are considered to be within the scope of the present invention.

  Although the description of the pharmaceutical composition provided herein is primarily directed to a pharmaceutical composition suitable for administration to humans, the composition is generally suitable for administration to all types of animals. Those skilled in the art will understand that. It is well understood that the pharmaceutical composition suitable for administration to humans is well understood and those skilled in veterinary medicine will make such amendments to make the pharmaceutical composition suitable for administration to various animals. Quality can be designed and / or implemented by routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's “The Science and Practice of Pharmacy”, 21st edition, Lippincott Williams & Wilkins, 2005. .

  Furthermore, pharmaceutical packs and / or kits are also encompassed by the present invention. Provided pharmaceutical packs and / or kits can include provided compositions and containers (eg, vials, ampoules, bottles, syringes, and / or dispenser packaging, or other suitable containers). In some embodiments, the provided kit can optionally further comprise a second container comprising an aqueous carrier suitable for dilution or suspension of the provided composition for preparation for administration 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, provided compositions of the present invention are useful in combination with a patient-controlled analgesic (PCA) device, in which case the patient has, for example, an opioid analgesic required for pain management. Can be administered.

  Optionally, a single container can comprise one or more compartments to contain the provided composition and / or a suitable aqueous carrier for suspension or dilution. In some embodiments, a single container is suitable for modification, so that the container can be physically modified to allow for the combination of compartments and / or components of individual compartments. For example, a foil or plastic bag comprises two or more compartments separated by a perforated seal that can be broken to allow a combination of the contents of two separate compartments once a signal to break the seal has occurred. be able to. Accordingly, a pharmaceutical pack or kit can comprise a container of such multiple compartments comprising the provided composition and a suitable solvent and / or a suitable aqueous carrier for suspension.

  Optionally, instructions for use are additionally provided within the kit of the present invention. Such instructions can generally provide, for example, instructions regarding dosage and administration. In another embodiment, the instructions can further provide additional details regarding the specified instructions for the particular container and / or administration system. Still further, the instructions can provide specific instructions regarding concurrent use and / or combination use with additional therapies. In one non-limiting example, the formulations of the present invention can be used concurrently with opioid analgesic administration, which may optionally include the use of a patient-controlled analgesic (PCA) device. Accordingly, instructions regarding the use of the provided formulation can include instructions regarding simultaneous use with a PCA dosing device.

(III. Methods of use and treatment)
The present invention is directed to treating a FAAH-mediated disorder by administering to a subject in need of treatment of a FAAH-mediated disorder, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof. Provide a way.

  The present invention also provides for inhibiting FAAH in a subject by administering to a subject in need of FAAH inhibition a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof. Provide a way.

  The present invention also provides for inhibiting in vitro or ex vivo activation of the FAAH pathway comprising contacting the FAAH protein with an amount of a compound of formula (I) sufficient to reduce FAAH pathway activation. Provide a method.

  The invention also provides the use of a compound of formula (I) for the treatment of a FAAH-mediated disorder in a subject.

  The present invention also provides the use of a compound of formula (I) in the manufacture of a medicament. In certain embodiments, the medicament is useful for the treatment of FAAH-mediated disorders.

  A `` subject '' intended for administration to it is a human (i.e. male or female of any age group, e.g. a pediatric subject (e.g. infant, child, adolescent) or an adult subject (e.g. young adult, middle-aged) Adults or elderly)), and / or primates (eg, cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs Animals; and / or birds including, but not limited to, commercially relevant birds such as chickens, ducks, geese, and / or turkeys.

  Unless otherwise specified, as used herein, the terms “treat”, “treating” and “treatment” refer to a subject while suffering from a particular disease, disorder or condition. It is intended to act to reduce or reduce the severity of the disease, disorder or condition, or to delay or slow the progression of the disease, disorder or condition.

  Unless otherwise specified, the terms “prevent”, “preventing” and “prevention” as used herein refer to a subject that inhibits or reduces the severity of a disease, disorder, or condition. Is intended to occur before it begins to suffer from a particular disease, disorder or condition.

  Unless otherwise specified, the terms “manage”, “managing” and “management” as used herein refer to a specific disease in a subject already suffering from a disease, disorder or condition. Preventing the recurrence of the disorder or condition, and / or extending the time that a subject suffering from the disease, disorder or condition remains in remission. The term encompasses altering the onset, development and / or duration of a disease, disorder or condition, or altering how a subject responds to a disease, disorder or condition.

  Unless otherwise specified, a “therapeutically effective amount” of a compound as used herein provides a therapeutic benefit in the treatment or management of a disease, disorder or condition, or is a disease, disorder or condition. An amount sufficient to delay or minimize one or more symptoms associated with. A therapeutically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of a disease, disorder, or condition. The term “therapeutically effective amount” can encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

  Unless otherwise specified, a `` prophylactically effective amount '' of a compound as used herein prevents a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, Alternatively, the amount is sufficient to prevent the recurrence. A prophylactically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

  As used herein, “inhibit”, “inhibit”, “inhibit”, “inhibitor”, etc., reduce the activity of certain biological processes in a cell (eg, FAAH activity) against a medium. , Refers to the ability of a compound to delay, stop or prevent.

  As used herein, “FAAH-mediated disorder” refers to a disease, disorder or condition that is treatable by inhibiting FAAH activity. “Disease”, “Disorder” or “Condition” are terms used interchangeably herein. FAAH-mediated disorders include, but are not limited to, painful conditions, inflammatory conditions, immune disorders, central nervous system disorders, metabolic disorders, heart disease and glaucoma.

  In certain embodiments, the FAAH mediated disorder is a painful condition. As used herein, `` painful condition '' refers to neuropathic pain (e.g., peripheral neuropathic pain), central pain, afferent blockage pain, chronic pain (e.g., chronic nociceptive pain). Pain, as well as other forms of chronic pain such as post-operative pain, such as pain after hip, knee and other replacement surgery), pre-operative pain, nociceptor stimulation (nociceptive pain), acute Pain (for example, phantom limb pain and transient acute pain), non-inflammatory pain, inflammatory pain, pain associated with cancer, trauma pain, burn pain, postoperative pain, pain associated with medical procedures, pruritus Pain, bladder pain syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with premature labor, pain associated with withdrawal from drug addiction, arthralgia, arthritic pain (E.g., crystal-induced arthritis, osteoarthritis, psoriatic Arthritis, gouty arthritis, reactive arthritis, pain associated with rheumatoid arthritis or Reiter arthritis), lumbosacral pain, musculoskeletal pain, headache, migraine, myalgia, low back pain, neck pain, toothache, dental / maxillofacial pain, and Including, but not limited to visceral pain.

  One or more painful states contemplated herein are a mixture of the various types of pain described above and herein (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). Can be included. In some embodiments, certain pain may be dominant. In another embodiment, the painful condition includes more than one type of pain, one not dominant. The skilled physician can determine the dose to achieve a therapeutically effective amount for a particular subject based on the painful condition.

  In certain embodiments, the painful condition is neuropathic pain. The term “neuropathic pain” refers to pain resulting from nerve injury. Neuropathic pain is distinguished from nociceptive pain, which is pain caused by acute tissue injury involving the dermal or small nerves in muscle or connective tissue. Neuropathic pain typically lasts for a long time or is chronic and often develops over days or months after the initial acute tissue injury. Neuropathic pain can include persistent spontaneous pain as well as allodynia, which is a painful response to a normally painless stimulus. Neuropathic pain can also be characterized by hyperalgesia with enhanced response to normally minor painful stimuli such as pin sticks. Neuropathic pain conditions occur following nerve injury and the resulting pain can persist for months or years after the initial injury has healed. Nerve injury can occur in specific areas of the peripheral nerve, dorsal root, spinal cord or brain. Neuropathic pain states include diabetic neuropathy (eg, diabetic peripheral neuropathy); sciatica; unspecified low back pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia; HIV-related neuropathy; Eg post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma (eg amputation; surgery, invasive medical procedures, toxins, burns, infections), pain resulting from cancer or chemotherapy (eg chemotherapy— Chemotherapy-induced pain, such as induced peripheral neuropathy), as well as pain due to inflammatory conditions (eg, chronic inflammatory conditions). Neuropathic pain can result from peripheral neuropathy such as neuroma; nerve compression; nerve crush, nerve extension or incomplete nerve amputation; single neuropathy or multiple neuropathy. Neuropathic pain can also result from disorders such as dorsal root ganglion compression; spinal cord inflammation; spinal cord contusion, tumor or hemisection; brainstem, thalamus or cortical tumor; or brainstem, thalamus or cortical trauma .

  Symptoms of neuropathic pain are heterogeneous and are often expressed as spontaneous severe and electric shock or continuous burn pain. In addition, pain associated with normally painless sensations such as `` pins and needles '' (sensory and sensory abnormalities), increased sensitivity to touch (sensory hypersensitivity), painfulness after non-noxious stimulation (dynamic, static Or thermal allodynia), strong sensitivity to nociceptive stimuli (thermal, cold, mechanical hyperalgesia), continuous pain after removal of the stimulus (abnormal hyperalgesia), or absence or defect of a selective sensory pathway (hyperalgesia) ) Exists.

  In certain embodiments, the painful condition is non-inflammatory pain. Non-inflammatory pain types include, but are not limited to, peripheral neuropathic pain (e.g., pain caused by peripheral nervous system lesions or dysfunction), central pain (e.g., central nervous system lesions or dysfunction) Pain caused by loss of sensory input to the central nervous system, chronic nociceptive pain (for example, certain types of cancer pain), nociceptive receptor nociception Sexual stimuli (e.g. pain felt in response to tissue damage or imminent tissue injury), phantom limb pain (e.g. pain felt in parts of the body that no longer exist, such as amputated limbs), felt by psychotic patients Pain (eg, pain for which there can be no physical cause), as well as mobile pain (eg, the location of pain repeatedly changes in the body).

  In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (eg, inflammatory pain) is associated with an inflammatory condition and / or an immune disorder.

  In certain embodiments, the FAAH mediated disorder is an inflammatory condition. The term `` inflammatory condition '' refers to symptoms of pain (pain due to the development of noxious substances and nerve stimulation), heat (heat due to vasodilation), redness (flushing due to vasodilation and increased blood flow), swelling (fluid) Tumors due to excessive influx or restricted outflow of) and / or loss of function (loss of function, which may be partial or full, temporary or permanent) such disease, disorder or condition Say. Inflammation takes many forms and is acute, adhesive, atrophic, catarrhal, chronic, sclerotic, diffusive, diffuse, exudative, fibrinous, fibrotic, focal, granulomatous, hyperplasia Sex, hypertrophic, interstitial, metastatic, necrotic, occlusive, substantial, plastic, proliferative, reproductive, pseudomembranous, purulent, sclerotic, serous plastic, serous, simplicity, specificity, Including but not limited to subacute, purulent, toxic, traumatic and / or ulcerative inflammation.

  Examples of inflammatory conditions are acne, anemia (e.g., aplastic anemia, autoimmune hemolytic anemia), asthma, arteritis (e.g., polyarthritis, temporal arteritis, nodular periarthritis, Takayasu Arteritis), arthritis (e.g., crystal-induced arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and lighter arthritis), ankylosing spondylitis, hay fever, amyotrophic lateral sclerosis Disease, autoimmune disease, allergy or allergic reaction, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (E.g., type I diabetes, type 2 diabetes), skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hyperemia Agility, headache (e.g. migraine, tension headache), ileus (e.g. postoperative ileus and septic ileus), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), Gastrointestinal disorders (e.g. peptic ulcer, localized ileitis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g. eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, Eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonymous GERD), inflammatory bowel disease (IBD) (e.g. Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytes) Olfactory colitis, ischemic colitis, empty colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, localized scleroderma, severe muscle Asthenia, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis, original Biliary cirrhosis, neuroinflammation associated with brain damage (e.g. Parkinson's disease, Huntington's chorea and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation disorders, pelvic inflammatory disease, reperfusion injury, localized ileitis, rheumatism Fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthropathy, Sjogren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritation) Substances, toxins, scarring, burns, physical injury), vasculitis, vitiligo and inflammation associated with Wegener's granulomatosis, but are not limited to these. In certain embodiments, the inflammatory disorder is selected from arthritis (eg, rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (eg, inflammation resulting from an infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (eg, a condition resulting from asthma, arthritis and inflammatory bowel disease). These compounds may also be useful in the treatment of inflammation associated with trauma and non-inflammatory myalgia. These compounds are also useful in the treatment of inflammation associated with cancer.

  In certain embodiments, the FAAH mediated disorder is an immune disorder. Examples of immune disorders such as autoimmune disorders include arthritis (rheumatoid arthritis, spondyloarthropathy, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, anaplastic spondylitis , Behcet's disease, hemolytic autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis, hay fever, acute shoulder pain, psoriatic and juvenile arthritis), asthma, atherosclerosis, osteoporosis, Bronchitis, tendinitis, bursitis, skin condition (e.g. psoriasis, eczema, burns, dermatitis, pruritus (itching)), enuresis, eosinophilic disease, gastrointestinal disorders (e.g. peptic ulcer, localized) Ileitis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, Diarrhea, gastroesophageal reflux disease (selected from GORD or nicknamed GERD), inflammatory bowel disease (IBD) (E.g., Crohn's disease, ulcerative colitis, collagen accumulitis, lymphocytic colitis, ischemic colitis, empty colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS) And disorders ameliorated by gastric motility-promoting drugs (eg, ileus, postoperative ileus and septic ileus; gastroesophageal reflux disease (GORD or nicknamed GERD); eosinophilic esophagitis; diabetic stomach Gastric paresis such as paresis; food intolerance and food allergies, and other functional bowel disorders such as non-ulcer dyspepsia (NUD), and non-cardiac chest pain (NCCP including chondritis)) However, it is not limited to them.

  In certain embodiments, the inflammatory disorder and / or immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is a gastrointestinal disorder (e.g., peptic ulcer, localized ileitis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorder (e.g., eosinophilic esophagitis, eosinophils). Gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or nicknamed GERD), inflammatory bowel disease (IBD) (e.g. Crohn's disease, ulcerative colitis, collagen accumulation colitis, lymphocytic colitis, ischemic colitis, empty colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)). In certain embodiments, the gastrointestinal disorder is inflammatory bowel disease (IBD).

  In certain embodiments, the inflammatory condition and / or immune disorder is a skin condition. In some embodiments, the skin condition is pruritus (itching), psoriasis, eczema, burns or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritus.

  In certain embodiments, the FAAH-mediated disorder is a central nervous system (CNS) disorder (“CNS disorder”). Examples of CNS disorders include neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, mental disorders, sleep disorders, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Examples include, but are not limited to Alzheimer's disease and drug addiction.

  In certain embodiments, the CNS disorder is, for example, acute nerve injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson's disease, Huntington's disease) Neurotoxicity and / or neurotrauma as a result of amyotrophic lateral sclerosis, Alzheimer's disease). In certain embodiments, the compounds of the invention provide a neuroprotective effect against, for example, acute nerve injury or chronic neurodegenerative disorders.

  In certain embodiments, the CNS disorder is a stroke (eg, ischemic stroke).

  In certain embodiments, the CNS disorder is multiple sclerosis.

  In certain embodiments, the CNS disorder is spinal cord injury.

  In certain embodiments, the CNS disorder is epilepsy.

  In certain embodiments, the CNS disorder is a psychiatric disorder, such as depression, anxiety or anxiety-related conditions, learning disorders or schizophrenia.

  In certain embodiments, the CNS disorder is depression. As used herein, `` depression '' refers to, for example, major depressive disorder (e.g., unipolar depression), dysthymic disorder (e.g., chronic mild depression), bipolar disorder (e.g., manic depression), seasonal affect Includes, but is not limited to, depressive disorders or conditions such as depression associated with disorders and / or drug addiction (eg withdrawal). The depression can be clinical depression or subclinical depression. Depression can be associated with premenstrual syndrome and / or premenstrual dysphoric disorder.

  In certain embodiments, the CNS disorder is anxiety. As used herein, “anxiety” refers to, for example, clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder, single fear, social phobia, obsessive compulsive disorder, acute stress disorder and post-traumatic stress Disorders, adaptation disorders with anxiety characteristics, anxiety disorders with depression, anxiety disorders with general medical conditions, and substance-induced anxiety disorders, anxiety related to drug addiction (e.g. withdrawal, dependence, resumption) and nausea And / or anxiety-related conditions such as those associated with vomiting, including but not limited to. This treatment can also induce or promote sleep in a subject (eg, a subject with anxiety).

  In certain embodiments, the CNS disorder is a learning disorder (eg, attention deficit disorder (ADD)).

  In certain embodiments, the CNS disorder is schizophrenia.

  In certain embodiments, the CNS disorder is a sleep disorder. Sleep disorders include insomnia, paroxysmal sleep, sleep apnea, non-rest leg syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eyeball Sleep problems (e.g., abnormal sleep behavior) such as motor behavioral syndrome (RBD), shift work sleep disorder (SWSD), and nightmares, night wonders, sleeping, head swipes, snoring, chewing and / or tooth grinding ), But is not limited thereto.

  In certain embodiments, the CNS disorder is a basal ganglia disorder such as, for example, Parkinson's disease, levodopa-induced dyskinesia, Huntington's chorea, Gilles de la Tourette's syndrome, tardive dysmotility and ataxia It is a movement disorder.

  In certain embodiments, the CNS disorder is Alzheimer's disease.

  In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

  In certain embodiments, the CNS disorder is nausea and / or vomiting.

  In certain embodiments, the CNS disorder is drug addiction (eg, preference for opiates, nicotine, cocaine, psychostimulants or alcohol).

  In yet another embodiment, the FAAH-mediated disorder is a heart disease selected from, for example, hypertension, circulatory shock, myocardial reperfusion injury, and atherosclerosis.

  In certain embodiments, the FAAH-mediated disorder is a metabolic disorder (eg, a wasting condition, an obesity-related condition or a complication thereof).

  In certain embodiments, the metabolic disorder is a debilitating condition. As used herein, “depleting condition” refers to anorexia and various types of cachexia (e.g., weight loss associated with cancer, weight loss associated with other general medical conditions, associated with developmental disorders) Weight loss etc.), but is not limited to these.

  In certain embodiments, the metabolic disorder is an obesity-related condition or a complication thereof. As used herein, `` obesity-related condition '' refers to obesity, unwanted weight gain (e.g., due to medically induced weight gain, due to smoking cessation) and excessive-eating disorders (e.g., bulimia, Including, but not limited to, bulimia, morbid eating, or optionally lack of appetite control that can lead to undesirable weight gain or obesity. As used herein, “obesity” and “obesity” are defined by the World Health Organization (WHO) as obesity class I, obesity class II, obesity class III and pre-obesity (eg, “overweight”). Say.

  Accumulated fat loss is expected to provide various primary and / or secondary benefits in subjects (e.g., subjects diagnosed with complications associated with obesity), e.g., increased insulin response (e.g., type II Reduced blood pressure; increased cholesterol levels; and / or ischemic heart disease, arteriovascular disease, angina, myocardial infarction, stroke, migraine, congestive heart failure , Deep vein thrombosis, pulmonary embolism, gallstones, gastroesophageal reflux disease, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, gout, decreased mobility, back pain, erectile dysfunction, urinary incontinence, liver disorders (e.g. , Fatty liver disease, cirrhosis, alcoholic cirrhosis, endotoxin-mediated liver injury) or reduced and / or reduced (or reduced risk or progression) of chronic renal failure. Therefore, the method of the present invention is applicable to obese subjects, diabetic subjects, and alcoholic subjects.

  In some embodiments, the treatment of obesity-related conditions or their complications is associated with weight loss of the subject. In some embodiments, the treatment of obesity-related conditions or their complications involves the management of the subject's appetite.

  In another embodiment, the FAAH mediated disorder is glaucoma.

(IV. Administration)
Any therapeutically effective dose and any route of administration can be used to administer the provided compound. The exact amount required will vary from subject to subject, depending on the type, age and general condition of the subject, the severity of the infection, the particular composition, its method of administration, the effect of its activity, and the like.

  The compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. However, it will be understood that the total daily dose of the composition of the invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject or organism is 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. Subject; age, weight, general health, sex and diet; time of administration, route of administration, and excretion rate of specific active ingredient employed; duration of treatment; specific active ingredient employed Drugs that are used in combination with or at the same time; as well as a variety of similar factors well known in the medical arts.

  The compounds and compositions provided herein can be administered orally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intraventricularly, transdermally, intradermally, rectal, intravaginally, intraperitoneally, By any route including topical (by powder, ointment, cream and / or drop), mucosa, nose, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation and / or inhalation; and Or, it can be administered as an oral spray, a nasal spray and / or an aerosol. Specifically contemplated routes are systemic intravenous injection, local administration via blood and / or lymph supply, and / or direct administration to the affected area. In general, the most appropriate route of administration is a wide variety of factors, including the nature of the drug (e.g. its stability within the gastrointestinal tract environment), the condition of the subject (e.g. whether the subject can tolerate oral administration), etc. Will depend on.

  The exact amount of compound required to achieve a therapeutically effective amount will depend, for example, on the type of subject, age and general condition, severity of the side effect or disorder, the identity of the particular compound and the method of administration, etc. Will be different for each subject. The desired dose 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 dose can be administered multiple times (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 times). , 13, 14 or 15 or more administrations).

  In certain embodiments, a therapeutically effective amount of a compound for administration once or more daily to a 70 kg adult is about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg of the compound of the invention per unit dosage form. About 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg Can contain up to about 1000 mg. It will be appreciated that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent is determined by a medical practitioner or a person skilled in the art and may be less than or the same as the amount administered to an adult.

  It will also be appreciated that the compounds or compositions described herein can be administered in combination with one or more additional therapeutically active agents. The compound or composition can be administered simultaneously with, before, or after one or more additional therapeutically active agents. In general, each drug will be administered at a dosage and / or time schedule determined for that drug. It will be further understood that the additional therapeutically active agents utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination employed for dosing will consider the compatibility of the compounds of the invention with the additional therapeutically active agent and / or the desired therapeutic effect to be achieved. In general, it is envisioned that additional therapeutically active agents utilized in combination will be utilized at a level that does not exceed the level at which they are utilized individually. In some embodiments, the levels utilized in combination are less than the levels utilized individually.

  Combining the compounds or compositions with agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution in the body Can be administered. The therapy employed can achieve the desired effect on the same disorder (e.g., the compound can be administered in combination with anti-inflammatory, anti-anxiety and / or antidepressant), and It will also be appreciated that different effects (eg, suppression of adverse side effects) can be achieved.

  Exemplary active agents include anticancer drugs, antibiotics, antiviral drugs, anesthetics, anticoagulants, enzyme inhibitors, steroid drugs, steroidal or nonsteroidal anti-inflammatory drugs, antihistamines, immunosuppression Drugs, antineoplastic drugs, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain relieving drugs, analgesics, antipyretics, hormones, prostaglandins, luteinizing hormone drugs, antiglaucoma drugs, ophthalmic drugs, anti Cholinergic agents, antidepressants, antipsychotics, hypnotics, tranquilizers, anticonvulsants / antiepileptics (e.g., neurotin, Lyrica, Valoproic acid (e.g. Depacon), and other nerve stabilizers), muscle relaxation Drugs, antispasmodic drugs, muscle contractors, channel blockers, miotic drugs, antisecretory drugs, antithrombotic drugs, anticoagulants, anticholinergics, beta-adrenergic blockers, diuretics, cardiovascular active drugs, Vasoactive drugs, vasodilators, antihypertensive drugs, Tube-forming agents, modulators of cell-extracellular matrix interactions (eg cell growth inhibitors and anti-adhesion molecules), or inhibitors / intercalators such as DNA, RNA, protein-protein interactions, protein-receptor interactions Include, but are not limited to: Active agents include small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drug Administration (FDA) as presented in the Federal Regulation Code (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligos Sugar, polysaccharide, nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, small molecule bound to protein, glycoprotein, steroid, nucleic acid, DNA, RNA, nucleotide, nucleoside, oligonucleotide, antisense oligonucleotide, lipid , Hormones, vitamins and cells.

In certain embodiments, the additional therapeutically active agent is a pain relieving drug. Exemplary pain relieving drugs include non-narcotic analgesics (e.g., aspirin, ibuprofen (MOTRIN®, ADVIL®), ketoprofen (ORUDIS®), naproxen (NAPROSYN®), Analgesics such as acetaminophen, salicylates such as indomethacin] or narcotic analgesics [eg opioid analgesics such as tramadol, fentanyl, sufentanil, morphine, hydromorphone, codeine, oxycodone, and buprenorphine]; Anti-inflammatory drugs (NSAIDs) [for example, aspirin, acetaminophen, COX-2 inhibitors]; steroid drugs or anti-rheumatic drugs; Ring antidepressants (eg amitriptyline, desipramine, imipramine); antiepileptic drugs (eg clonazepam (c lonaxepam), valproic acid, phenobarbital, phenytoin, tiagaine, gabapentin, carbamazepine, topiramate, sodium valproate); α ₂ agonist; selective serotonin reuptake inhibitor (SSRI), selective norepinephrine reuptake inhibitor; Benzodiazepines; mexiletine (MEXITIL); flecainides (TAMBOCOR); NMDA receptor antagonists [eg ketamine, detromethorphan, methadone]; and topical drugs [eg capsaicin (Zostrix), EMLA cream, lidocaine, prilocaine] It is not limited to these.

  In another embodiment, the additional therapeutically active agent is an anti-inflammatory agent. Exemplary anti-inflammatory drugs include: aspirin; ibuprofen; ketoprofen; naproxen; etodolac (LODINE®); celecoxib (CELEBREX®), rofecoxib (VIOXX®), valdecoxib (BEXTRA®) ), Parecoxib, etlicoxib (MK663), delacoxib, 2- (4-ethoxy-phenyl) -3- (4-methanesulfonyl-phenyl) -pyrazolo [1,5-b] pyridazine, 4- (2-oxo-3 -Phenyl-2,3-dihydrooxazol-4-yl) benzenesulfonamide, dulbferon, furolide, 4- (4-cyclohexyl-2-methyl-5-oxazolyl) -2-fluorobenzenesulfonamide), meloxicam, nimesulide, 1-methylsulfonyl-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) -benzothiopyrano (4,3-c) pyrazol-1-yl) benzenesulfonamide, 4,4-dimethyl-2-phenyl-3- (4-methylsulfonyl) phenyl) cyclo-butenone, 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-cyclopropylbutan-1-one or physiologically acceptable salts, esters or solvates thereof, such as COX-2 inhibitors; Sulindac (CLINORIL®) Diclofenac (VOLTAREN®); piroxicam (FELDENE®); diflunisal (DOLOBID®), nabumetone (RELAFEN®), oxaprozin (DAYPRO®), indomethacin (INDOCIN ( (Registered trademark)); or PEDIAPED (registered trademark) prednisolone sodium phosphate oral solution, SOLU-MEDROL (registered trademark) for injection Examples include, but are not limited to, steroids such as luprednisolone sodium succinate and PRELONE® brand prednisolone syrup.

  Further examples of anti-inflammatory drugs include EC-NAPROSYN® delayed release tablets, NAPROSYN®, ANAPROX® and ANAPROX® DS tablets and NAPROSYN® from Roche. Naproxen commercially available in the form of a suspension, celecoxib tablets under the commercial name CELEBREX®, rofecoxib under the commercial name VIOXX®, betamethasone under the commercial name CELESTONE®, commercial name CUPRAMINE® Penicillamine capsules, commercially available DEPEN (R) titratable penicillamine tablets, commercially available DEPO-MEDROL methylprednisolone acetate injectable suspension, ARAVA (R) leflunomide tablets, AZULFIDIINE EN-tabs (R) brand sulfasalazine Delayed release tablets, FELDENE® brand piroxicam capsules, CATAFLAM® diclofenac potassium tablets, VOLTAREN® diclofenac sodium delayed release tablets, VOLTAREN®-X R diclofenac sodium sustained release tablets, or ENBREL® etanercept products.

(V. Method of measuring biological activity)
Methods for measuring the activity of the compounds provided herein for various therapeutic uses are known in the art. These methods include, but are not limited to, high throughput screening to identify compounds that bind to and / or alter the activity of isolated FAAH, and in vitro and in vivo therapeutic models.

  Assays useful for screening the compounds provided herein include reaction products (e.g., fatty acids) produced by binding of an inhibitor to FAAH or hydrolysis of a substrate such as oleoylethanolamide or ananadamide. Amide or ethanolamine) release can be detected. The substrate can be labeled to facilitate detection of the released reaction product. US Pat. No. 5,559,410 discloses a high-throughput screening method for proteins, and US Pat. Nos. 5,576,220 and 5,541,061 disclose high-throughput methods for screening for ligand / antibody binding.

  Methods for screening FAAH inhibitors for anti-nociceptive effects are known in the art. For example, compounds can be tested in the mouse hot plate test and mouse formalin test to determine nociceptive responses to thermal or chemical tissue damage (e.g., U.S. Pat. See also Cravatt et al., Proc. Natl. Acad. Sci. USA (2001), 98: 9371-9376).

  Two pharmacologically validated animal models of anxiety are the height zero maze test and the isolation-induced ultrasound radiation test. The zero maze consists of an aerial platform with two open and two closed quadrants and is based on a contradiction between the instinct of the animal exploring its environment and fear of open space (e.g. Bickerdike, MJ et al. Eur. J. Pharmacol, (994) 271, 403-411; Shepherd, JK et al., Psychopharmacology, (1994) 116, 56-64). Clinically used anxiolytics such as benzodiazepines increase the percentage of time spent in the open section and the number of times that section is entered.

  A second test for anxiolytic compounds is an ultrasonic vocalization model that measures the number of stress-induced vocalizations produced by pups removed from their nests (see, for example, Insel, TR et al., Pharmacol. Biochem. Behav., 24, 1263-1267 (1986); see Miczek, KA et al., Psychopharmacology, 121, 38-56 (1995); Winslow, JT et al., Biol. Psychiatry, 15, 745-757 (1991). ).

  The efficacy of the compounds provided herein in treating depression can be tested in a model of chronic mild stress-induced loss of pleasure in rats. This model is based on the observation that chronic mild stress gradually reduces sensitivity to rewards, such as sucrose consumption, and this decrease is reversed in a dose-dependent manner by chronic treatment with antidepressants (e.g. Willner , Paul, Psychopharmacology, 1997, 134, 319-329).

  Another test for antidepressant activity is the forced swimming test (Nature 266, 730-732, 1977). In this test, drugs are administered to animals 30 or 60 minutes prior to placement in a water container and the time that the animals remain stationary is recorded. A decrease in mouse rest time indicates antidepressant activity.

  A similar test for antidepressant activity is the mouse tail suspension test (Psychopharmacology, 85, 367-370, 1985). In this study, drugs are administered to animals 30 or 60 minutes before hanging from the tail and the animal's rest time is recorded. A decrease in mouse rest time indicates antidepressant activity.

  Animal models are available to assess the anticonvulsant activity of test compounds (see, eg, US Pat. Nos. 6,309,406 and 6,326,156).

  Inhibition of FAAH has been reported to induce sleep in test animals (see, eg, US Pat. No. 6,096,784). Methods for testing sleep inducing compounds are known in the art (see, eg, US Pat. Nos. 6,096,784 and 6,271,015). Administering the compound to a test animal (e.g. rat or mouse) or human and monitoring the subsequent time spent on sleep (e.g. closed eyes, exercise pause) (e.g. start time, duration) Can do. See also WO 98/24396.

  Methods for screening for FAAH inhibitors that induce catalepsy are also well known in the art (e.g., Quistand et al., "Toxicology and Applied Pharmacology", 173: 48-55 (2001). Cracrat et al., Proc. Natl. Acad. Sci. USA 98: 9371-9376 (2001)).

  Methods for assessing appetite behavior are known in the art (see, eg, US Pat. No. 6,344,474). One way to evaluate the effects on appetite behavior is to administer FAAH inhibitors to rats and evaluate their effects on sucrose solution ingestion (e.g., WC Lynch et al., Physiol. Behav., 1993, 54 877-880).

  Two pharmacologically validated animal models of neuropathic pain are the rat spinal nerve ligation model (Chung model) and the rat model of chemotherapy-induced neuropathic pain. After establishing neuropathy in these models, paw withdrawal thresholds were measured by stimulation using von Frey filaments as a measure of mechanical allodynia (eg, Kim SH and Chung JM, Pain (1992) 50 , 355-63; Nozaki-Taguchi N et al., Pain (2001) 93, 69-76). Clinically used neuropathic pain medications such as gabapentin (neurontin) increase the paw withdrawal threshold from stimulation with von Frey filaments.

  Two pharmacologically validated animal models of inflammation and mechanical pain are joint compression models in rats treated with adjuvants or substances that produce joint degeneration. Treatment with clinically used anti-inflammatory drugs such as naproxen increases the threshold of behavioral responses to joint compression (eg Wilson AW et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius SA Et al., Pain (2007) 128, 272-282).

  A pharmacologically validated animal model of cancer pain is a mouse model in which fibrosarcoma cell rib transplantation results in hyperalgesia of the foot. Treatment with clinically used analgesics such as morphine increases the threshold of behavioral responses to mechanical nociception (see, eg, Khasabova et al., J. Neurscience (2008) 28, 11141-52).

(Example)
The present invention will now be described generally. The present invention will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

3-ブロモ-イソオキサゾリン調製の一般的条件：アルケン(1.2当量)及び炭酸水素カリウム(2.5当量)を、酢酸エチル(アルケンに対して0.40M)中に懸濁した。N,N-ジブロモホルムアルドキシム(1.0当量)を添加し、この反応物を、23℃で14〜28時間攪拌させた。薄層クロマトグラフィー分析により完了と判断された時点で、この反応物を、水とtert-ブチルメチルエーテルの間で分配し、かつ有機層を水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望の3-ブロモ-イソオキサゾリンを生じた。 (General synthesis method)
(Method 1)

General conditions for the preparation of 3-bromo-isoxazoline: Alkenes (1.2 eq) and potassium bicarbonate (2.5 eq) were suspended in ethyl acetate (0.40 M with respect to alkene). N, N-dibromoformaldoxime (1.0 eq) was added and the reaction was allowed to stir at 23 ° C. for 14-28 hours. When judged complete by thin layer chromatographic analysis, the reaction is partitioned between water and tert-butyl methyl ether and the organic layer is 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 / hexane) to yield the desired 3-bromo-isoxazoline.

3-ブロモ-イソオキサゾリン調製の一般的条件：フラスコに、グリオキシル酸一水和物(1.0当量)及び塩酸ヒドロキシルアミン(1.1当量)を充填した。この混合物を、水(グリオキシル酸一水和物に対して2.0M)中に溶解し、23℃で24時間攪拌した。この混合物を、水で希釈し、酢酸エチルにより抽出した。有機層を硫酸ナトリウム上で乾燥し、かつ濃縮し、所望の粗オキシムを生じ、これを直接次の付加環化において使用した。第一工程から得られたオキシム(1.1当量)を、ジメトキシエタン：水の3：1(v/v)混合液(オキシムに対して0.15M)中に懸濁し、かつ0℃に冷却した。N-ブロモスクシンイミド(NBS)(2.0当量)を添加し、この反応物を、23℃で20分間攪拌した。次に得られた混合物を、ジメトキシエタン(アルケンに対して1.50M)中のアルケン(1.0当量)及び炭酸水素カリウム(2.5当量)の溶液に添加し、この反応物を、23℃で20時間攪拌させた。薄層クロマトグラフィー分析により完了と判断された時点で、この反応物を、水とtert-ブチルメチルエーテルの間で分配し、かつ有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望の3-ブロモ-イソオキサゾリンを生じた。 (Method 2)

General conditions for the preparation of 3-bromo-isoxazoline: A flask was charged with glyoxylic acid monohydrate (1.0 eq) and hydroxylamine hydrochloride (1.1 eq). This mixture was dissolved in water (2.0 M for glyoxylic acid monohydrate) and stirred at 23 ° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to yield the desired crude oxime, which was used directly in the next cycloaddition. The oxime obtained from the first step (1.1 eq) was suspended in a 3: 1 (v / v) mixture of dimethoxyethane: water (0.15M relative to oxime) and cooled to 0 ° C. N-bromosuccinimide (NBS) (2.0 eq) was added and the reaction was stirred at 23 ° C. for 20 minutes. The resulting mixture was then added to a solution of alkene (1.0 eq) and potassium bicarbonate (2.5 eq) in dimethoxyethane (1.50 M relative to alkene) and the reaction was stirred at 23 ° C. for 20 h. I let you. When judged complete by thin layer chromatography analysis, the reaction is partitioned between water and tert-butyl methyl ether, and the organic layer is washed with brine, dried over sodium sulfate and in vacuo. Concentrated with. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired 3-bromo-isoxazoline.

3-アリールオキシ-イソオキサゾリン又は3-ヘテロアリールオキシ-イソオキサゾリン調製の一般的条件：マイクロ波用反応バイアルに、所与の3-ブロモ-イソオキサゾリン(1.0当量)及びアルコール(例えばフェノール又はヒドロキシピリジン)(3.0当量)を充填し、N-メチルピロリジン(イソオキサゾリンに対して0.50M)中に溶解した。粉砕した水酸化ナトリウム(2.0当量)を添加し、この混合物をマイクロ波用反応器中で密封し、かつ150℃で30分間加熱した。次にこの反応物を、水とtert-ブチルメチルエーテルの間で分配し、かつ有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のイソオキサゾリンを生じた。 (Method 3)

General conditions for the preparation of 3-aryloxy-isoxazoline or 3-heteroaryloxy-isoxazoline: In a microwave reaction vial, place a given 3-bromo-isoxazoline (1.0 eq) and alcohol (eg phenol or hydroxypyridine) ) (3.0 equivalents) and dissolved in N-methylpyrrolidine (0.50M relative to isoxazoline). Triturated sodium hydroxide (2.0 eq) was added and the mixture was sealed in a microwave reactor and heated at 150 ° C. for 30 minutes. 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 silica gel chromatography (ethyl acetate / hexane) to yield the desired isoxazoline.

3-アリールオキシ-イソオキサゾリン又は3-ヘテロアリールオキシ-イソオキサゾリン調製の一般的条件：フラスコに、所与の3-ブロモ-イソオキサゾリン(1.0当量)及びアルコール(例えばフェノール又はヒドロキシピリジン)(2.0当量)を充填し、かつN,N-ジメチルホルムアミド(N,N-dimethylforamide)(イソオキサゾリンに対して0.4M)中に溶解した。水素化ナトリウム(2.0当量)を添加し、この反応物を、全ての気体の発生が静まるまで、10分間攪拌した。次に反応物を、150℃で1〜5時間加熱した。この反応が薄層クロマトグラフィー分析により完了と決定された後、反応物を、水と酢酸エチルの間で分配し、有機層を1N NaOH及びブラインで洗浄し、次に硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のイソオキサゾリンを生じた。 (Method 4)

General conditions for the preparation of 3-aryloxy-isoxazoline or 3-heteroaryloxy-isoxazoline: In a flask, place the given 3-bromo-isoxazoline (1.0 eq) and alcohol (eg phenol or hydroxypyridine) (2.0 eq) ) And was dissolved in N, N-dimethylforamide (0.4M for isoxazoline). Sodium hydride (2.0 eq) was added and the reaction was stirred for 10 minutes until all gas evolution subsided. The reaction was then heated at 150 ° C. for 1-5 hours. After the reaction was determined to be complete by thin layer chromatography analysis, the reaction was partitioned between water and ethyl acetate, the organic layer was washed with 1N NaOH and brine, then dried over sodium sulfate, Concentrated in vacuo. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired isoxazoline.

3-アリールオキシ-イソオキサゾリン調製の一般的条件：フラスコに、所与の3-ブロモ-イソオキサゾリン(1.0当量)及びアルコール(例えばフェノール又はヒドロキシピリジン)(2.0当量)を充填し、N,N-ジメチルホルムアミド又はN-メチルピロリジノン(イソオキサゾールに対して0.15M)中に溶解した。炭酸セシウム(1.2〜3当量)を添加し、この反応物を油浴中で120℃で1時間加熱した。次にこの反応物を、水とtert-ブチルメチルエーテルの間で分配し、有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(メタノール/塩化メチレン)により精製し、所望のイソオキサゾリンを生じた。 (Method 5)

General conditions for the preparation of 3-aryloxy-isoxazolines: A flask is charged with a given 3-bromo-isoxazoline (1.0 eq) and an alcohol (eg phenol or hydroxypyridine) (2.0 eq) and N, N- Dissolved in dimethylformamide or N-methylpyrrolidinone (0.15M relative to isoxazole). Cesium carbonate (1.2-3 equivalents) was added and the reaction was heated in an oil bath at 120 ° C. for 1 hour. 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 silica gel chromatography (methanol / methylene chloride) to yield the desired isoxazoline.

アルケン調製の一般的条件：窒素大気下で、テトラヒドロフラン中に溶解した0.25Mメチルトリフェニルホスホニウムブロミド(1.1当量)を、0℃に冷却し、その後この混合物を、テトラヒドロフラン中のヘキサメチルジシラザンナトリウム(NaHMDS)(1.0M, 1.2当量)を滴加し処理した。更に30分間0℃で攪拌した後、所与のアルデヒド又はケトンを添加し、この反応物を、23℃で一晩穏やかに温めた。この混合物を、飽和塩化アンモニウムによりクエンチし、かつ濃縮し、テトラヒドロフランを除去した。この混合物を次に、水で希釈し、酢酸エチルで抽出した。有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のアルケンを生じた。 (Method 6)

General conditions for alkene preparation: 0.25 M methyltriphenylphosphonium bromide (1.1 eq) dissolved in tetrahydrofuran under nitrogen atmosphere was cooled to 0 ° C., after which the mixture was dissolved in sodium hexamethyldisilazane ( NaHMDS) (1.0 M, 1.2 eq) was added dropwise. After stirring for an additional 30 minutes at 0 ° C., the given aldehyde or ketone was added and the reaction was warmed gently at 23 ° C. overnight. The mixture was quenched with saturated ammonium chloride and concentrated to remove tetrahydrofuran. This 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 silica gel chromatography (ethyl acetate / hexane) to yield the desired alkene.

アルケン調製の一般的条件：窒素大気下で、テトラヒドロフラン中に溶解した0.15Mメチルトリフェニルホスホニウムブロミド(1.5当量)を、-78℃に冷却し、その後この混合物を、ヘキサン中のn-ブチルリチウム(2.5M, 1.5当量)を滴加し処理した。更に1時間-78℃で攪拌した後、所与のアルデヒド又はケトンを添加し、この反応物を、23℃で一晩穏やかに温めた。この混合物を、飽和塩化アンモニウムによりクエンチし、かつ濃縮し、テトラヒドロフランを除去した。この混合物を次に、水で希釈し、酢酸エチルで抽出した。有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のアルケンを生じた。 (Method 7)

General conditions for alkene preparation: 0.15 M methyltriphenylphosphonium bromide (1.5 eq) dissolved in tetrahydrofuran under nitrogen atmosphere was cooled to −78 ° C., after which the mixture was diluted with n-butyllithium in hexane ( 2.5M, 1.5 eq) was added dropwise. After stirring for an additional hour at −78 ° C., the given aldehyde or ketone was added and the reaction was warmed gently at 23 ° C. overnight. The mixture was quenched with saturated ammonium chloride and concentrated to remove tetrahydrofuran. This 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 silica gel chromatography (ethyl acetate / hexane) to yield the desired alkene.

アルケン調製の一般的条件：窒素大気下で、0.12Mメチルトリフェニルホスホニウムブロミド(2.5当量)を、テトラヒドロフラン中に溶解し、その後カリウムtert-ブトキシド(4.0当量)を6部分で添加した。更に1時間23℃で攪拌した後、所与のアルデヒド又はケトンを添加し、この反応物を、55℃で2時間加熱した。この混合物を、飽和塩化アンモニウムによりクエンチし、かつ濃縮し、テトラヒドロフランを除去した。この混合物を次に、1N HClでpH5〜6まで酸性とし、塩化メチレンで抽出した。有機層をブラインで洗浄し、次に硫酸ナトリウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のアルケンを生じた。 (Method 8)

General conditions for alkene preparation: Under nitrogen atmosphere, 0.12M methyltriphenylphosphonium bromide (2.5 eq) was dissolved in tetrahydrofuran, followed by addition of potassium tert-butoxide (4.0 eq) in 6 portions. After stirring for an additional hour at 23 ° C., the given aldehyde or ketone was added and the reaction was heated at 55 ° C. for 2 hours. The mixture was quenched with saturated ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then acidified with 1N HCl to pH 5-6 and extracted with methylene chloride. The organic layer was washed with brine, then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired alkene.

スチレン調製の一般的条件：アルゴン大気下で乾燥フラスコに、臭化アリール(1.0当量)、ビニルトリフルオロホウ酸カリウム(1.2当量)、1,1"-ビス(ジフェニルホスフィノ)-フェロセンジクロロパラジウム(II)塩化メチレン付加物(0.02当量)及びトリエチルアミン(1.0当量)を充填し、かつこの混合物を、イソプロパノール(臭化アリールに対して0.25M)中で懸濁し、80℃で2〜24時間加熱した。次にこの混合物を水で希釈し、ジエチルエーテルで抽出した。有機層をブラインで洗浄し、次に硫酸マグネシウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のスチレンを生じた。 (Method 9)

General conditions for the preparation of styrene: In a dry flask under argon atmosphere, aryl bromide (1.0 eq), potassium vinyltrifluoroborate (1.2 eq), 1,1 "-bis (diphenylphosphino) -ferrocenedichloropalladium ( II) Methylene chloride adduct (0.02 eq) and triethylamine (1.0 eq) were charged and the mixture was suspended in isopropanol (0.25 M for aryl bromide) and heated at 80 ° C. for 2-24 h. The mixture was then diluted with water and extracted with diethyl ether.The organic layer was washed with brine, then dried over magnesium sulfate and concentrated in vacuo.The concentrated reaction mixture was subjected to flash silica gel chromatography. Purification by chromatography (ethyl acetate / hexane) yielded the desired styrene.

スチレン調製の一般的条件：窒素大気下で乾燥フラスコに、臭化アリール(1.0当量)、トリブチルビニルスズ(1.1当量)を充填し、かつトルエン(臭化物に対して0.3M)中に溶解した。得られた混合物を、窒素で10分間更に掃流し、その後テトラキス(トリフェニルホスフィン)パラジウム(0.1当量)を添加し、この反応物を1.5時間還流した。TLC分析により反応が完了と決定された後、これを冷却し、シリカゲルカラム上に直接装加し、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のスチレンを生じた。 (Method 10)

General conditions for styrene preparation: A dry flask under nitrogen atmosphere was charged with aryl bromide (1.0 eq), tributylvinyltin (1.1 eq) and dissolved in toluene (0.3 M with respect to bromide). The resulting mixture was further purged with nitrogen for 10 minutes, after which tetrakis (triphenylphosphine) palladium (0.1 eq) was added and the reaction was refluxed for 1.5 hours. After the reaction was determined to be complete by TLC analysis, it was cooled, loaded directly onto a silica gel column and purified by flash silica gel chromatography (ethyl acetate / hexanes) to yield the desired styrene.

ピリジル及びピリミジニルボロン酸のそれらの対応するフェノールへの加水分解の一般的条件：フラスコに、所与のボロン酸又はそれらのエステル(1.0当量)を充填し、かつテトラヒドロフラン(1.1M、10容量)中に溶解した。過ホウ酸ナトリウム(1.0当量)を、水(ボロン酸に対して1.1M、10容量)中に溶解し、10分間音波処理した。次にこの過ホウ酸塩懸濁液を、テトラヒドロフラン(1.6容量)を用いたTHF溶液に添加し、残存する固形の過ホウ酸塩をこの反応混合物にすすぎ入れた。この反応物を、室温で攪拌させ(反応は少し発熱する)、その後塩化アンモニウムを3部分で添加し(10当量)、この反応物を冷却し室温に戻した。40分後、反応物を、全てのテトラヒドロフランが除去されるまで、真空下で濃縮した。得られた固形物を、真空濾過により収集し、過剰な水で洗浄し、かつ真空炉において40℃で3日間乾燥し、所望のフェノールを収率80％で生じた。 (Method 11)

General conditions for hydrolysis of pyridyl and pyrimidinylboronic acids to their corresponding phenols: Flasks are charged with the given boronic acids or their esters (1.0 eq) and in tetrahydrofuran (1.1M, 10 vol) Dissolved in. Sodium perborate (1.0 eq) was dissolved in water (1.1M relative to boronic acid, 10 vol) and sonicated for 10 minutes. The perborate suspension was then added to the THF solution using tetrahydrofuran (1.6 vol) and the remaining solid perborate was rinsed into the reaction mixture. The reaction was allowed to stir at room temperature (the reaction was slightly exothermic), after which ammonium chloride was added in 3 portions (10 eq) and the reaction was 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 3 days to yield the desired phenol in 80% yield.

(Chiral HPLC method)
Enantiomeric or diastereomeric mixtures of compounds can be separated using known methods, including chiral high pressure liquid chromatography (HPLC) and chiral supercritical liquid chromatography (SFC). Examples of chiral columns useful for the separation of such mixtures of compounds of the invention include ChiralPak® AD-H, ChiralPak® OD-H, ChiralPak® AY, RegisPack®, And S, S WhelkO®-1 and LUX® cellulose 2 columns, but are not limited to these. To obtain a substantially enantiomerically pure compound, one or more of these columns were used to separate enantiomeric mixtures of the compounds of the invention.

Synthesis of exemplary compounds of formula I
The synthesis of exemplary compounds is described below. The compounds were assayed as inhibitors of human FAAH using the method detailed in Example 351. Activity indicated as "A" refers to a compound having the following K _i 100 nM, "B" refers to compounds having a K _i of 100NM～1myuM, and "C", a K _i of greater than 1μM The compound which has.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-1a及びI-1bを、スチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝225.0m/z。活性：B。 (Example 1)

3-Bromo-4,5-dihydroisoxazole I-1a and I-1b were prepared from styrene in one step using Method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 225.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-2a及びI-2bを、4-フルオロスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。活性：B。 (Example 2)

3-Bromo-4,5-dihydroisoxazole I-2a and I-2b were prepared from 4-fluorostyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-3a及びI-3bを、4-クロロスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝259.0m/z。活性：A。 (Example 3)

3-Bromo-4,5-dihydroisoxazole I-3a and I-3b were prepared from 4-chlorostyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 259.0m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-4a及びI-4bを、3-クロロスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝258.9m/z。活性：B。 (Example 4)

3-Bromo-4,5-dihydroisoxazole I-4a and I-4b were prepared from 3-chlorostyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 258.9m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-5a及びI-5bを、2-クロロスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝258.9m/z。活性：B。 (Example 5)

3-Bromo-4,5-dihydroisoxazole I-5a and I-5b were prepared from 2-chlorostyrene using method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 258.9m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-6a及びI-6bを、4-メトキシスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝255.0m/z。活性：A。 (Example 6)

3-Bromo-4,5-dihydroisoxazole I-6a and I-6b were prepared from 4-methoxystyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 255.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-7a及びI-7bを、3-メトキシスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝255.0m/z。活性：B。 (Example 7)

3-Bromo-4,5-dihydroisoxazoles I-7a and I-7b were prepared from 3-methoxystyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 255.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-8a及びI-8bを、2-メトキシスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝255.0m/z。活性：C。 (Example 8)

3-Bromo-4,5-dihydroisoxazole I-8a and I-8b were prepared from 2-methoxystyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 255.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-9a及びI-9bを、4-ビニルビフェニルから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝301.6m/z。活性：A。 (Example 9)

3-Bromo-4,5-dihydroisoxazole I-9a and I-9b were prepared from 4-vinylbiphenyl using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 301.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-10a及びI-10bを、4-フェノキシスチレンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝317.0m/z。活性：A。 (Example 10)

3-Bromo-4,5-dihydroisoxazole I-10a and I-10b were prepared from 4-phenoxystyrene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 317.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-11a及びI-11bを、3-フェノキシベンズアルデヒドから、方法8を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝317.0m/z。活性：A。 (Example 11)

3-Bromo-4,5-dihydroisoxazole I-11a and I-11b starting from 3-phenoxybenzaldehyde in alkene formation using Method 8, followed by two steps of cycloaddition using Method 2 It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 317.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-12a及びI-12bを、4-(ピリジン-3-イルオキシ)ベンズアルデヒドから、方法8を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝318.0m/z。活性：A。 (Example 12)

3-Bromo-4,5-dihydroisoxazole I-12a and I-12b are started from 4- (pyridin-3-yloxy) benzaldehyde in alkene formation using Method 8, followed by Method 2. Prepared in 2 steps of cycloaddition. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 318.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-13a及びI-13bを、4-(ピリミジン-2-イルオキシ)-ベンズアルデヒドから、方法8を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝319.0m/z。活性：A。 (Example 13)

3-Bromo-4,5-dihydroisoxazole I-13a and I-13b were started from 4- (pyrimidin-2-yloxy) -benzaldehyde in alkene formation using Method 8, followed by Method 2. Prepared in 2 steps of cycloaddition. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 319.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-14a及びI-14bを、4-トリフルオロメトキシベンズアルデヒドから、方法8を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝309.6m/z。活性：A。 (Example 14)

3-Bromo-4,5-dihydroisoxazole I-14a and I-14b were started from 4-trifluoromethoxybenzaldehyde in alkene formation using Method 8, followed by cycloaddition using Method 1. Prepared in 2 steps. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 309.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-15a及びI-15bを、4-イソプロポキシベンズアルデヒドから、方法8を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝238.0m/z。活性：A。 (Example 15)

3-Bromo-4,5-dihydroisoxazole I-15a and I-15b were started from 4-isopropoxybenzaldehyde in alkene formation using Method 8, followed by cycloaddition 2 using Method 2. Prepared in process. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 238.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-16a及びI-16bを、ピペロナールから、方法7を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝269.0m/z。活性：A。 (Example 16)

3-Bromo-4,5-dihydroisoxazoles I-16a and I-16b were prepared from piperonal in two steps, starting with alkene formation using Method 7, followed by cycloaddition using Method 2. . These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 269.0 m / z. Activity: A.

3-クロロ-4,5-ジヒドロイソオキサゾールI-17a及びI-17bを、N-クロロスクシンアミドを、N-ブロモスクシンアミドの代わりに使用する以外は、実施例10と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝273.1m/z。活性：A。 (Example 17)

The same procedure as in Example 10 was used, except that 3-chloro-4,5-dihydroisoxazole I-17a and I-17b were used instead of N-chlorosuccinamide instead of N-bromosuccinamide. Used and prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 273.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-18a及びI-18bを、3-(4-ボロモフェノキシ)-6-メチルピリダジンから、方法9を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝333.0m/z。活性：B。 (Example 18)

3-Bromo-4,5-dihydroisoxazole I-18a and I-18b were started from 3- (4-boromophenoxy) -6-methylpyridazine in alkene formation using Method 9, followed by Prepared in 2 steps of cycloaddition using 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 333.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-19a及びI-19bを、2-(4-ブロモフェニル)-5-フェニル-1,3,4-オキサジアゾールから、方法9を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝369.0m/z。活性：A。 (Example 19)

3-Bromo-4,5-dihydroisoxazole I-19a and I-19b are converted from 2- (4-bromophenyl) -5-phenyl-1,3,4-oxadiazole to an alkene using method 9. Prepared in two steps starting from formation followed by cycloaddition using method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 369.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-20a及びI-20bを、4-ブトキシベンズアルデヒドから、方法8を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝297.0m/z。活性：A。 (Example 20)

2-Bromo-4,5-dihydroisoxazole I-20a and I-20b starting from 4-butoxybenzaldehyde in alkene formation using Method 8, followed by two steps of cycloaddition using Method 1 It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 297.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-21a及びI-21bは、下記のような、4-ビニル安息香酸とベンジルアルコールの間のカップリングで始まる2工程で調製した：4-ビニル安息香酸(1.0当量)を、N,N-ジメチルホルムアミド(酸に対して0.20M)中に溶解した。ベンジルアルコールを添加し(2.0当量)、引き続きEDC(1.05当量)及び触媒量のDMAP(0.05当量)を添加した。この反応物を、23℃で14時間攪拌させ、その時点の後この反応物を、水とtert-ブチルメチルエーテルの間で分配し、かつ有機層を、0.5Mクエン酸溶液(2×)及び飽和炭酸水素ナトリウム溶液(1×)で洗浄し、硫酸マグネシウム上で乾燥し、真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のエステルを生じた。この化合物を次に、方法1を用い、所望の3-ブロモ-4,5-ジヒドロイソオキサゾールに変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝359.8m/z。活性：A。 (Example 21)

3-Bromo-4,5-dihydroisoxazole I-21a and I-21b were prepared in two steps starting with coupling between 4-vinylbenzoic acid and benzyl alcohol as follows: 4-vinylbenzoic The acid (1.0 eq) was dissolved in N, N-dimethylformamide (0.20M with respect to the acid). Benzyl alcohol was added (2.0 eq) followed by EDC (1.05 eq) and a catalytic amount of DMAP (0.05 eq). The reaction was allowed to stir at 23 ° C. for 14 hours after which time the reaction was partitioned between water and tert-butyl methyl ether and the organic layer was washed with 0.5 M citric acid solution (2 ×) and Washed with saturated sodium bicarbonate solution (1 ×), dried over magnesium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 359.8 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-22a及びI-22bを、ベンジルアミンを、ベンジルアルコールの代わりに使用する以外は、実施例21と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝358.9m/z。活性：B。 (Example 22)

3-Bromo-4,5-dihydroisoxazoles I-22a and I-22b were prepared using a procedure similar to 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. See, for example, the chiral HPLC method disclosed herein. [MH]-= 358.9m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-23a及びI-23bを、化合物I-10及びフェノールから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝331.1m/z。活性：C。 (Example 23)

3-phenoxy-4,5-dihydroisoxazole I-23a and I-23b were prepared from compound I-10 and phenol in one step using Method 3. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 331.1m / z. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-24a及びI-24bを、化合物I-10及び4-フルオロフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝350.3m/z。活性：C。 (Example 24)

3-phenoxy-4,5-dihydroisoxazole I-24a and I-24b were prepared from compound I-10 and 4-fluorophenol in one step using method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 350.3 m / z. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-25a及びI-25bを、化合物I-10及び3-フルオロフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝349.3m/z。活性：B。 (Example 25)

3-phenoxy-4,5-dihydroisoxazole I-25a and I-25b were prepared from compound I-10 and 3-fluorophenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 349.3 m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-26a及びI-26bを、化合物I-10及び3-トリフルオロメチルフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝400.3m/z。活性：C。 (Example 26)

3-phenoxy-4,5-dihydroisoxazole I-26a and I-26b were prepared from compound I-10 and 3-trifluoromethylphenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 400.3 m / z. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-27a及びI-27bを、化合物I-10及び4-シアノフェノールから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝356.1m/z。活性：A。 (Example 27)

3-phenoxy-4,5-dihydroisoxazole I-27a and I-27b were prepared from compound I-10 and 4-cyanophenol in one step using method 3. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 356.1m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-28a及びI-28bを、化合物I-10及び2-シアノフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝357.3m/z。活性：C。 (Example 28)

3-phenoxy-4,5-dihydroisoxazole I-28a and I-28b were prepared from compound I-10 and 2-cyanophenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 357.3 m / z. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-29a及びI-29bを、化合物I-10及び4-ニトロフェノール(nitrolphenol)から、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝376.8m/z。活性：B。 (Example 29)

3-phenoxy-4,5-dihydroisoxazole I-29a and I-29b were prepared from compound I-10 and 4-nitrophenol using Method 4 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 376.8 m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-30a及びI-30bを、化合物I-10及び4-メチルスルホニルフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝409.0m/z。活性：A。 (Example 30)

3-phenoxy-4,5-dihydroisoxazole I-30a and I-30b were prepared from compound I-10 and 4-methylsulfonylphenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 409.0 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-31a及びI-31bを、化合物I-10及び4-メチル-3-フルオロフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝364.4m/z。活性：C。 (Example 31)

3-phenoxy-4,5-dihydroisoxazole I-31a and I-31b were prepared from compound I-10 and 4-methyl-3-fluorophenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 364.4 m / z. Activity: C.

マイクロ波用反応バイアルに、ラセミ化合物I-10(1.0当量)及びアニリン(4.0当量)を充填した。この混合物を、マイクロ波用反応器内で密封し、かつ150℃で2時間加熱した。次にこの反応物を、水とtert-ブチルメチルエーテルの間で分配し、この有機層を、ブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望の3-アミノ-4,5-ジヒドロイソオキサゾールI-32a及びI-32bを生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝330.1m/z。活性：C。 (Example 32)

A microwave reaction vial was charged with racemic compound I-10 (1.0 eq) and aniline (4.0 eq). The mixture was sealed in a microwave reactor and heated at 150 ° C. for 2 hours. 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 silica gel chromatography (ethyl acetate / hexane) to yield the desired 3-amino-4,5-dihydroisoxazoles I-32a and I-32b. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 330.1 m / z. Activity: C.

1-(4,5-ジヒドロイソオキサゾール-3-イル)ピリジン-2(1H)-オンI-33a及びI-33bを、ラセミ化合物I-10及び2-ヒドロキシピリジンから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝332.1m/z。活性：C。 (Example 33)

1- (4,5-dihydroisoxazol-3-yl) pyridin-2 (1H) -one I-33a and I-33b were obtained from racemic I-10 and 2-hydroxypyridine using Method 3. Prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 332.1 m / z. Activity: C.

マイクロ波用反応バイアルに、ラセミ化合物I-10(1.0当量)及び1,2,4-トリアゾールのナトリウム塩(2.0当量)を充填した。これらの試薬は、N-メチルピロリジン(化合物I-10に対して0.18M)中に溶解した。この混合物を、マイクロ波用反応器内で密封し、かつ100℃で30分間加熱した。過剰な水を添加し、茶色固形物を粉砕し、これを真空濾過を用いて分離し、かつ乾燥し、所望の3-(1H-1,2,4-トリアゾール-1-イル)-4,5-ジヒドロイソオキサゾールI-34a及びI-34bを生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝306.1m/z。活性：C。 Example 34

A microwave reaction vial was charged with racemic compound I-10 (1.0 eq) and 1,2,4-triazole sodium salt (2.0 eq). These reagents were dissolved in N-methylpyrrolidine (0.18M for compound I-10). The mixture was sealed in a microwave reactor and heated at 100 ° C. for 30 minutes. Excess water is added to break up the brown solid, which is separated using vacuum filtration and dried to give the desired 3- (1H-1,2,4-triazol-1-yl) -4, This gave 5-dihydroisoxazoles I-34a and I-34b. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 306.1m / z. Activity: C.

ピラゾール(3.0当量)を、N,N-ジメチルホルムアミド(ピラゾール(pyraole)に対して0.60M)中に溶解し、かつNaH(鉱油中60％分散液、3.0当量)を添加し、この反応物を、窒素下で5分間攪拌させた。この時点の後、ラセミ化合物I-10を添加した。次にこの反応物を、90℃で14時間加熱し、その後冷却し、メタノール(ピラゾールに対し0.30M)によりクエンチした。この粗混合物を、綿を通して濾過し、半-分取逆相クロマトグラフィーにより直接精製し、所望の3-(1H-ピラゾール-1-イル)-4,5-ジヒドロイソオキサゾールI-35a及びI-35bを生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝306.4m/z。活性：C。 (Example 35)

Pyrazole (3.0 eq) is dissolved in N, N-dimethylformamide (0.60 M relative to pyraole) and NaH (60% dispersion in mineral oil, 3.0 eq) is added and the reaction is added. And allowed to stir under nitrogen for 5 minutes. After this point, racemic compound I-10 was added. The reaction was then heated at 90 ° C. for 14 hours, then cooled and quenched with methanol (0.30M for pyrazole). The crude mixture was filtered through cotton and purified directly by semi-preparative reverse phase chromatography to give the desired 3- (1H-pyrazol-1-yl) -4,5-dihydroisoxazole I-35a and I- 35b was produced. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 306.4 m / z. Activity: C.

3-(ピリジン-4-イルオキシ)-4,5-ジヒドロイソオキサゾールI-36a及びI-36bを、化合物I-10及び4-ヒドロキシピリジンから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝332.1m/z。活性：C。 Example 36

3- (Pyridin-4-yloxy) -4,5-dihydroisoxazole I-36a and I-36b were prepared from compound I-10 and 4-hydroxypyridine using Method 3 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 332.1 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-37a及びI-37bを、ラセミ化合物I-10及び3-ヒドロキシピリジンから、方法3又は方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝332.1m/z。活性：A。 (Example 37)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-37a and I-37b were obtained from racemic compounds I-10 and 3-hydroxypyridine using Method 3 or Method 5 in one step. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 332.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-38a及びI-38bを、ラセミ化合物I-6及び3-ヒドロキシピリジンから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝270.1m/z。活性：B。 (Example 38)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-38a and I-38b were prepared from racemic compound I-6 and 3-hydroxypyridine using Method 3 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 270.1 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-39a及びI-39bを、ラセミ化合物I-10及び5-ヒドロキシニコチン酸メチルから、方法3又は方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.2m/z。活性：A。 (Example 39)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-39a and I-39b were obtained from racemic compound I-10 and methyl 5-hydroxynicotinate using Method 3 or Method 5; Prepared in process. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-40a及びI-40bを、ラセミ化合物I-10及び5-ヒドロキシ-2-メチルピリジンから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝346.1m/z。活性：A。 (Example 40)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-40a and I-40b from racemic compound I-10 and 5-hydroxy-2-methylpyridine using method 4, one step It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 346.1 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-41a及びI-41bを、ラセミ化合物I-10及び5-ヒドロキシピリミジンから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝333.1m/z。活性：A。 (Example 41)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-41a and I-41b were prepared from racemic compound I-10 and 5-hydroxypyrimidine in one step using Method 3. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 333.1 m / z. Activity: A.

3-(キノリン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-42a及びI-42bを、ラセミ化合物I-10及び3-ヒドロキシキノリンから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝382.1m/z。活性：A。 (Example 42)

3- (Quinolin-3-yloxy) -4,5-dihydroisoxazole I-42a and I-42b were prepared from racemic compound I-10 and 3-hydroxyquinoline in one step using Method 3. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 382.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-43a及びI-43bを、ラセミ化合物I-10及び5-フルオロ-3-ヒドロキシピリジンから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝350.1m/z。活性：A。 (Example 43)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-43a and I-43b from racemic compound I-10 and 5-fluoro-3-hydroxypyridine using method 3, one step It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 350.1 m / z. Activity: A.

3-(1-メチル-1H-ピロロ[2,3-b]ピリジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-44a及びI-44bを、ラセミ化合物I-10及び1メチル-1H-ピロロ[2,3-b]ピリジン-5-オールから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝385.1m/z。活性：B。 (Example 44)

3- (1-Methyl-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4,5-dihydroisoxazole I-44a and I-44b were converted to racemic compounds I-10 and 1methyl-1H. Prepared in 1 step from Method 3 using pyrrolo [2,3-b] pyridin-5-ol. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 385.1 m / z. Activity: B.

バイアルに、ラセミ化合物I-10(1.0当量)を充填し、かつメタノール(イソオキサゾール(isoxazaole)に対して0.05M)中に溶解した。炭酸カリウム(5.0当量)を添加し、この反応物を密封し、50℃で24時間加熱した。次にこの反応物を、水と酢酸エチルの間で分配し、かつ有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望の3-メトキシ-4,5-ジヒドロイソオキサゾールI-45a及びI-45bを生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝269.1m/z。活性：C。 (Example 45)

A vial was charged with racemic compound I-10 (1.0 eq) and dissolved in methanol (0.05M relative to isoxazaole). Potassium carbonate (5.0 eq) was added and the reaction was sealed and heated at 50 ° C. for 24 hours. 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 silica gel chromatography (ethyl acetate / hexane) to yield the desired 3-methoxy-4,5-dihydroisoxazoles I-45a and I-45b. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 269.1 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-46a及びI-46bを、ラセミ化合物I-14及び5-ヒドロキシニコチン酸メチルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝384.0m/z。活性：B。 Example 46

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-46a and I-46b were prepared from racemic compound I-14 and methyl 5-hydroxynicotinate in one step using method 5. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 384.0 m / z. Activity: B.

ラセミ化合物I-39を、メタノール中のアンモニア(メタノール中7.0M、イソオキサゾールに対して0.02M)中に溶解した。この反応物を、密封し、23℃で24時間攪拌させ、この時点の後、溶媒及び過剰なアンモニアを、窒素流れ下で除去し、明茶色固形物を生じ、これをヘキサンでトリチュレートし、所望のアミドI-47a及びI-47bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝374.0m/z。活性：B。 (Example 47)

Racemic compound I-39 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M for isoxazole). The reaction is sealed and allowed to stir at 23 ° C. for 24 hours, after which time the solvent and excess ammonia are removed under a stream of nitrogen to yield a light brown solid, which is triturated with hexanes, desired Of amides I-47a and I-47b as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 374.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-48a及びI-48bを、3-フェニル-1-プロペンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝239.0m/z。活性：C。 Example 48

3-Bromo-4,5-dihydroisoxazole I-48a and I-48b were prepared from 3-phenyl-1-propene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 239.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-49a及びI-49bを、4-フェニル-1-ブテンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝253.0m/z。活性：B。 (Example 49)

3-Bromo-4,5-dihydroisoxazole I-49a and I-49b were prepared from 4-phenyl-1-butene using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 253.0 m / z. Activity: B.

フェノール(1.0当量)を、エタノール(フェノールに対して0.5M)中に溶解し、水酸化ナトリウム (1.0当量)を添加し、引き続き4-ブロモ-1-ブテンを添加した。この混合物を、1時間還流加熱し、その後溶媒の大部分を真空下で除去した。その後この反応物を、水とtert-ブチルメチルエーテルの間で分配し、かつ有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、真空中で濃縮し、粗アルケンを生じ、これは所望の3-ブロモ-4,5-ジヒドロイソオキサゾールI-50a及びI-50bに、方法2を使用する1工程で直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝269.0m/z。活性：B。 (Example 50)

Phenol (1.0 eq) was dissolved in ethanol (0.5 M relative to phenol) and sodium hydroxide (1.0 eq) was added followed by 4-bromo-1-butene. The mixture was heated at reflux for 1 hour, after which most of the solvent was removed under vacuum. The reaction is then partitioned between water and tert-butyl methyl ether and the organic layer is washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude alkene, which is the desired Direct conversion to 3-bromo-4,5-dihydroisoxazole I-50a and I-50b in one step using Method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 269.0 m / z. Activity: B.

フェノール(1.2当量)を、N,N-ジメチルホルムアミド(フェノールに対して0.4M)中に溶解し、炭酸セシウム(1.3当量)を添加し、引き続き5-ブロモ-1-ペンテン(1.0当量)及びヨウ化テトラブチルアンモニウム (0.10当量)を添加した。この混合物を、50℃で16時間加熱した。次にこの反応物を、水とtert-ブチルメチルエーテルの間で分配し、有機層を、希水酸化ナトリウム溶液、水、ブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮した。この粗アルケンを、所望の3-ブロモ-4,5-ジヒドロイソオキサゾールI-51a及びI-51bに、方法2を使用する1工程で直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝283.0m/z。活性：A。 (Example 51)

Phenol (1.2 eq) is dissolved in N, N-dimethylformamide (0.4 M relative to phenol), cesium carbonate (1.3 eq) is added, followed by 5-bromo-1-pentene (1.0 eq) and iodine. Tetrabutylammonium bromide (0.10 equivalent) was added. The mixture was heated at 50 ° C. for 16 hours. The reaction was then partitioned between water and tert-butyl methyl ether and the organic layer was washed with dilute sodium hydroxide solution, water, brine, dried over sodium sulfate and concentrated in vacuo. . This crude alkene was converted directly to the desired 3-bromo-4,5-dihydroisoxazole I-51a and I-51b in one step using Method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 283.0 m / z. Activity: A.

2-フェニルエタノール(1.0当量)を、N,N-ジメチルホルムアミド(アルコールに対して0.8M)中に溶解し、かつ粉砕した水酸化ナトリウム(2.0当量)を添加し、引き続き臭化アリル(1.0当量)及びヨウ化テトラブチルアンモニウム (0.10当量)を添加した。この混合物を、室温で48時間攪拌した。次にこの反応物を、水とtert-ブチルメチルエーテルの間で分配し、かつ有機層を、希Na₂S₂O₃溶液及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のアルケンを生じ、これを所望の3-ブロモ-4,5-ジヒドロイソオキサゾールI-52a及びI-52bに、方法1を使用する1工程で直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝285.6m/z。活性：B。 (Example 52)

2-Phenylethanol (1.0 eq) is dissolved in N, N-dimethylformamide (0.8 M relative to alcohol) and crushed sodium hydroxide (2.0 eq) is added followed by allyl bromide (1.0 eq). ) And tetrabutylammonium iodide (0.10 equivalent). The mixture was stirred at room temperature for 48 hours. The reaction is then partitioned between water and tert-butyl methyl ether, and the organic layer is washed with dilute Na ₂ S ₂ O ₃ solution and brine, dried over sodium sulfate, and in vacuo. Concentrated. The concentrated reaction mixture is purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired alkene, which is converted to the desired 3-bromo-4,5-dihydroisoxazoles I-52a and I-52b. Direct conversion in one step using Method 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 285.6 m / z. Activity: B.

ラセミ化合物I-46を、メタノール中のアンモニア(メタノール中7.0M、イソオキサゾールに対して0.02M)中に溶解した。この反応物を密封し、23℃で72時間攪拌させ、この時点の後、溶媒及び過剰なアンモニアを窒素流れ下で除去し、明茶色固形物を生じ、これをヘキサンでトリチュレートし、所望のアミドI-53a及びI-53bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝366.0m/z。活性：B。 (Example 53)

Racemic compound I-46 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M for isoxazole). The reaction was sealed and allowed to stir at 23 ° C. for 72 hours, after which time the solvent and excess ammonia were removed under a stream of nitrogen to yield a light brown solid that was triturated with hexane to give the desired amide. I-53a and I-53b were produced as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 366.0 m / z. Activity: B.

ラセミ化合物I-46を、メチルアミン中のアンモニア(テトラヒドロフラン中2.0M、イソオキサゾールに対して0.02M)中に溶解した。この反応物を密封し、23℃で72時間攪拌させ、この時点の後、溶媒及び過剰なアンモニアを窒素流れ下で除去し、明茶色固形物を生じ、これをヘキサンでトリチュレートし、所望のアミドI-54a及びI-54bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝380.0m/z。活性：A。 Example 54

Racemic compound I-46 was dissolved in ammonia in methylamine (2.0 M in tetrahydrofuran, 0.02 M for isoxazole). The reaction was sealed and allowed to stir at 23 ° C. for 72 hours, after which time the solvent and excess ammonia were removed under a stream of nitrogen to yield a light brown solid that was triturated with hexane to give the desired amide. I-54a and I-54b were produced as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 380.0 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-55a及びI-55bを、ラセミ化合物I-46及び5-ヒドロキシニコチン酸メチルから、方法5を使用し、1工程で調製し、かつフラッシュシリカゲルクロマトグラフィーの間にこの反応物から副産物として単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝367.0m/z。活性：C。 Example 55

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-55a and I-55b prepared from racemic compound I-46 and methyl 5-hydroxynicotinate in one step using method 5 And isolated as a by-product from this reaction during flash silica gel chromatography. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 367.0 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-56a及びI-56bを、ラセミ化合物I-10及び5-ヒドロキシ-2-トリフルオロメチルピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝401.5m/z。活性：A。 Example 56

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-56a and I-56b were prepared from racemic compound I-10 and 5-hydroxy-2-trifluoromethylpyridine using Method 5. Prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 401.5 m / z. Activity: A.

3-(1H-ピロロ[3,2-b]ピリジン-6-イルオキシ)-4,5-ジヒドロイソオキサゾールI-57a及びI-57bを、ラセミ化合物I-10及び1H-ピロロ[3,2-b]ピリジン-6-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝370.0m/z。活性：A。 (Example 57)

3- (1H-Pyrrolo [3,2-b] pyridin-6-yloxy) -4,5-dihydroisoxazole I-57a and I-57b are converted to racemic compounds I-10 and 1H-Pyrrolo [3,2- b] Prepared in 1 step from pyridin-6-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 370.0 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-58a及びI-58bを、ラセミ化合物I-10及び3-シアノフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝356.8m/z。活性：B。 (Example 58)

3-phenoxy-4,5-dihydroisoxazole I-58a and I-58b were prepared from racemic compound I-10 and 3-cyanophenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 356.8 m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-59a及びI-59bを、ラセミ化合物I-10及び2-フルオロフェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝350.3m/z。活性：B。 (Example 59)

3-phenoxy-4,5-dihydroisoxazole I-59a and I-59b were prepared from racemic compound I-10 and 2-fluorophenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 350.3 m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-60a及びI-60bを、ラセミ化合物I-10及び4-フルオロ-3-(トリフルオロメチル)フェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。活性：C。 (Example 60)

3-Phenoxy-4,5-dihydroisoxazole I-60a and I-60b prepared from racemic compound I-10 and 4-fluoro-3- (trifluoromethyl) phenol in one step using Method 4 did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-61a及びI-61bを、ラセミ化合物I-10及び3-ヒドロキシ安息香酸メチルから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝390.5m/z。活性：A。 (Example 61)

3-phenoxy-4,5-dihydroisoxazole I-61a and I-61b were prepared from racemic compound I-10 and methyl 3-hydroxybenzoate in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 390.5 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-62a及びI-62bを、ラセミ化合物I-10及び4-ヒドロキシ安息香酸メチルから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝389.7m/z。活性：A。 (Example 62)

3-phenoxy-4,5-dihydroisoxazole I-62a and I-62b were prepared from racemic compound I-10 and methyl 4-hydroxybenzoate in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 389.7 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-63a及びI-63bを、ラセミ化合物I-10及び3-(メチルスルホニル)フェノールから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝409.0m/z。活性：C。 (Example 63)

3-phenoxy-4,5-dihydroisoxazole I-63a and I-63b were prepared from racemic I-10 and 3- (methylsulfonyl) phenol in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 409.0 m / z. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-64a及びI-64bを、ラセミ化合物I-10及び3-ヒドロキシベンゼンスルホンアミドから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝409.0m/z。活性：C。 (Example 64)

3-phenoxy-4,5-dihydroisoxazole I-64a and I-64b were prepared from racemic compound I-10 and 3-hydroxybenzenesulfonamide in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 409.0 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-65a及びI-65bを、ラセミ化合物I-10及び5-メトキシピリジン-3-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝363.2m/z。活性：A。 Example 65

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-65a and I-65b from racemic compound I-10 and 5-methoxypyridin-3-ol using method 5 in one step It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 363.2 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-66a及びI-66bを、ラセミ化合物I-10及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝364.6m/z。活性：A。 Example 66

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-66a and I-66b were prepared from racemic compound I-10 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 364.6 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-67a及びI-67bを、ラセミ化合物I-10及び5-ヒドロキシピコリン酸メチルから、方法3を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.1m/z。活性：A。 Example 67

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-67a and I-67b prepared from racemic compound I-10 and methyl 5-hydroxypicolinate in one step using Method 3 did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.1 m / z. Activity: A.

3-(1H-ピロロ[2,3-6]ピリジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-68a及びI-68bを、ラセミ化合物I-10及び1H-ピロロ[2,3-b]ピリジン-5-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝370.0m/z。活性：A。 Example 68

3- (1H-pyrrolo [2,3-6] pyridin-5-yloxy) -4,5-dihydroisoxazole I-68a and I-68b are converted to racemic compounds I-10 and 1H-pyrrolo [2,3- b] Prepared in 1 step from pyridin-5-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 370.0 m / z. Activity: A.

6-(4,5-ジヒドロイソオキサゾール-3-イルオキシ)フロ[3,2-b]ピリジンI-69a及びI-69bを、フロ[3,2-b]ピリジン-6-オールを、方法11を使用し、6-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フロ[3,2-b]ピリジンから調製した後、ラセミ化合物I-10及びフロ[3,2-b]ピリジン-6-オールから、方法5を使用する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝374.2m/z。活性：A。 (Example 69)

6- (4,5-dihydroisoxazol-3-yloxy) furo [3,2-b] pyridine I-69a and I-69b, furo [3,2-b] pyridin-6-ol, method 11 Prepared from 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo [3,2-b] pyridine and then racemic compound I-10 and Prepared from furo [3,2-b] pyridin-6-ol in 2 steps using method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 374.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-70a及びI-70bを、ラセミ化合物I-14及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝324.1m/z。活性：A。 Example 70

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-70a and I-70b were prepared from racemic compound I-14 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 324.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-71a及びI-71bを、ラセミ化合物I-14及び5-ブロモ-3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝402.5m/z。活性：A。 Example 71

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-71a and I-71b from racemic compound I-14 and 5-bromo-3-hydroxypyridine using method 5, one step It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 402.5 m / z. Activity: A.

ラセミ化合物I-71(1.0当量)、フェニルボロン酸(1.1当量)、酢酸カリウム(1.0当量)、炭酸セシウム(3.0当量)、及びジクロロ[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロロメタン付加物(14mol％)を、DMSO 1mL中に懸濁し、かつArでパージした。得られた混合物を密封し、80℃で1時間加熱した。この粗混合物を、過剰な水と共に分液漏斗に移し、tert-ブチルメチルエーテル(2×)で抽出した。これらの有機層を一緒にし、Na₂SO₄上で乾燥し、フラッシュシリカゲルクロマトグラフィー(2〜10％MeOHの勾配)を使用し精製し、所望の3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-72a及びI-72bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝402.3m/z。活性：B。 (Example 72)

Racemic compound I-71 (1.0 eq), phenylboronic acid (1.1 eq), potassium acetate (1.0 eq), cesium carbonate (3.0 eq), and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium ( II) Dichloromethane adduct (14 mol%) was suspended in 1 mL DMSO and purged with Ar. The resulting mixture was sealed and heated at 80 ° C. for 1 hour. The crude mixture was transferred to a separatory funnel with excess water and extracted with tert-butyl methyl ether (2 ×). The organic layers are combined, dried over Na ₂ SO _{4 and} purified using flash silica gel chromatography (gradient 2-10% MeOH) to give the desired 3- (pyridin-3-yloxy) -4, 5-Dihydroisoxazole I-72a and I-72b were produced as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 402.3 m / z. Activity: B.

ラセミ化合物I-71(1.0当量)、3-カルバモイルフェニルボロン酸(1.1当量)、酢酸カリウム(1.0当量)、炭酸セシウム(3.0当量)、及びジクロロ[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロロメタン付加物(14mol％)を、DMSO 1mL中に懸濁し、かつArでパージした。得られた混合物を密封し、80℃で1時間加熱した。この粗混合物を、過剰な水と共に分液漏斗に移し、tert-ブチルメチルエーテル(2×)で抽出した。これらの有機層を一緒にし、Na₂SO₄上で乾燥し、フラッシュシリカゲルクロマトグラフィー(2〜10％MeOHの勾配)を使用し精製し、所望の3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-73a及びI-73bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝442.0m/z。活性：A。 (Example 73)

Racemic compound I-71 (1.0 eq), 3-carbamoylphenylboronic acid (1.1 eq), potassium acetate (1.0 eq), cesium carbonate (3.0 eq), and dichloro [1,1′-bis (diphenylphosphino) ferrocene ] Palladium (II) dichloromethane adduct (14 mol%) was suspended in 1 mL DMSO and purged with Ar. The resulting mixture was sealed and heated at 80 ° C. for 1 hour. The crude mixture was transferred to a separatory funnel with excess water and extracted with tert-butyl methyl ether (2 ×). The organic layers are combined, dried over Na ₂ SO _{4 and} purified using flash silica gel chromatography (gradient 2-10% MeOH) to give the desired 3- (pyridin-3-yloxy) -4, 5-Dihydroisoxazole I-73a and I-73b were produced as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 442.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-74a及びI-74bを、4-ビニル安息香酸メチルから、方法1を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝283.6m/z。活性：A。 Example 74

3-Bromo-4,5-dihydroisoxazole I-74a and I-74b were prepared from methyl 4-vinylbenzoate using Method 1 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 283.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-75a及びI-75bを、4'(トリフルオロメトキシ)アセトフェノンから、方法6を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝323.0m/z。活性：A。 (Example 75)

3-Bromo-4,5-dihydroisoxazoles I-75a and I-75b are started from 4 ′ (trifluoromethoxy) acetophenone in alkene formation using Method 6, followed by addition ring using Method 1. It was prepared in two steps. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 323.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-76a及びI-76bを、4'-フェノキシアセトフェノンから、方法6を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝331.0m/z。活性：A。 (Example 76)

3-Bromo-4,5-dihydroisoxazole I-76a and I-76b were started from 4'-phenoxyacetophenone in alkene formation using Method 6, followed by cycloaddition 2 using Method 2. Prepared in process. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 331.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-77a及びI-77bを、trans-アネトールから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝269.0m/z。活性：C。 Example 77

3-Bromo-4,5-dihydroisoxazole I-77a and I-77b were prepared from trans-anethole in one step using method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 269.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-78a及びI-78bを、4-フェノキシベンズアルデヒドから、方法6(エチルトリフェニルホスホニウムブロミドを、メチルトリフェニルホスホニウムブロミドの代わりに使用する点を除く)を使用するアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝331.0m/z。活性：A。 (Example 78)

3-Bromo-4,5-dihydroisoxazole I-78a and I-78b from 4-phenoxybenzaldehyde, method 6 (except that ethyltriphenylphosphonium bromide is used instead of methyltriphenylphosphonium bromide) Prepared in two steps of cycloaddition using method 2, starting with alkene formation using These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 331.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-82a及びI-82bを、4-フェノキシベンズアルデヒドから、下記のように、3工程で調製した：4-フェノキシベンズアルデヒド(1.0当量)を、テトラヒドロフラン(テトラヒドロフランに対して0.20M)中に溶解し、かつ0℃に冷却した。エチルマグネシウムブロミド(THF中1.0M、1.2当量)を滴加し、その後この反応物を23℃で2時間攪拌させた。この混合物を、飽和塩化アンモニウムによりクエンチし、かつ濃縮し、テトラヒドロフランを除去した。次に混合物を水で希釈し、tert-ブチルメチルエーテルにより抽出した。この有機層を、水及びブラインで洗浄し、次に硫酸ナトリウム上で乾燥し、かつ真空中で濃縮した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のアルコールI-80を生じた。 (Example 79)

3-Bromo-4,5-dihydroisoxazole I-82a and I-82b were prepared from 4-phenoxybenzaldehyde in three steps as follows: 4-phenoxybenzaldehyde (1.0 eq) was prepared in tetrahydrofuran (tetrahydrofuran In 0.20M) and cooled to 0 ° C. Ethyl magnesium bromide (1.0 M in THF, 1.2 eq) was added dropwise, after which the reaction was allowed to stir at 23 ° C. for 2 hours. The mixture was quenched with saturated ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then diluted with water and extracted with tert-butyl methyl ether. The organic layer was washed with water and brine, then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired alcohol I-80.

The purified alcohol I-80 was then dissolved in pyridine (0.80M for alcohol). Phosphorus oxychloride (1.1 eq) was added and the mixture was heated at reflux for 2 hours. After this time, the reaction was cooled to 0 ° C. and quenched by the addition of excess water. The mixture was then diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired alkene I-81.

  Alkene I-81 was then converted to the desired 3-bromo-4,5-dihydroisoxazoles I-82a and I-82b using Method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M-H]-= 331.0 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-83a及びI-83bを、ラセミ化合物I-14及び3-(5-ヒドロキシピリジン-2-イル)安息香酸メチルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝460.1m/z。活性：B。 Example 80

Method of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-83a and I-83b from racemic compound I-14 and methyl 3- (5-hydroxypyridin-2-yl) benzoate 5 was used and prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 460.1 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-84a及びI-84bを、ラセミ化合物I-14及び3-(5-ヒドロキシピリジン-2-イル)安息香酸エチルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝474.1m/z。活性：B。 Example 81

Method of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-84a and I-84b from racemic compound I-14 and ethyl 3- (5-hydroxypyridin-2-yl) benzoate 5 was used and prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 474.1 m / z. Activity: B.

ラセミ化合物I-83(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を、室温で1時間攪拌させ、その時点の後、窒素流れ下でテトラヒドロフランを除去し、残存した溶液を、1N HClによりpH＜2まで酸性とし、所望の酸I-85a及びI-85bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝443.0m/z。活性：B。 (Example 82)

Racemic compound I-83 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids I-85a and I- 85b was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 443.0 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-86a及びI-86bを、ラセミ化合物I-14及び6-フェニルピリジン-3-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝402.2m/z。活性：B。 Example 83

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-86a and I-86b from racemic compound I-14 and 6-phenylpyridin-3-ol, using method 5, one step Was prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 402.2 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-87a及びI-87bを、ラセミ化合物I-12及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝333.5m/z。活性：A。 (Example 84)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-87a and I-87b were prepared from racemic compound I-12 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 333.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-88a及びI-88bを、ラセミ化合物I-75及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝340.2m/z。活性：B。 Example 85

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-88a and I-88b were prepared from racemic compound I-75 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 340.2 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-89a及びI-89bを、ラセミ化合物I-76及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝348.4m/z。活性：A。 Example 86

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-89a and I-89b were prepared from racemic compound I-76 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 348.4 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-90a及びI-90bを、ラセミ化合物I-10及び4-ヒドロキシベンゼンスルホンアミドから、方法4を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝410.8m/z。活性：A。 Example 87

3-phenoxy-4,5-dihydroisoxazole I-90a and I-90b were prepared from racemic I-10 and 4-hydroxybenzenesulfonamide in one step using Method 4. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 410.8 m / z. Activity: A.

trans 3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-91a及びI-91bを、ラセミ化合物I-78又はI-82のいずれか及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝346.2m/z。活性：C。 Example 88

Use method 5 from trans 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-91a and I-91b from either racemic compound I-78 or I-82 and 3-hydroxypyridine. And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 346.2 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-92a及びI-92bを、5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2-イルカルバミン酸tert-ブチルから、方法11を使用し、(5-ヒドロキシ-ピリジン-2-イル)-カルバミン酸tert-ブチルエステルの形成後、ラセミ化合物I-10及び(5-ヒドロキシ-ピリジン-2-イル)-カルバミン酸tert-ブチルエステルから、方法5を使用し、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝447.9m/z。活性：C。 Example 89

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-92a and I-92b were converted to 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) pyridin-2-ylcarbamate tert-butyl using method 11 and after formation of (5-hydroxy-pyridin-2-yl) -carbamic acid tert-butyl ester, racemic compounds I-10 and (5 Prepared in 2 steps using method 5 from -hydroxy-pyridin-2-yl) -carbamic acid tert-butyl ester. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 447.9 m / z. Activity: C.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-92を、トリフルオロ酢酸(イソオキサゾールに対して0.20M)中に溶解し、室温で1時間攪拌した。次に溶媒を真空下で除去し、粗残渣をトルエン(2×)と共沸し、I-93a及びI-93bをTFA塩(白色固形物)として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝347.1m/z。活性：A。 Example 90

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-92 was dissolved in trifluoroacetic acid (0.20M relative to isoxazole) and stirred at room temperature for 1 hour. The solvent was then removed under vacuum and the crude residue was azeotroped with toluene (2 ×) to yield I-93a and I-93b as TFA salts (white solid). These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 347.1 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-93を、塩化メチレン(イソオキサゾールに対して0.03M)中に溶解し、この後トリエチルアミン(4.0当量)及び無水酢酸(3.0当量)を添加した。この反応物を16時間攪拌させ、この時点の後酢酸エチルで希釈し、飽和NaHCO₃(2×)及びブライン(1×)により洗浄した。次に有機層を、硫酸ナトリウム上で乾燥し、真空下で濃縮し、酢酸塩I-94a及びI-94bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝388.1m/z。活性：A。 Example 91

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-93 is dissolved in methylene chloride (0.03M relative to isoxazole) followed by triethylamine (4.0 eq) and acetic anhydride. (3.0 eq) was added. The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with saturated NaHCO ₃ (2 ×) and brine (1 ×). The organic layer was then dried over sodium sulfate and concentrated under vacuum to yield acetates I-94a and I-94b as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 388.1m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-95a及びI-95bを、1-(4-フェノキシフェニル)プロパン-1-オンから、方法8を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝347.7m/z。活性：A。 (Example 92)

3-Bromo-4,5-dihydroisoxazole I-95a and I-95b were started from 1- (4-phenoxyphenyl) propan-1-one in alkene formation using Method 8, followed by Method 1. Prepared in 2 steps of cycloaddition using These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 347.7 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-96a及びI-96bを、ラセミ化合物I-14及び5-ヒドロキシピコリン酸メチルエステルから、以下の手順に従い、1工程で調製した：3-ブロモ-5-(4-(トリフルオロメトキシ)フェニル)-4,5-ジヒドロイソオキサゾール(1.0当量)、5-ヒドロキシピコリン酸メチルエステル(1.2当量)、及び炭酸水素セシウム(1.50当量)を、N,N-ジメチルホルムアミド(ジヒドロイソオキサゾールに対して0.32M)中に懸濁した。次にこの混合物を、アルゴンで脱気し、その後これを130℃で4時間加熱し、この時点の後所望の生成物及び対応する酸のみがLC/MSにより視認できた。この反応物を、室温まで冷却し、水中の塩化アンモニウム溶液(30重量％、ジヒドロイソオキサゾールに対して0.08M)中に注ぐことによりクエンチした。この水相を、酢酸エチル(2×)により抽出し、硫酸ナトリウム上で乾燥し、濾過し、かつ濃縮し、茶色固形物を生じ、これを無水エタノールから再結晶し、ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-96を生じ、これは濾過により白色固形物として単離した(収率25％)。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝383.8m/z。活性：A。 (Example 93)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-96a and I-96b were prepared from racemic compound I-14 and 5-hydroxypicolinic acid methyl ester in one step according to the following procedure 3-bromo-5- (4- (trifluoromethoxy) phenyl) -4,5-dihydroisoxazole (1.0 eq), 5-hydroxypicolinic acid methyl ester (1.2 eq), and cesium bicarbonate (1.50 eq) ) Was suspended in N, N-dimethylformamide (0.32M relative to dihydroisoxazole). The mixture was then degassed with argon, after which it was heated at 130 ° C. for 4 hours, after which only the desired product and the corresponding acid were visible by LC / MS. The reaction was cooled to room temperature and quenched by pouring into a solution of ammonium chloride in water (30 wt%, 0.08M for dihydroisoxazole). The aqueous phase is extracted with ethyl acetate (2 ×), dried over sodium sulfate, filtered and concentrated to yield a brown solid which is recrystallized from absolute ethanol and racemic 3- (pyridine 3-yloxy) -4,5-dihydroisoxazole I-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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 383.8 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-96(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を室温で1時間攪拌させ、この時点の後、テトラヒドロフランを窒素流れ下で除去し、かつ残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸の鏡像異性体I-97a及びI-97bを白色固形物として生じ、これらを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝369.3m/z。活性：A。 Example 94

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-96 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) ) Was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acid enantiomer I- 97a and I-97b were produced as white solids, which were isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 369.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-98a及びI-98bを、ラセミ化合物I-10及び3-(5-ヒドロキシピリジン-2-イル)プロパン酸メチルエステルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝418.1m/z。活性：A。 Example 95

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-98a and I-98b were obtained from racemic compounds I-10 and 3- (5-hydroxypyridin-2-yl) propanoic acid methyl ester, Using method 5, prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 418.1 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-98(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を室温で1時間攪拌させ、この時点の後、テトラヒドロフランを窒素流れ下で除去し、かつ残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸I-99a及びI-99bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝402.8m/z。活性：A。 Example 96

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-98 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) ) Was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids I-99a and I- 99b was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 402.8m / z. Activity: A.

ラセミ化合物I-98を、メタノール中のアンモニア(メタノール中7.0M、イソオキサゾールに対して0.02M)中に溶解した。この反応物を密封し、かつ23℃で72時間攪拌させ、この時点の後、溶媒及び過剰なアンモニアを、窒素流れ下で除去し、明茶色固形物を生じ、これをヘキサンによりトリチュレートし、所望のアミドI-100a及びI-100bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝404.5m/z。活性：A。 Example 97

Racemic compound I-98 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M for isoxazole). The reaction was sealed and allowed to stir at 23 ° C. for 72 hours, after which time the solvent and excess ammonia were removed under a stream of nitrogen to yield a light brown solid, which was triturated with hexanes, desired Of amide I-100a and I-100b as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 404.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-101a及びI-101bを、ラセミ化合物I-9及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝316.8m/z。活性：A。 Example 98

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-101a and I-101b were prepared from racemic compound I-9 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 316.8 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-102a及びI-102bを、1-(ビフェニル-4-イル)エタノンから、方法8を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝315.7m/z。活性：A。 Example 99

3-Bromo-4,5-dihydroisoxazole I-102a and I-102b are started from 1- (biphenyl-4-yl) ethanone in alkene formation using Method 8, followed by Method 1. Prepared in 2 steps of cycloaddition. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 315.7 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-103a及びI-103bを、ラセミ化合物I-9及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝318.7m/z。活性：A。 (Example 100)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-103a and I-103b were prepared from racemic compound I-9 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 318.7 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-104a及びI-104bを、ラセミ化合物I-102及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝332.6m/z。活性：A。 (Example 101)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-104a and I-104b were prepared from racemic compound I-102 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 332.6 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-97(1.0当量)を、塩化メチレン(イソオキサゾールに対して0.03M)中に溶解した。塩化チオニルを添加し(2.0当量)、かつこの反応物を室温で1時間攪拌し、この時点の後、これを真空下で濃縮し、ベージュ色固形物とし、これをトルエン(2×)で共沸した。得られた固形物を、テトラヒドロフラン(イソオキサゾールに対して0.03M)中に再度溶解し、その後グリシンメチルエステル(1.5当量)を添加し、引き続きトリエチルアミン(3.0当量)を添加した。この反応物を、室温で1時間攪拌し、この時点の後、これを過剰な水及び酢酸エチルと共に分液漏斗へ移した。次に有機層を、飽和NaHCO₃溶液及びブラインで洗浄し、硫酸マグネシウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、アミドI-105a及びI-105bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝437.5m/z。活性：A。 Example 102

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-97 (1.0 eq) was dissolved in methylene chloride (0.03M relative to isoxazole). Thionyl chloride was added (2.0 eq) and the reaction was stirred at room temperature for 1 h after which time it was concentrated in vacuo to a beige solid that was co-solved with toluene (2 ×). Boiled. The resulting solid was redissolved in tetrahydrofuran (0.03M relative to isoxazole), after which glycine methyl ester (1.5 eq) was added, followed by triethylamine (3.0 eq). The reaction was stirred at room temperature for 1 hour after which time it was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer is then washed with saturated NaHCO ₃ solution and brine, dried over magnesium sulfate and concentrated in vacuo to yield a crude material which is purified by flash silica gel chromatography (ethyl acetate / hexanes). Gave amides I-105a and I-105b as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 437.5 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-105(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を室温で1時間攪拌させ、この時点の後、テトラヒドロフランを窒素流れ下で除去し、かつ残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸I-106a及びI-106bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝423.7m/z。活性：A。 (Example 103)

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-105 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) ) Was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids I-106a and I- 106b was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 423.7 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-107a及びI-107bは、メチルアミンをグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝382.5m/z。活性：A。 (Example 104)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-107a and I-107b were prepared using the same procedure as Example 102, except that methylamine was used instead of glycine methyl ester. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 382.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-108a及びI-108bは、ジメチルアミンをグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝396.6m/z。活性：B。 (Example 105)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-108a and I-108b were prepared using a procedure similar to Example 102 except that dimethylamine was used in place of glycine methyl ester. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 396.6 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-109a及びI-109bは、エタノールアミンをグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝409.9m/z。活性：A。 (Example 106)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-109a and I-109b were prepared using the same procedure as Example 102, except that ethanolamine was used instead of glycine methyl ester. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 409.9m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-67(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を室温で1時間攪拌させ、この時点の後、テトラヒドロフランを窒素流れ下で除去し、かつ残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸I-110a及びI-110bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝376.5m/z。活性：A。 (Example 107)

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) ) Was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids I-110a and I- 110b was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 376.5 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-67を、メタノール中のジメチルアミン(テトラヒドロフラン中2.0M、イソオキサゾールに対して0.02M)中に溶解した。この反応物を密封し、かつ23℃で72時間攪拌させ、この時点の後、溶媒及び過剰なジメチルアミンを、窒素流れ下で除去し、明茶色固形物を生じ、これをヘキサンによりトリチュレートし、所望のアミドI-111a及びI-111bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝405.1m/z。活性：A。 (Example 108)

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67 was dissolved in dimethylamine in methanol (2.0 M in tetrahydrofuran, 0.02 M for isoxazole). The reaction was sealed and allowed to stir at 23 ° C. for 72 hours, after which time the solvent and excess dimethylamine were removed under a stream of nitrogen to yield a light brown solid that was triturated with hexane, The desired amides I-111a and I-111b were produced as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 405.1 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-112a及びI-112bを、ラセミ化合物I-14及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。活性：A。 (Example 109)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-112a and I-112b were prepared from racemic compound I-14 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-113a及びI-113bを、ラセミ化合物I-75及び5-ヒドロキシピコリン酸メチルエステルから、方法5を使用し、それに続き実施例94と同じ条件下で加水分解する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝380.7m/z。活性：A。 (Example 110)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-113a and I-113b were prepared from racemic compound I-75 and 5-hydroxypicolinic acid methyl ester using method 5 followed by Prepared in two steps, hydrolyzing under the same conditions as Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 380.7 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-114a及びI-114bは、ラセミ化合物I-113から、メチルアミン(テトラヒドロフラン中2.0M)をグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝396.4m/z。活性：A。 (Example 111)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-114a and I-114b use racemic compound I-113 with methylamine (2.0M in tetrahydrofuran) instead of glycine methyl ester Except for the above, it was prepared using the same procedure as in Example 102. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 396.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-115a及びI-115bは、ラセミ化合物I-113から、エチルアミンをグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝411.1m/z。活性：A。 (Example 112)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-115a and I-115b are the same as in Example 102 except that ethylamine is used in place of glycine methyl ester from racemic compound I-113 Prepared using a similar procedure. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 411.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-116a及びI-116bは、ラセミ化合物I-113から、トリフルオロエチルアミンをグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝461.7m/z。活性：B。 (Example 113)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-116a and I-116b are examples except for using trifluoroethylamine instead of glycine methyl ester from racemic compound I-113. Prepared using a procedure similar to 102. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 461.7m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-117a及びI-117bは、ラセミ化合物I-113から、塩酸ヒドロキシルアミンをグリシンメチルエステルの代わりに使用する以外は、実施例102と同様の手順を用いて調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+-＝398.4m/z。活性：A。 (Example 114)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-117a and I-117b were prepared from the racemic compound I-113 except that hydroxylamine hydrochloride was used in place of glycine methyl ester. Prepared using a procedure similar to 102. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] +-= 398.4 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-105を、メタノール中のアンモニア(メタノール中7.0M、イソオキサゾールに対して0.02M)中に溶解した。この反応物を密封し、かつ23℃で72時間攪拌させ、この時点の後、溶媒及び過剰なアンモニアを、窒素流れ下で除去し、明茶色固形物を生じ、これをヘキサンによりトリチュレートし、所望のアミドI-118a及びI-118bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝325.1m/z。活性：B。 (Example 115)

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-105 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M for isoxazole). The reaction was sealed and allowed to stir at 23 ° C. for 72 hours, after which time the solvent and excess ammonia were removed under a stream of nitrogen to yield a light brown solid, which was triturated with hexanes, desired Of amide I-118a and I-118b as white solids. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 325.1 m / z. Activity: B.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-119a及びI-119bを、方法9を使用する、4-ブロモ-3,3'-ジフルオロビフェニルのその対応するアルケンへの変換で出発し、それに続き方法1を使用する付加環化、それに続き方法5を使用する、5-ヒドロキシピリミジン(hydroxyprimidine）との置換の3工程で合成した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝354.3m/z。活性：A。 (Example 116)

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-119a and I-119b were converted to 4-bromo-3,3′-difluorobiphenyl to its corresponding alkene using Method 9. The synthesis was performed in 3 steps starting with the transformation followed by cycloaddition using method 1 followed by substitution with 5-hydroxyprimidine using method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 354.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-120a及びI-120bは、方法8を使用する3-フルオロ-4-(トリフルオロメトキシ)ベンズアルデヒドからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝327.5m/z。活性：A。 (Example 117)

3-Bromo-4,5-dihydroisoxazole I-120a and I-120b start with alkene formation from 3-fluoro-4- (trifluoromethoxy) benzaldehyde using Method 8, followed by Method 1. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 327.5 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-121a及びI-121bを、ラセミ化合物I-120及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝344.1m/z。活性：A。 (Example 118)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-121a and I-121b were prepared from racemic compound I-120 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 344.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-122a及びI-122bを、ラセミ化合物I-120及び5-ヒドロキシピコリン酸メチルエステルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝400.3m/z。活性：A。 (Example 119)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-122a and I-122b were prepared from racemic compound I-120 and 5-hydroxypicolinic acid methyl ester in one step using method 5. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 400.3 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-122(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を室温で1時間攪拌させ、この時点の後、テトラヒドロフランを窒素流れ下で除去し、かつ残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸I-123a及びI-123bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝386.3m/z。活性：A。 (Example 120)

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-122 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) ) Was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids I-123a and I-123. 123b was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 386.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-124a及びI-124bを、3-クロロ-4-(トリフルオロメトキシ)ベンズアルデヒドからの方法8を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝345.5m/z。活性：A。 (Example 121)

3-Bromo-4,5-dihydroisoxazole I-124a and I-124b were started with alkene formation using Method 8 from 3-chloro-4- (trifluoromethoxy) benzaldehyde, followed by Method 1. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 345.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-125a及びI-125bを、ラセミ化合物I-124及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝359.7m/z。活性：A。 (Example 122)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-125a and I-125b were prepared from racemic compound I-124 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 359.7m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-126a及びI-126bを、2,2-ジフルオロ-1,3-ベンゾジオキソール-5-カルボキシアルデヒドからの方法8を使用するアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝305.6m/z。活性：A。 (Example 123)

3-Bromo-4,5-dihydroisoxazole I-126a and I-126b started with alkene formation using method 8 from 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde Followed by two cycloaddition steps using Method 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 305.6 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-127a及びI-127bを、ラセミ化合物I-126及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝321.8m/z。活性：B。 (Example 124)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-127a and I-127b were prepared from racemic compound I-126 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 321.8m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-128a及びI-128bを、ラセミ化合物I-14をラセミ化合物I-10の代わりの出発物質として使用した以外は実施例96における化合物I-99へと類似の様式で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝398.2m/z。活性：A。 (Example 125)

Example 96 except that 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-128a and I-128b were used as racemate I-14 as starting material instead of racemic compound I-10. Was prepared in an analogous manner to compound I-99. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 398.2 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-129a及びI-129bを、ラセミ化合物I-75及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝339.8m/z。活性：A。 Example 126

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-129a and I-129b were prepared from racemic compound I-75 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 339.8 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-130a及びI-130bを、下記のように、4-フェノキシフェニルボロン酸と2-ブロモ-3,3,3-トリフルオロプロパ-1-エンの間のカップリングにより出発する2工程で調製した：トルエン溶液(ボロン酸に対して0.25M)を、密封したチューブ内で0℃まで冷却し、この時点の後、2-ブロモ-3,3,3-トリフルオロプロパ-1-エン(0.83当量)を添加し、引き続きテトラキスパラジウム(2.5mol％)を添加した。この混合物をArでパージし、この時点の後、2.0M炭酸ナトリウム溶液(1.5当量)を添加し、引き続きメタノール中のボロン酸(1.0当量)(ボロン酸に対して1.0M)を添加した。この混合物を、Arで2回目のパージを行い、この時点の後、油浴中70℃で20時間加熱した。この反応物を冷却し、その後過剰な水及び酢酸エチルと共に分液漏斗に移し、2.0M炭酸ナトリウム溶液(1×)及び水(2×)で洗浄した。有機層を乾燥し、濃縮し、黒色油状物を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のアルケンを油状物として収率35％で生じ、これを所望のラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-130に方法1を用いて直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝385.6m/z。活性：B。 (Example 127)

3-Bromo-4,5-dihydroisoxazole I-130a and I-130b can be converted to 4-phenoxyphenylboronic acid and 2-bromo-3,3,3-trifluoroprop-1-ene as follows: Prepared in two steps starting with coupling between: Toluene solution (0.25M against boronic acid) was cooled to 0 ° C. in a sealed tube, after which time 2-bromo-3,3, 3-Trifluoroprop-1-ene (0.83 equivalent) was added, followed by tetrakis palladium (2.5 mol%). The mixture was purged with Ar, at which point 2.0 M sodium carbonate solution (1.5 eq) was added followed by boronic acid (1.0 eq) in methanol (1.0 M relative to boronic acid). The mixture was purged with Ar a second time, after which time it was heated in an oil bath at 70 ° C. for 20 hours. The reaction was cooled and then transferred to a separatory funnel with excess water and ethyl acetate and washed with 2.0 M sodium carbonate solution (1 ×) and water (2 ×). The organic layer is dried and concentrated to yield a black oil which is purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired alkene as an oil in 35% yield, which is the desired racemic. The product 3-bromo-4,5-dihydroisoxazole I-130 was directly converted using Method 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 385.6 m / z. Activity: B.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-131a及びI-131bを、ラセミ化合物I-130及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝401.4m/z。活性：A。 (Example 128)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-131a and I-131b were prepared from racemic compound I-130 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 401.4 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-132a及びI-132bを、最初に2-(メチルチオ)ピリミジン-5-オールを方法11を使用し2-(メチルチオ)ピリミジン-5-イルボロン酸から調製した後、方法5を使用し、ラセミ化合物I-14及び2-(メチルチオ)ピリミジン-5-オールから、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝372.2m/z。活性：B。 (Example 129)

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-132a and I-132b, first using 2- (methylthio) pyrimidin-5-ol using method 11, 2- (methylthio) pyrimidine After preparation from -5-ylboronic acid, it was prepared in one step from racemic compound I-14 and 2- (methylthio) pyrimidin-5-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 372.2 m / z. Activity: B.

ラセミ体3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-132を、塩化メチレン(イソオキサゾールに対して0.5M)中に溶解し、この時点の後、m-クロロ過安息香酸(2.0当量)を、1部分で添加し、かつこの反応物を、室温で1時間攪拌させた。この反応が完了したことをLC/MSにより確認した後、溶媒を蒸発させた。次に粗混合物を、tert-ブチルメチルエーテル(0.5M)中に再溶解させ、その後ヘキサンを固形物が沈殿するまでゆっくり添加した。次にこの固形物を、真空濾過により収集し、1:1ヘキサン/tert-ブチルメチルエーテルで洗浄し、所望の3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-133a及びI-133bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝404.1m/z。活性：A。 (Example 130)

Racemic 3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-132 is dissolved in methylene chloride (0.5M relative to isoxazole) and after this point m-chloroperbenzoic acid is dissolved. Acid (2.0 eq) was added in one portion and the reaction was allowed to stir at room temperature for 1 hour. After confirming the completion of the reaction by LC / MS, the solvent was evaporated. The crude mixture was then redissolved in tert-butyl methyl ether (0.5M), after which hexane was slowly added until a solid precipitated. The solid is then collected by vacuum filtration and washed with 1: 1 hexane / tert-butyl methyl ether to give the desired 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-133a and I-133b was produced as a white solid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 404.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-134a及びI-134bを、最初に6-(メチルチオ)ピリジン-3-オールを方法11を使用し6-(メチルチオ)ピリジン-3-イルボロン酸から調製した後、方法5を使用し、ラセミ化合物I-14及び6-(メチルチオ)ピリジン-3-オールから、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝372.4m/z。活性：A。 (Example 131)

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-134a and I-134b, first 6- (methylthio) pyridin-3-ol using method 11, After preparation from -3-ylboronic acid, it was prepared in one step from racemic compound I-14 and 6- (methylthio) pyridin-3-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 372.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾール I-135a及びI-135bを、I-134から、実施例130における化合物I-133に類似の様式で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝403.2m/z。活性：A。 (Example 132)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-135a and I-135b were prepared from I-134 in a manner similar to compound I-133 in Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 403.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-136a及びI-136bを、最初に5-フルオロ-6-メトキシピリジン-3-オールを方法11を使用し5-フルオロ-6-メトキシピリジン-3-ボロン酸から調製した後、方法5を使用し、ラセミ化合物I-14及び5-フルオロ-6-メトキシピリジン-3-オールから、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝373.4m/z。活性：B。 (Example 133)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-136a and I-136b, first 5-fluoro-6-methoxypyridin-3-ol using method 11, After preparing from 6-methoxypyridine-3-boronic acid, it was prepared in one step from racemic compound I-14 and 5-fluoro-6-methoxypyridin-3-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 373.4 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-137a及びI-137bを3工程で、4-ブトキシベンズアルデヒドから方法8を使用し、それに続き方法1を使用する付加環化で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、5-ヒドロキシピコリン酸メチルエステルと反応させた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝370.1m/z。活性：A。 (Example 134)

Cycloaddition of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-137a and I-137b from 4-butoxybenzaldehyde using method 8 followed by method 1 It was prepared with. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 370.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-138a及びI-138bを、実施例94と類似の加水分解条件を使用し、化合物I-137から1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝357.7m/z。活性：A。 (Example 135)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-138a and I-138b were prepared in one step from compound I-137 using similar hydrolysis conditions as Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 357.7 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-139a及びI-139bを3工程で、4-ブトキシベンズアルデヒドから方法8を使用し、それに続き方法1を使用する付加環化で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、5-ヒドロキシピリミジンと反応させた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝314.9m/z。活性：A。 (Example 136)

Cycloaddition of 3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-139a and I-139b from 4-butoxybenzaldehyde using method 8 followed by method 1 It was prepared with. 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 314.9 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-140a及びI-140bを4工程で、4-iso-プロポキシベンズアルデヒドから方法8を使用し、それに続き方法1を使用する付加環化で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、5-ヒドロキシピコリン酸メチルエステルと反応させ、それに続き実施例94と類似の条件を使用し、加水分解した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝343.5m/z。活性：A。 (Example 137)

Addition of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-140a and I-140b in 4 steps from 4-iso-propoxybenzaldehyde using method 8 followed by method 1 Prepared by cyclization. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5, followed by hydrolysis using conditions similar to Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 343.5 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-141a及びI-141bを3工程で、4-iso-プロポキシベンズアルデヒドから方法8を使用し、それに続き方法1を使用する付加環化で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、5-ヒドロキシピリミジンと反応させた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝299.3m/z。活性：A。 (Example 138)

Addition of 3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-141a and I-141b from 4-iso-propoxybenzaldehyde using method 8 followed by method 1 Prepared by cyclization. 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 299.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-142a及びI-142bを、方法1の付加環化条件を使用し、酢酸4-ビニルフェニルから3工程で調製した。得られた酢酸塩を、テトラヒドロフラン(1.0当量、ブロモイソオキサゾールに対して0.18M)中に溶解し、かつ氷浴で0℃に冷却した。水酸化リチウム(3.0当量、水中1.0M)を添加し、かつこの反応物を30分間攪拌させ、この時点の後、これを過剰な水及び酢酸エチルと共に分液漏斗へ移した。有機層を、飽和塩化アンモニウムで抽出し、硫酸ナトリウム上で乾燥し、かつ蒸発させ、所望のフェノールを定量的収率で生じ、これを直接使用した。フェノール(1.00当量)を、アセトニトリル(出発物質に対して0.20M)中に溶解し、氷浴中で0℃に冷却した。臭化プロパルギル(2.0当量)を添加し、引き続き炭酸セシウム(3.0当量)を添加した。この反応物を2時間攪拌させ、その後飽和塩化アンモニウムでクエンチし、かつ過剰な水及び酢酸エチルと共に分液漏斗に移した。有機層を、硫酸ナトリウム上で乾燥し、蒸発させ、所望のラセミ体アルキンI-142を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、所望のラセミ化合物を収率70％で生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝279.7m/z。活性：A。 (Example 139)

3-Bromo-4,5-dihydroisoxazole I-142a and I-142b were prepared in 3 steps from 4-vinylphenyl acetate using the cycloaddition conditions of Method 1. The resulting acetate salt was dissolved in tetrahydrofuran (1.0 eq, 0.18M relative to bromoisoxazole) and cooled to 0 ° C. with an ice bath. Lithium hydroxide (3.0 eq, 1.0 M in water) was added and the reaction was allowed to stir for 30 minutes, after which time it was 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 yield the desired phenol in quantitative yield, which was used directly. Phenol (1.00 eq) was dissolved in acetonitrile (0.20 M relative to starting material) and cooled to 0 ° C. in an ice bath. Propargyl bromide (2.0 eq) was added followed by cesium carbonate (3.0 eq). The reaction was allowed to stir for 2 hours, then 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 give the desired racemic alkyne I-142, which was purified by flash silica gel chromatography (ethyl acetate / hexane) to yield the desired racemic compound in 70% yield. It occurred in. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 279.7 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-143a及びI-143bを、ラセミ化合物I-142及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝296.5m/z。活性：B。 (Example 140)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-143a and I-143b were prepared from racemic compound I-142 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 296.5 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-144a及びI-144bを、ラセミ化合物I-142及び5-ヒドロキシピコリン酸メチルエステルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝353.5m/z。活性：A。 (Example 141)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-144a and I-144b from racemic compound I-142 and 5-hydroxypicolinic acid methyl ester in one step using method 5. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 353.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-145a及びI-145bを、ラセミ化合物I-144から、実施例94と同様の加水分解条件を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝338.8m/z。活性：A。 (Example 142)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-145a and I-145b were prepared from racemic compound I-144 in one step using hydrolysis conditions similar to Example 94. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 338.8 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-146a及びI-146bを、ラセミ化合物I-61から、実施例94と同様の加水分解条件を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝376.2m/z。活性：B。 (Example 143)

3-phenoxy-4,5-dihydroisoxazole I-146a and I-146b were prepared from racemic compound I-61 in one step using the same hydrolysis conditions as in Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 376.2m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-147a及びI-147bを、ラセミ化合物I-62から、実施例94と同様の加水分解条件を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝375.7m/z。活性：A。 (Example 144)

3-phenoxy-4,5-dihydroisoxazole I-147a and I-147b were prepared from racemic compound I-62 in one step using the same hydrolysis conditions as Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 375.7 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-148a及びI-148bを、1-ブロモ-4-ビニルベンゼンから、方法1を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝350.5m/z。活性：A。 (Example 145)

3-Bromo-4,5-dihydroisoxazole I-148a and I-148b were prepared from 1-bromo-4-vinylbenzene using Method 1 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 350.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-149a及びI-149bを、ラセミ化合物I-148及び5-ヒドロキシピコリン酸メチルエステルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝378.4m/z。活性：A。 (Example 146)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-149a and I-149b were prepared from racemic compound I-148 and 5-hydroxypicolinic acid methyl ester in one step using method 5. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 378.4m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-150a及びI-150bを、ラセミ化合物I-149から、実施例94と同様の加水分解条件を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝362.6m/z。活性：A。 (Example 147)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-150a and I-150b were prepared from racemic compound I-149 in one step using the same hydrolysis conditions as Example 94 did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 362.6 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-151a及びI-151bを、ラセミ化合物I-14及び4-ヒドロキシピコリン酸メチルエステルから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝384.2m/z。活性：A。 (Example 148)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-151a and I-151b from racemic compound I-14 and 4-hydroxypicolinic acid methyl ester in one step using method 5. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 384.2 m / z. Activity: A.

ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-151(1.0当量)を、1:1のテトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を室温で1時間攪拌させ、この時点の後、テトラヒドロフランを窒素流れ下で除去し、かつ残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸I-152a及びI-152bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝368.9m/z。活性：A。 (Example 149)

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-151 (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) ) Was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids I-152a and I-- 152b was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 368.9m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-153a及びI-153bを、1-クロロ-4-ビニルベンゼンから、方法1を使用し、2工程で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を用い、5-ヒドロキシピリミジンと反応させた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝277.3m/z。活性：B。 (Example 150)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-153a and I-153b were prepared from 1-chloro-4-vinylbenzene using Method 1 in two steps. 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 277.3 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-154a及びI-154bを、ラセミ化合物I-75及び6-(フラン-3-イル)ピリジン-3-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.3m/z。活性：A。 (Example 151)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-154a and I-154b were prepared from racemic compounds I-75 and 6- (furan-3-yl) pyridin-3-ols by method 5 And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-155a及びI-155bを、以下の手順に従い、ラセミ酸I110から調製した：マイクロ波反応チューブ内で、アセチルヒドラジド(1.0当量)及び酸I110(1.0当量)を、乾燥アセトニトリル中に溶解した(各0.1M)。ポリスチレン-担持されたトリフェニルホスフィン(3.0当量)及びトリクロロアセトニトリル(2.0当量)を添加し、この混合物をマイクロ波用反応器中に密封し、かつ130℃3fで2時間加熱した。この時点の後、この反応が完了していないことをLC/MSにより決定し、その結果トリフェニルホスフィン樹脂の追加1.5当量を添加し、引き続きトリクロロアセトニトリルの追加1.0当量を添加した。この容器を再度密封し、更に130℃で2時間加熱した。完了時に、濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、所望のラセミ体オキサジアゾールI-155を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝415.5m/z。活性：A。 (Example 152)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-155a and I-155b were prepared from racemic acid I110 according to the following procedure: Acetyl hydrazide (1.0 eq) in a microwave reaction tube ) And acid I110 (1.0 eq) were dissolved in dry acetonitrile (0.1 M each). Polystyrene-supported triphenylphosphine (3.0 eq) and trichloroacetonitrile (2.0 eq) were added and the mixture was sealed in a microwave reactor and heated at 130 ° C. 3 f for 2 h. After this point, it was determined by LC / MS that the reaction was not complete, so an additional 1.5 equivalents of triphenylphosphine resin was added followed by an additional 1.0 equivalent of trichloroacetonitrile. The vessel was resealed and further heated at 130 ° C. for 2 hours. Upon completion, the concentrated reaction mixture was purified by flash silica gel chromatography (hexane / ethyl acetate) to yield the desired racemic oxadiazole I-155. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 415.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-156a及びI-156bを、ラセミ化合物I-113を出発酸として使用する以外は、実施例152と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝422.0m/z。活性：A。 (Example 153)

A procedure similar to that in Example 152 was used, except that 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-156a and I-156b were used as the starting acid racemic compound I-113. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 422.0 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-157a及びI-157bを、ラセミ化合物I-97を出発酸として使用する以外は、実施例152と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝407.2m/z。活性：A。 (Example 154)

A procedure similar to that in Example 152 was used, except that 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-157a and I-157b were used as racemic compound I-97 as the starting acid. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 407.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-158a及びI-158bを、以下の手順に従い、ラセミ酸I-113から調製した：アセチルヒドラジド(1.0当量)及び酸I-113(1.0当量)を、乾燥ジクロロメタン中に溶解し(各0.1M)、EDC(1.05当量)及びDMAP(0.10当量)で処理し、その後この反応混合物を、23℃で6時間攪拌した。反応が完了した後、これを過剰なジクロロメタン及び水と共に分液漏斗に希釈し、かつ有機層を、0.5Mクエン酸水溶液及び飽和炭酸水素ナトリウム水溶液で各々2回洗浄した。有機層を、硫酸マグネシウム上で乾燥し、白色固形物まで濃縮した。この固形物を、乾燥THF中に溶解し、かつ1.2当量ローソン試薬を添加した。混合物をチューブ内に密封し、マイクロ波用反応器内で115℃で30分間加熱した。濃縮された反応混合物を、フラッシュシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、所望のラセミ体チアジアゾールI-158を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝438.2m/z。活性：A。 Example 155

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-158a and I-158b were prepared from racemic acid I-113 according to the following procedure: acetyl hydrazide (1.0 eq) and acid I- 113 (1.0 eq) was dissolved in dry dichloromethane (0.1 M each) and treated with EDC (1.05 eq) and DMAP (0.10 eq), after which the reaction mixture was stirred at 23 ° C. for 6 h. After the reaction was complete, it was diluted into a separatory funnel with excess dichloromethane 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 1.2 eq. Lawesson's reagent was added. The mixture was sealed in a tube and heated at 115 ° C. for 30 minutes in a microwave reactor. The concentrated reaction mixture was purified by flash silica gel chromatography (hexane / ethyl acetate) to yield the desired racemic thiadiazole I-158. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 438.2 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-159a及びI-159bを、ラセミ化合物I-147を出発酸として使用する以外は、実施例152と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝413.6m/z。活性：A。 (Example 156)

3-phenoxy-4,5-dihydroisoxazole I-159a and I-159b were prepared using a procedure similar to Example 152 except that racemic compound I-147 was used as the starting acid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 413.6 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-160a及びI-160bは、ラセミ化合物I-146を出発酸として使用する以外は、実施例152と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝414.4m/z。活性：A。 (Example 157)

3-phenoxy-4,5-dihydroisoxazole I-160a and I-160b were prepared using a procedure similar to Example 152 except that racemic compound I-146 was used as the starting acid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 414.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-162a及びI-162bを、以下の手順に従い調製した：ラセミ体ジヒドロイソオキサゾールI-161を、化合物I-14及び6-ブロモピリジン-3-オールから、方法5を使用し、1工程で調製した。化合物I-161を、マイクロ波用バイアル内に配置し、次にジオキサン(0.02M)中に溶解した。2-(トリブチルスタンニル)チアゾール及びテトラキスパラジウムを添加し、この反応物をアルゴンでパージした。この時点で、この反応物を、マイクロ波用反応器内で20分間加熱し、その後TLC分析により出発物質は存在しなかった。この混合物を濃縮し、フラッシュシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、所望のラセミ体チアゾールI-162を収率50％で生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝407.3m/z。活性：A。 (Example 158)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-162a and I-162b were prepared according to the following procedure: Racemic dihydroisoxazole I-161 was prepared from compounds I-14 and 6- Prepared in 1 step from bromopyridin-3-ol using Method 5. Compound I-161 was placed in a microwave vial and then dissolved in dioxane (0.02M). 2- (Tributylstannyl) thiazole and tetrakis palladium were added and the reaction was purged with argon. At this point, the reaction was heated in a microwave reactor for 20 minutes, after which no starting material was present by TLC analysis. The mixture was concentrated and purified by flash silica gel chromatography (hexane / ethyl acetate) to give the desired racemic thiazole I-162 in 50% yield. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 407.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-163a及びI-163bは、2-(トリブチルスタンニル)オキサゾールを、2-(トリブチルスタンニル)チアゾールの代わりに使用する以外は、実施例158と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝393.2m/z。活性：A。 (Example 159)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-163a and I-163b, except that 2- (tributylstannyl) oxazole is used instead of 2- (tributylstannyl) thiazole Was prepared using the same procedure as Example 158. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 393.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-164a及びI-164bは、出発物質としてラセミ化合物I-75を化合物I-14の代わりに使用する以外は、実施例158と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝423.4m/z。活性：A。 (Example 160)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-164a and I-164b are the same as in Example 158 except that racemic compound I-75 is used in place of compound I-14 as the starting material. Prepared using a similar procedure. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 423.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-165a及びI-165bを、以下の手順に従い調製した：ラセミ体ジヒドロイソオキサゾールI-161及び炭酸ナトリウム(10.0当量)を、マイクロ波用バイアル内に配置した。トルエン、エタノール及び水の2:2:1混合液(I-161に対して0.02M)を添加し、引き続き4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルボロン酸(1.5当量)を添加した。この混合物を、Arで20分間パージし、この時点の後、テトラキスパラジウム(4mol％)を添加し、この反応物を密封し、かつ油浴中で80℃で17時間加熱した。次に反応混合物を冷却し、その後過剰な酢酸エチル及び水と共に分液漏斗に移した。有機層を、水及び飽和塩化ナトリウムで洗浄した。水層を、酢酸エチルで戻し抽出した。有機層を一緒にし、硫酸ナトリウム上で乾燥し、濃縮し、粗油状物を生じ、これをフラッシュシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、所望のラセミ体ピラゾールI-165を収率36％で生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.4m/z。活性：C。 (Example 161)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-165a and I-165b were prepared according to the following procedure: Racemic dihydroisoxazole I-161 and sodium carbonate (10.0 equiv.) Placed in microwave vial. Add a 2: 2: 1 mixture of toluene, ethanol and water (0.02M to I-161) followed by 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) -1H-pyrazole-1-carboxylic acid tert-butylboronic acid (1.5 eq) was added. The mixture was purged with Ar for 20 minutes, after which time tetrakis palladium (4 mol%) was added, the reaction was sealed and heated in an oil bath at 80 ° C. for 17 hours. The reaction mixture was then cooled and then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride. The aqueous layer was back extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and concentrated to give a crude oil, which is purified by flash silica gel chromatography (hexane / ethyl acetate) to yield the desired racemic pyrazole I-165 in 36% yield. %. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.4 m / z. Activity: C.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-166a及びI-166bを、ラセミ化合物1及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。[M-H]-＝241.5m/z。活性：B。 (Example 162)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-166a and I-166b were prepared from racemate 1 and 5-hydroxypyrimidine in one step using Method 5. [MH]-= 241.5 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-167a及びI-167bを、ラセミ化合物I-75を出発物質ブロモ-イソオキサゾールとして使用する以外は、実施例132の化合物I-135と同様の様式で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝417.3m/z。活性：A。 (Example 163)

Compound I of Example 132 except that 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-167a and I-167b were used racemic compound I-75 as the starting material bromo-isoxazole. -Prepared in the same manner as -135. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 417.3 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-168a及びI-168bを、1-(トリフルオロメチル)-4-ビニルベンゼンから、方法1からの付加環化条件を使用する、2工程で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、5-ヒドロキシピリミジンと反応させ、ラセミ化合物I-168を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝309.8m/z。活性：B。 (Example 164)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-168a and I-168b from 1- (trifluoromethyl) -4-vinylbenzene using cycloaddition conditions from Method 1 Prepared in two steps. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using Method 5 to give racemic compound I-168. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 309.8 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-169a及びI-169bを、1-(トリフルオロメチル)-4-ビニルベンゼンから、方法1からの付加環化条件を使用する、3工程で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、6-(メチルチオ)ピリジン-3-オール(方法11を使用し6-(メチルチオ)ピリジン-3-イルボロン酸から調製)と反応させ、引き続き実施例130に類似した条件下で酸化した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝387.2m/z。活性：A。 Example 165

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-169a and I-169b from 1- (trifluoromethyl) -4-vinylbenzene using cycloaddition conditions from Method 1 Prepared in 3 steps. The resulting bromo-4,5-dihydroisoxazole was prepared using method 5 and 6- (methylthio) pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11). And subsequently oxidized under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 387.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-170a及びI-170bを、1-(トリフルオロメチル)-4-ビニルベンゼンから、方法5からの付加環化条件を使用する、3工程で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、5-ヒドロキシピコリン酸メチルエステルと反応させ、引き続き実施例94に類似した条件下で加水分解した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝353.0m/z。活性：A。 Example 166

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-170a and I-170b from 1- (trifluoromethyl) -4-vinylbenzene using cycloaddition conditions from Method 5 Prepared in 3 steps. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5 and subsequently hydrolyzed under conditions similar to Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 353.0 m / z. Activity: A.

1-(4,5-ジヒドロイソオキサゾール-3-イル)-1H-1,2,4-トリアゾール-3-カルボン酸I-171a及びI-171bは、ラセミ化合物I-75を出発ブロモ-イソオキサゾールとして、及び1H-1,2,4-トリアゾール-3-カルボン酸メチルエステルを求核試薬として使用する以外は、実施例35と同様の手順を使用し調製した。加えて、この反応又は後処理の過程のいずれかの時点で、エステルを、対応する酸に加水分解した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝356.6m/z。活性：C。 (Example 167)

1- (4,5-Dihydroisoxazol-3-yl) -1H-1,2,4-triazole-3-carboxylic acid I-171a and I-171b were prepared from bromo-isoxazole starting from racemic compound I-75. And 1H-1,2,4-triazole-3-carboxylic acid methyl ester was used using the same procedure as Example 35, except that it was used as the nucleophile. In addition, at some point during this reaction or work-up, the ester was hydrolyzed to the corresponding acid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 356.6 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-172a及びI-172bを、ラセミ化合物I-75及びピラゾロ[1,5-α]ピリジン-2-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝378.1m/z。活性：C。 Example 168

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-172a and I-172b were prepared from racemic compound I-75 and pyrazolo [1,5-α] pyridin-2-ol by the method 5. Used and prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 378.1 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-173a及びI-173bを、2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピロール-1-カルボン酸tert-ブチルを、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は、実施例161と同様の手順を使用し調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝390.6m/z。活性：A。 (Example 169)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-173a and I-173b were converted to 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) -1H-pyrrole-1-carboxylate tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate Prepared using a procedure similar to that of Example 161 except that it was used instead of tert-butyl acid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 390.6 m / z. Activity: A.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-174a及びI-174bを、ラセミ化合物I-14及び3-(1H-テトラゾール-5-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.3m/z。活性：B。 (Example 170)

3-Phenoxy-4,5-dihydroisoxazoles I-174a and I-174b were prepared from racemic compounds I-14 and 3- (1H-tetrazol-5-yl) phenol in one step using Method 5. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.3 m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-175a及びI-175bを、ラセミ化合物I-14及び4-(1H-テトラゾール-5-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝391.6m/z。活性：B。 (Example 171)

3-Phenoxy-4,5-dihydroisoxazoles I-175a and I-175b were prepared from racemic compounds I-14 and 4- (1H-tetrazol-5-yl) phenol in one step using Method 5. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 391.6 m / z. Activity: B.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-176a及びI-176bを、ラセミ化合物I-14から、2工程で調製した。ブロモ-4,5-ジヒドロイソオキサゾールI-14を、方法5を使用し、3-ヒドロキシ安息香酸メチルエステルと反応させ、引き続き実施例94と類似の条件を用いて加水分解した。[M+H]+＝368.0m/z。活性：C。 (Example 172)

3-phenoxy-4,5-dihydroisoxazole I-176a and I-176b were prepared from racemic compound I-14 in two steps. Bromo-4,5-dihydroisoxazole I-14 was reacted with 3-hydroxybenzoic acid methyl ester using Method 5 and subsequently hydrolyzed using conditions similar to Example 94. [M + H] + = 368.0 m / z. Activity: C.

3-フェノキシ-4,5-ジヒドロイソオキサゾールI-177a及びI-177bを、ラセミ化合物I-14から、2工程で調製した。ブロモ-4,5-ジヒドロイソオキサゾールI-14を、方法5を使用し、4-ヒドロキシ安息香酸メチルエステルと反応させ、引き続き実施例94と類似の条件を用いて加水分解した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝368.0m/z。活性：B。 (Example 173)

3-phenoxy-4,5-dihydroisoxazole I-177a and I-177b were prepared from racemic compound I-14 in two steps. Bromo-4,5-dihydroisoxazole I-14 was reacted with 4-hydroxybenzoic acid methyl ester using Method 5 and subsequently hydrolyzed using conditions similar to Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 368.0 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-178a及びI-178bを、5-ヒドロキシピコリノニトリルを5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピコリノニトリルから方法11を使用し調製した後、方法5を使用し、ラセミ化合物I-14及び5-ヒドロキシピコリノニトリルから、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝350.0m/z。活性：B。 Example 174

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-178a and I-178b were converted to 5-hydroxypicolinonitrile 5- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) picolinonitrile was prepared using Method 11 and then using Method 5 from racemic compound I-14 and 5-hydroxypicolinonitrile in two steps. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 350.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-179a及びI-179bを、1-ペンチル-4-ビニルベンゼンから、方法1を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝283.6m/z。活性：A。 (Example 175)

3-Bromo-4,5-dihydroisoxazole I-179a and I-179b were prepared from 1-pentyl-4-vinylbenzene using Method 1 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 283.6 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-180a及びI-180bを、ラセミ化合物I-179及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝298.7m/z。活性：A。 (Example 176)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-180a and I-180b were prepared from racemic compound I-179 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 298.7 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-181a及びI-181bを、ラセミ化合物I-179から、最初に方法5を使用し化合物I-179を6-(メチルチオ)ピリジン-3-オール(方法11を使用し6-(メチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝375.4m/z。活性：A。 (Example 177)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-181a and I-181b are obtained from racemic compound I-179, first using method 5 to convert compound I-179 to 6- (methylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using Method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 375.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-182a及びI-182bを、ラセミ化合物I-14から、最初に方法5を使用し化合物I-14を6-(エチルチオ)ピリジン-3-オール(方法11を使用し6-(エチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝417.1m/z。活性：A。 (Example 178)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-182a and I-182b are prepared from racemic compound I-14, first using method 5 to convert compound I-14 to 6- (ethylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (ethylthio) pyridin-3-ylboronic acid using Method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 417.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾール I-183a及びI-183bを、ラセミ化合物I-14から、最初に方法5を使用し化合物I-14を6-(シクロペンチルチオ)ピリジン-3-オール(方法11を使用し6-(シクロペンチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝456.8m/z。活性：B。 (Example 179)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-183a and I-183b are obtained from racemic compound I-14, using method 5 first to convert compound I-14 to 6- (cyclopentylthio Prepared in two steps, reacted with pyridin-3-ol (prepared from 6- (cyclopentylthio) pyridin-3-ylboronic acid using Method 11) and subsequently oxidized under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 456.8 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-184a及びI-184bを、ラセミ化合物I-14から、最初に方法5を使用し化合物I-14を6-(イソ-ブチルチオ)ピリジン-3-オール(方法11を使用し6-(イソ-ブチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝444.7m/z。活性：B。 (Example 180)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-184a and I-184b are obtained from racemic compound I-14, first using method 5 to convert compound I-14 to 6- (iso- Prepared in 2 steps, reacted with (butylthio) pyridin-3-ol (prepared from 6- (iso-butylthio) pyridin-3-ylboronic acid using Method 11) and subsequently oxidized under conditions similar to Example 130 did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 444.7 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-185a及びI-185bは、ラセミ化合物I-75を、出発物質として化合物I-75の代わりに、及び2-(トリブチルスタンニル)オキサゾールを2-(トリブチルスタンニル)チアゾールの代わりに使用する(実施例158のように)以外は実施例178と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝407.2m/z。活性：A。 (Example 181)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-185a and I-185b are prepared from racemic compound I-75 as starting material instead of compound I-75 and 2- (tributylstan Prepared using a procedure similar to Example 178 except that (nyl) oxazole was used in place of 2- (tributylstannyl) thiazole (as in Example 158). These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 407.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾール I-186a及びI-186bは、2-フリルボロン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+Η]+＝392.2m/z。活性：A。 (Example 182)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-186a and I-186b represent 2-furylboronic acid as 4- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1H-pyrazole-1- Prepared using the same procedure as in Example 161 except that it was used instead of tert-butyl carboxylate. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + Η] + = 392.2m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-187a及びI-187bは、5-メチルフラン-2-イルボロン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.3m/z。活性：A。 (Example 183)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-187a and I-187b are 5-methylfuran-2-ylboronic acid converted to 4- (4,4,5,5-tetramethyl- Prepared using a procedure similar to that of Example 161 except that it was used instead of tert-butyl 1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールの鏡像異性体I-188a及びI-188bは、5-ボロノフラン-2-カルボン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝435.5m/z。活性：C。 (Example 184)

The enantiomers I-188a and I-188b of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole represent 5-boronofuran-2-carboxylic acid as 4- (4,4,5,5- Prepared using a procedure similar to that of Example 161 except that it was used instead of tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 435.5 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-189a及びI-189bは、1-メチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールを4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.2m/z。活性：A。 (Example 185)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-189a and I-189b are 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2- Of dioxaborolan-2-yl) -1H-pyrazole to tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate Prepared using a procedure similar to that of Example 161 except that it was used instead. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-190a及びI-190bは、1,3-ジメチル-1H-ピラゾール-5-イルボロン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝419.4m/z。活性：A。 (Example 186)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-190a and I-190b represent 1,3-dimethyl-1H-pyrazol-5-ylboronic acid as 4- (4,4,5, Prepared using a procedure similar to that of Example 161 except that it was used instead of tert-butyl 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 419.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-191a及びI-191bは、1-メチル-3-(トリフルオロメチル)-1H-ピラゾール-5-イルボロン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝473.3m/z。活性：C。 (Example 187)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-191a and I-191b represent 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ylboronic acid as 4- ( The same procedure as in Example 161 was used, except that 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate was used instead of tert-butyl. Used and prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 473.3 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-192a及びI-192bは、1H-ピラゾール-5-イルボロン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝391.4m/z。活性：A。 (Example 188)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-192a and I-192b represent 1H-pyrazol-5-ylboronic acid as 4- (4,4,5,5-tetramethyl-1 , 3,2-Dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate was prepared using the same procedure as in Example 161 except that it was used instead of tert-butyl. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 391.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-193a及びI-193bは、5-ボロノチオフェン-2-カルボン酸を4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝450.6m/z。活性：B。 (Example 189)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-193a and I-193b are 5-boronothiophene-2-carboxylic acid 4- (4,4,5,5-tetramethyl Prepared using a procedure similar to that of Example 161 except that it was used instead of tert-butyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 450.6 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-194a及びI-194bを、以下の手順に従い調製した：ラセミ体ジヒドロイソオキサゾールI-161、三塩基性リン酸カリウム(3.0当量)、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)イソオキサゾール(1.2当量)、及びパラジウム触媒(10mol％)を、マイクロ波用バイアル内に配置した。ジオキサン(I-161に対して0.1M)を添加し、この混合物を、Arで20分間パージし、この時点の後、この反応物を密封し、油浴中で85℃で17時間加熱した。その後反応混合物を冷やし、その後これを過剰な酢酸エチル及び水と共に分液漏斗に移した。有機層を水及び飽和塩化ナトリウムで洗浄した。水層を、酢酸エチルで戻し抽出した。これらの有機層を一緒にし、硫酸ナトリウム上で乾燥し、濃縮し、粗油状物を生じ、フラッシュシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、所望のラセミ体ピラゾールI-194を収率＜5％で生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.2m/z。活性：A。 (Example 190)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-194a and I-194b were prepared according to the following procedure: racemic dihydroisoxazole I-161, tribasic potassium phosphate (3.0 Equivalent)), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole (1.2 eq), and palladium catalyst (10 mol%) in a microwave vial. Arranged. Dioxane (0.1M relative to I-161) was added and the mixture was purged with Ar for 20 minutes, after which time the reaction was sealed and heated in an oil bath at 85 ° C. for 17 hours. The reaction mixture was then cooled and then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride. The aqueous layer was back extracted with ethyl acetate. These organic layers were combined, dried over sodium sulfate and concentrated to give a crude oil that was purified by flash silica gel chromatography (hexane / ethyl acetate) to yield the desired racemic pyrazole I-194 in < Occurs at 5%. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-195a及びI-195bを、以下の手順に従い調製した：ラセミ体ジヒドロイソオキサゾールI-178(1.0当量)を、N,N-ジメチルホルムアミド(イソオキサゾールに対して0.1M)中に溶解し、その後塩化アンモニウム(3.1当量)及びアジ化ナトリウム(1.5当量)を添加した。次にこの反応物を、油浴で120℃で4時間加熱し、この時点の後、この反応物を、過剰な酢酸エチル及び水と共に分液漏斗へ移した。この有機層を、水及び飽和塩化ナトリウムで洗浄し、硫酸ナトリウム上で乾燥し、かつ濃縮し、粗油状物を生じ、これをフラッシュシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)により精製し、所望のラセミ体テトラゾールI-195を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝393.2m/z。活性：A。 (Example 191)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-195a and I-195b were prepared according to the following procedure: Racemic dihydroisoxazole I-178 (1.0 equiv.) Was added N, N -Dissolved in dimethylformamide (0.1 M relative to isoxazole), followed by addition of ammonium chloride (3.1 eq) and sodium azide (1.5 eq). The reaction was then heated in an oil bath at 120 ° C. for 4 hours, after which time the reaction was transferred to a separatory funnel with excess ethyl acetate and water. The organic layer is washed with water and saturated sodium chloride, dried over sodium sulfate and concentrated to give a crude oil which is purified by flash silica gel chromatography (hexane / ethyl acetate) to give the desired racemic. The body tetrazole I-195. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 393.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-196a及びI-196bを、ラセミ化合物I-75から、最初に方法5を使用し化合物I-75を6-(エチルチオ)ピリジン-3-オール(方法11を使用し6-(エチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝431.3m/z。活性：A。 (Example 192)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-196a and I-196b are obtained from racemic compound I-75, first using method 5 to convert compound I-75 to 6- (ethylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (ethylthio) pyridin-3-ylboronic acid using Method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 431.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-197a及びI-197bを、ラセミ化合物I-10から、最初に方法5を使用し化合物I-10を6-(メチルチオ)ピリジン-3-オール(方法11を使用し6-(メチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝411.4m/z。活性：A。 (Example 193)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-197a and I-197b are obtained from racemic compound I-10, first using method 5 to convert compound I-10 to 6- (methylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using Method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 411.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-198a及びI-198bを、6-(1H-ピラゾール-1-イル)ピリジン-3-オールを2-(1H-ピラゾール-1-イル)-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジンから方法11を使用し合成した後、ラセミ化合物I-75及び6-(1H-ピラゾール-1-イル)ピリジン-3-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝405.3m/z。活性：A。 (Example 194)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-198a and I-198b were converted to 6- (1H-pyrazol-1-yl) pyridin-3-ol 2- (1H-pyrazol- 1-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine was synthesized using method 11, followed by racemic compounds I-75 and 6- Prepared in 1 step from (1H-pyrazol-1-yl) pyridin-3-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 405.3 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-199a及びI-199bを、ラセミ化合物I-14及び3-(3-メチル-1,2,4-オキサジアゾール-5-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.3m/z。活性：C。 (Example 195)

3- (phenoxy) -4,5-dihydroisoxazole I-199a and I-199b were converted to racemic compounds I-14 and 3- (3-methyl-1,2,4-oxadiazol-5-yl) phenol Was prepared in one step using method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.3 m / z. Activity: C.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-200a及びI-200bを、ラセミ化合物I-14及び4-(2-メチル-2H-テトラゾール-5-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.4m/z。活性：B。 (Example 196)

Use 3- (phenoxy) -4,5-dihydroisoxazole I-200a and I-200b from racemic compounds I-14 and 4- (2-methyl-2H-tetrazol-5-yl) phenol And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.4 m / z. Activity: B.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-201a及びI-201bを、ラセミ化合物I-14及び4-(1,3,4-オキサジアゾール-2-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.2m/z。活性：A。 (Example 197)

3- (phenoxy) -4,5-dihydroisoxazole I-201a and I-201b were prepared from racemic compounds I-14 and 4- (1,3,4-oxadiazol-2-yl) phenol by method 5 And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.2 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-202a及びI-202bを、以下の手順に従い、2工程で調製した：4-ビニルベンゾイルクロリド(1.0当量)を、塩化メチレン(スチレンに対して0.375M)中に溶解し、その後モルホリン(3.0当量)を添加した。この反応物を、室温で14時間攪拌させ、その間に白色沈殿が形成され始めた。次にこの反応物を、過剰な水及び塩化メチレンと共に分液漏斗に移した。有機層を、水(1×)、1N HCl(1×)、飽和炭酸水素ナトリウム(1×)及びブライン(1×)で洗浄し、この時点の後これを硫酸ナトリウム上で乾燥し、濃縮し、黄色油状物を生じた。この粗物質を次に直接使い、所望のラセミ体ブロモイソオキサゾールを方法1を使用し形成した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝338.7m/z。活性：B。 (Example 198)

3-Bromo-4,5-dihydroisoxazole I-202a and I-202b were prepared in two steps according to the following procedure: 4-Vinylbenzoyl chloride (1.0 eq) was added methylene chloride (0.375 to styrene). M) and then morpholine (3.0 eq) was added. The reaction was allowed to stir at room temperature for 14 hours during which time a white precipitate began to form. The reaction was then transferred to a separatory funnel with excess water and methylene chloride. The organic layer is washed with water (1 ×), 1N HCl (1 ×), saturated sodium bicarbonate (1 ×) and brine (1 ×), after which time it is dried over sodium sulfate and concentrated. Yielded 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 338.7 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-203a及びI-203bは、テトラヒドロフラン中のジメチルアミン(2.0M)をモルホリンの代わりに使用する以外は実施例198と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝299.3m/z。活性：A。 (Example 199)

3-Bromo-4,5-dihydroisoxazole I-203a and I-203b were prepared using a procedure similar to Example 198 except that dimethylamine (2.0 M) in tetrahydrofuran was used instead of morpholine. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 299.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-204a及びI-204bは、テトラヒドロフラン中のメチルアミン(2.0M)をモルホリンの代わりに使用する以外は実施例198と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝282.6m/z。活性：B。 (Example 200)

3-Bromo-4,5-dihydroisoxazole I-204a and I-204b were prepared using a procedure similar to Example 198 except that methylamine (2.0 M) in tetrahydrofuran was used instead of morpholine. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 282.6 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-205a及びI-205bを、以下の手順に従い2工程で調製した：4-ビニルベンゼン-1-スルホニルクロリド(1.0当量)を、塩化メチレン(スチレンに対して0.50M)中に溶解し、その後モルホリン(3.0当量)を添加した。この反応物を室温で90分間攪拌し、この時点の後これを、過剰な水及び塩化メチレンと共に分液漏斗へ移した。有機層を、水(1×)、1N HCl(1×)、飽和炭酸水素ナトリウム(1×)及びブライン(1×)で洗浄し、この時点の後これを硫酸ナトリウム上で乾燥し、かつ濃縮し、黄色油状物を生じた。この粗物質を次に直接使い、所望のラセミ体ブロモイソオキサゾールを方法1を使用し形成した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝374.6m/z。活性：A。 (Example 201)

3-Bromo-4,5-dihydroisoxazole I-205a and I-205b were prepared in two steps according to the following procedure: 4-vinylbenzene-1-sulfonyl chloride (1.0 eq) was added to methylene chloride (to styrene). Relative to 0.50M) followed by the addition of morpholine (3.0 equivalents). The reaction was stirred at room temperature for 90 minutes after which time it was transferred to a separatory funnel with excess water and methylene chloride. The organic layer is washed with water (1 ×), 1N HCl (1 ×), saturated sodium bicarbonate (1 ×) and brine (1 ×), after which time it is dried over sodium sulfate and concentrated. To yield 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 374.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-206a及びI-206bは、THF中のジメチルアミン(2.0M)をモルホリンの代わりに使用する以外は実施例201と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝332.6m/z。活性：A。 (Example 202)

3-Bromo-4,5-dihydroisoxazole I-206a and I-206b were prepared using the same procedure as Example 201 except that dimethylamine (2.0 M) in THF was used instead of morpholine. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 332.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-207a及びI-207bは、THF中のメチルアミン(2.0M)をモルホリンの代わりに使用する以外は実施例201と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝318.6m/z。活性：A。 (Example 203)

3-Bromo-4,5-dihydroisoxazole I-207a and I-207b were prepared using the same procedure as Example 201, except that methylamine (2.0M) in THF was used instead of morpholine. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 318.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-208a及びI-208bは、ピペリジンをモルホリンの代わりに使用する以外は実施例198と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝339.3m/z。活性：A。 (Example 204)

3-Bromo-4,5-dihydroisoxazole I-208a and I-208b were prepared using a procedure similar to Example 198 except that piperidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 339.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-209a及びI-209bは、ピロリジンをモルホリンの代わりに使用する以外は実施例198と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝322.6m/z。活性：A。 Example 205

3-Bromo-4,5-dihydroisoxazole I-209a and I-209b were prepared using a procedure similar to Example 198 except that pyrrolidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 322.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-210a及びI-210bは、ピペリジンをモルホリンの代わりに使用する以外は実施例201と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝472.6m/z。活性：A。 Example 206

3-Bromo-4,5-dihydroisoxazole I-210a and I-210b were prepared using a procedure similar to Example 201, except that piperidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 472.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールI-211a及びI-211bは、ピロリジンをモルホリンの代わりに使用する以外は実施例201と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝358.6m/z。活性：A。 (Example 207)

3-Bromo-4,5-dihydroisoxazole I-211a and I-211b were prepared using a procedure similar to Example 201 except that pyrrolidine was used instead of morpholine. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 358.6m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-212a及びI-212bを、ラセミ化合物I-203から、最初に方法5を使用し化合物I-203を6-(メチルチオ)ピリジン-3-オール(6-(メチルチオ)ピリジン-3-イルボロン酸から方法11を使用して調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝390.4m/z。活性：B。 (Example 208)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-212a and I-212b are obtained from racemic compound I-203 by first using method 5 to convert compound I-203 to 6- (methylthio). Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 390.4 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-213a及びI-213bを、ラセミ化合物I-202から、最初に方法5を使用し化合物I-202を6-(メチルチオ)ピリジン-3-オール(6-(メチルチオ)ピリジン-3-イルボロン酸から方法11を使用して調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝426.2m/z。活性：A。 (Example 209)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-213a and I-213b are obtained from racemic compound I-202, first using method 5 to convert compound I-202 to 6- (methylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 426.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-214a及びI-214bを、ラセミ化合物I-21から、最初に方法5を使用し化合物I-21を6-(メチルチオ)ピリジン-3-オール(6-(メチルチオ)ピリジン-3-イルボロン酸から方法11を使用して調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝352.2m/z。活性：A。 (Example 210)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-214a and I-214b are prepared from racemic compound I-21, first using method 5 to convert compound I-21 to 6- (methylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 352.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-215a及びI-215bを、ラセミ化合物I-21からの化合物の2工程で調製した。ブロモ-4,5-ジヒドロイソオキサゾールI-21を、方法5を使用し、5-ヒドロキシピコリン酸メチルエステルと反応させ、引き続き実施例94と類似の条件を使用し加水分解した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝418.3m/z。活性：B。 (Example 211)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-215a and I-215b were prepared in two steps of the compound from racemic compound I-21. Bromo-4,5-dihydroisoxazole I-21 was reacted with 5-hydroxypicolinic acid methyl ester using Method 5, followed by hydrolysis using conditions similar to Example 94. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 418.3 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-216a及びI-216bを、1-(トリフルオロメチル)-4-ビニルベンゼンから、方法1からの付加環化条件を使用する2工程で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、2-ブロモ-5-ヒドロキシピリジンと反応させ、ラセミ化合物I-216を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝389.1m/z。活性：B。 (Example 212)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-216a and I-216b from 1- (trifluoromethyl) -4-vinylbenzene using cycloaddition conditions from Method 1 Prepared in two steps. The resulting bromo-4,5-dihydroisoxazole was reacted with 2-bromo-5-hydroxypyridine using Method 5 to give racemic compound I-216. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 389.1 m / z. Activity: B.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-217a及びI-217bを、3-(1,3,4-オキサジアゾール-2-イル)フェノールを2-ブロモ-5-ヒドロキシピリジンの代わりに使用する以外は実施例212と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝376.4m/z。活性：A。 (Example 213)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-217a and I-217b were replaced with 3- (1,3,4-oxadiazol-2-yl) phenol 2-bromo-5 Prepared using a procedure similar to that in Example 212 except that it was used in place of -hydroxypyridine. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 376.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-218a及びI-218bを、1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールを4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝404.8m/z。活性：A。 (Example 214)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-218a and I-218b were converted to 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2- Of dioxaborolan-2-yl) -1H-pyrazole to tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate Prepared using a procedure similar to that of Example 161 except that it was used instead. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 404.8 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-219a及びI-219bを、1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールを4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボン酸tert-ブチルの代わりに使用し、かつラセミ体ブロモピリジンI-216を化合物I-161ではなく出発物質として使用する以外は実施例161と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝390.3m/z。活性：A。 (Example 215)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-219a and I-219b were converted to 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2- Of dioxaborolan-2-yl) -1H-pyrazole to tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate Prepared using a similar procedure as Example 161 except that it was used instead and racemic bromopyridine I-216 was used as the starting material instead of compound I-161. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 390.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-220a及びI-220bを、以下の手順に従い調製した：酸I-97(1.0当量)を、塩化メチレン(0.08M)中に溶解した。塩化オキサリル(1.5当量)を添加し、引き続きN,N-ジメチルホルムアミド1滴を添加した。この反応物を、室温で20分間攪拌し、その後これを真空下で濃縮した。次にこの粗物質を、塩化メチレン中に再溶解し、その後メタンスルホンアミド(1.2当量)、DMAP(10mol％)及びトリエチルアミン(1.5当量)を添加した。3時間後、反応が完了したことをLC/MS分析により決定した。次に反応混合物を、過剰な酢酸エチル及び水と共に、分液漏斗へ移した。有機層を、1N HCl及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、所望のスルホンアミドを生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝446.1m/z。活性：A。 (Example 216)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-220a and I-220b were prepared according to the following procedure: Acid I-97 (1.0 eq) in methylene chloride (0.08M) Dissolved in. Oxalyl chloride (1.5 eq) was added followed by 1 drop of N, N-dimethylformamide. The reaction was stirred at room temperature for 20 minutes before it was concentrated in vacuo. The crude material was then redissolved in methylene chloride, after which methanesulfonamide (1.2 eq), DMAP (10 mol%) and triethylamine (1.5 eq) were added. After 3 hours, it was determined by LC / MS analysis that the reaction was complete. 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 yield the desired sulfonamide. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 446.1 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾール I-221a及びI-221bを、ラセミ化合物I-14及び3-(4H-1,2,4-トリアゾール-4-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.0m/z。活性：C。 (Example 217)

3- (phenoxy) -4,5-dihydroisoxazole I-221a and I-221b were prepared from racemic compounds I-14 and 3- (4H-1,2,4-triazol-4-yl) phenol by method 5 And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.0 m / z. Activity: C.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-222a及びI-222bを、以下の手順に従い3工程で調製した：3-ヒドロキシ安息香酸メチルエステルを、方法5を使用し、ラセミ体ブロモイソオキサゾールI-75と反応させた。得られたメチルエステル(1.0当量)を、メタノール(0.08M)中に溶解し、その後ヒドラジン(50当量、水中50重量％)を添加し、この反応物を14時間攪拌させた。次に反応混合物を、真空下で濃縮し、直接次工程で使用した。オルト酢酸トリエチル(8.0当量)を添加し、この反応物を密封し、かつ14時間還流加熱した。この反応物を次に、過剰な酢酸エチル及び水と共に、分液漏斗へ移した。有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)を使用し精製し、所望のラセミ体オキサジアゾールI-222を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝420.5m/z。活性：A。 (Example 218)

3- (Phenoxy) -4,5-dihydroisoxazole I-222a and I-222b were prepared in 3 steps according to the following procedure: 3-hydroxybenzoic acid methyl ester was prepared using racemic bromo using method 5. Reacted with isoxazole I-75. The resulting methyl ester (1.0 eq) was dissolved in methanol (0.08M), followed by the addition of hydrazine (50 eq, 50 wt% in water) and the reaction was allowed to stir for 14 hours. The reaction mixture was then concentrated in vacuo and used directly in the next step. Triethyl orthoacetate (8.0 eq) was added and the reaction was sealed and heated to reflux for 14 hours. The reaction was then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give the crude material which is purified using flash silica gel chromatography (ethyl acetate / hexane gradient) to give the desired Of racemic oxadiazole I-222. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 420.5 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-223a及びI-223bを、ラセミ化合物I-15を、出発物質として化合物I-75の代わりに使用する以外は実施例218と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.5m/z。活性：A。 (Example 219)

Procedure similar to Example 218 except that 3- (phenoxy) -4,5-dihydroisoxazole I-223a and I-223b were used racemic compound I-15 instead of compound I-75 as starting material. Was used to prepare. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.5 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-224a及びI-224bを、以下の手順に従い3工程で調製した：3-フルオロ-5-ヒドロキシ安息香酸メチルエステルを、方法5を使用し、ラセミ体ブロモイソオキサゾールI-14と反応させた。得られたメチルエステル(1.0当量)を、メタノール(0.08M)中に溶解し、その後ヒドラジン(50当量、水中50重量％)を添加し、この反応物を14時間攪拌させた。次に反応混合物を、真空下で濃縮し、直接次工程で使用した。オルト酢酸トリエチル(8.0当量)を添加し、この反応物を密封し、かつ14時間還流加熱した。この反応物を次に、過剰な酢酸エチル及び水と共に、分液漏斗へ移した。有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)を使用し精製し、所望のラセミ体オキサジアゾールI-224を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝424.5m/z。活性：A。 (Example 220)

3- (Phenoxy) -4,5-dihydroisoxazole I-224a and I-224b were prepared in 3 steps according to the following procedure: 3-Fluoro-5-hydroxybenzoic acid methyl ester was prepared using Method 5. And reacted with racemic bromoisoxazole I-14. The resulting methyl ester (1.0 eq) was dissolved in methanol (0.08M), followed by the addition of hydrazine (50 eq, 50 wt% in water) and the reaction was allowed to stir for 14 hours. The reaction mixture was then concentrated in vacuo and used directly in the next step. Triethyl orthoacetate (8.0 eq) was added and the reaction was sealed and heated to reflux for 14 hours. The reaction was then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give the crude material which is purified using flash silica gel chromatography (ethyl acetate / hexane gradient) to give the desired Of racemic oxadiazole I-224. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 424.5 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-225a及びI-225bを、オルトギ酸トリエチルをオルト酢酸トリエチルの代わりに使用する以外は実施例220と同様の手順を使用し、調製し、所望のオキサジアゾールを形成した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝410.3m/z。活性：A。 (Example 221)

3- (phenoxy) -4,5-dihydroisoxazole I-225a and I-225b were prepared using the same procedure as Example 220, except that triethyl orthoformate was used instead of triethyl orthoacetate, The desired oxadiazole was formed. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 410.3 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-226a及びI-226bを、第一の工程で4-フルオロ-5-ヒドロキシ安息香酸メチルエステルを3-フルオロ-5-ヒドロキシ安息香酸メチルエステルの代わりに使用する以外は実施例220と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝410.4m/z。活性：A。 (Example 222)

3- (phenoxy) -4,5-dihydroisoxazole I-226a and I-226b, 4-fluoro-5-hydroxybenzoic acid methyl ester in the first step, 3-fluoro-5-hydroxybenzoic acid methyl ester Prepared using a procedure similar to that of Example 220, except that was used instead of These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 410.4 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-227a及びI-227bを、ラセミ化合物I-75を出発物質として化合物I-14の代わりに使用する以外は実施例222と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝424.2m/z。活性：A。 (Example 223)

The same procedure as Example 222 was used, except that 3- (phenoxy) -4,5-dihydroisoxazole I-227a and I-227b were used in place of compound I-14 starting from racemic compound I-75. Used and prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 424.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-228a及びI-228bを、以下の手順に従い3工程で調製した：5-ヒドロキシニコチン酸メチルエステルを、方法5を使用し、ラセミ体ブロモイソオキサゾールI-75と反応させた。得られたメチルエステル(1.0当量)を、メタノール(0.08M)中に溶解し、その後ヒドラジン(50当量、水中50重量％)を添加し、この反応物を14時間攪拌させた。次に反応混合物を、真空下で濃縮し、直接次工程で使用した。オルトギ酸トリエチル(8.0当量)を添加し、この反応物を密封し、かつ14時間還流加熱した。この反応物を次に、過剰な酢酸エチル及び水と共に、分液漏斗へ移した。有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)を使用し精製し、所望のラセミ体オキサジアゾールI-228を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝407.5m/z。活性：A。 (Example 224)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-228a and I-228b were prepared in 3 steps according to the following procedure: 5-hydroxynicotinic acid methyl ester was prepared using Method 5. And reacted with racemic bromoisoxazole I-75. The resulting methyl ester (1.0 eq) was dissolved in methanol (0.08M), followed by the addition of hydrazine (50 eq, 50 wt% in water) and the reaction was allowed to stir for 14 hours. The reaction mixture was then concentrated in vacuo and used directly in the next step. Triethylorthoformate (8.0 eq) was added and the reaction was sealed and heated to reflux for 14 hours. The reaction was then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give the crude material which is purified using flash silica gel chromatography (ethyl acetate / hexane gradient) to give the desired Of racemic oxadiazole I-228. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 407.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-229a及びI-229bを、オルト酢酸トリエチルをオルトギ酸トリエチルの代わりに使用し、所望のオキサジアゾールを形成する以外は実施例224と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝422.0m/z。活性：A。 (Example 225)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-229a and I-229b were performed except that triethyl orthoacetate was used in place of triethyl orthoformate to form the desired oxadiazole. Prepared using a procedure similar to Example 224. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 422.0 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-230a及びI-230bを、ラセミ化合物I-14を出発物質として化合物75の代わりに使用する以外は実施例224と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝393.2m/z。活性：A。 (Example 226)

A procedure similar to that of Example 224 was used, except that 3- (phenoxy) -4,5-dihydroisoxazole I-230a and I-230b were used in place of compound 75 starting with racemic compound I-14. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 393.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾール I-231a及びI-231bを、以下の手順に従い3工程で調製した：5-ヒドロキシニコチン酸メチルエステルを、ラセミ体ブロモイソオキサゾールI-75と、方法5を使用し反応させた。得られたメチルエステル(1.0当量)を、メタノール(0.08M)中に溶解し、その後ヒドラジン(50当量、水中50重量％)を添加し、この反応物を14時間攪拌させた。次に反応混合物を、真空下で濃縮し、直接次工程で使用した。このヒドラジドを、ジオキサン(ヒドラジドに対して0.12M)中に溶解した。N,N-カルボニルジイミダゾール(carbonydiimidazole)(1.2当量)を添加し、かつこの反応物を密封し、4時間還流加熱した。この反応物を次に、過剰な酢酸エチル及び水と共に、分液漏斗へ移した。有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(メタノール/ジクロロメタン勾配)を使用し精製し、所望のラセミ体1,3,4-オキサジアゾール-2(3H)-オンI-231を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝423.4m/z。活性：B。 Example 227

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-231a and I-231b were prepared in 3 steps according to the following procedure: 5-hydroxynicotinic acid methyl ester was prepared as racemic bromoisoxazole. Reacted with I-75 using Method 5. The resulting methyl ester (1.0 eq) was dissolved in methanol (0.08M), followed by the addition of hydrazine (50 eq, 50 wt% in water) and the reaction was allowed to stir for 14 hours. The reaction mixture was then concentrated in vacuo and used directly in the next step. This hydrazide was dissolved in dioxane (0.12M relative to hydrazide). N, N-carbonydiimidazole (1.2 eq) was added and the reaction was sealed and heated to reflux for 4 hours. The reaction was then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give the crude material which is purified using flash silica gel chromatography (methanol / dichloromethane gradient) to give the desired This gave the racemic 1,3,4-oxadiazol-2 (3H) -one I-231. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 423.4 m / z. Activity: B.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-232a及びI-232bを、ラセミ化合物I-75及び4-(1,3,4-オキサジアゾール-2-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.5m/z。活性：A。 (Example 228)

3- (phenoxy) -4,5-dihydroisoxazole I-232a and I-232b were prepared from racemic compounds I-75 and 4- (1,3,4-oxadiazol-2-yl) phenol by method 5. And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.5 m / z. Activity: A.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-233a及びI-233bを、ラセミ化合物I-75及び3-ヒドロキシ-N,N-ジメチルベンゼンスルホンアミドから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝445.4m/z。活性：C。 (Example 229)

3- (phenoxy) -4,5-dihydroisoxazole I-233a and I-233b from racemic compound I-75 and 3-hydroxy-N, N-dimethylbenzenesulfonamide using method 5 in one step It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 445.4 m / z. Activity: C.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-234a及びI-234bを、ラセミ化合物I-75及び4-(メチルスルホニル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝415.6m/z。活性：B。 (Example 230)

3- (Phenoxy) -4,5-dihydroisoxazole I-234a and I-234b were prepared from racemic compound I-75 and 4- (methylsulfonyl) phenol in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 415.6 m / z. Activity: B.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-235a及びI-235bを、ラセミ化合物I-75及び4-ヒドロキシ-N,N-ジメチルベンゼンスルホンアミドから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝445.3m/z。活性：C。 (Example 231)

3- (phenoxy) -4,5-dihydroisoxazole I-235a and I-235b from racemic compound I-75 and 4-hydroxy-N, N-dimethylbenzenesulfonamide using method 5 in one step It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 445.3 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-236a及びI-236bを、以下の手順に従い3工程で調製した：ラセミ体ジヒドロイソオキサゾールI-161(1.0当量)を、N,N-ジメチルホルムアミド(0.1M)中に溶解した。ヨウ化銅(1.0当量)を添加し、引き続きトリメチルシリルアセチレン(3.0当量)及びN,N-ジイソプロピルエチルアミン(2.0当量)を添加した。テトラキスパラジウム(15mol％)を添加し、かつこの反応物を密封し、マイクロ波用反応器において100℃で1時間加熱した。この反応物を冷却し、その後これを酢酸エチル及び水と共に分液漏斗へ移した。次に有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、濃縮し、かつフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)により精製した。次にこの物質をメタノール(0.07M)中に溶解し、かつ炭酸カリウム(3.0当量)を添加することにより、TMS基を脱保護した。室温で4時間攪拌した後、この反応物を、酢酸エチル及び水と共に分液漏斗に移した。次に有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、濃縮し、かつフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)により精製した。得られたアルキンを次に、最初に無希釈のトリメチルシリルアジド(80当量)中に溶解し、この反応混合物をアルゴンでパージし、かつマイクロ波用反応器中で110℃で3時間加熱することにより、所望のトリアゾールに変換した。更に4時間加熱後、LC/MS分析によりこの反応が60％完了しており、この時点でこれを濃縮し、かつフラッシュシリカゲルクロマトグラフィー(メタノール/塩化メチレン勾配)により直接精製し、所望のラセミ体トリアゾールI-236を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.9m/z。活性：A。 (Example 232)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-236a and I-236b were prepared in 3 steps according to the following procedure: Racemic dihydroisoxazole I-161 (1.0 equiv.) Dissolved in N, N-dimethylformamide (0.1M). Copper iodide (1.0 eq) was added, followed by trimethylsilylacetylene (3.0 eq) and N, N-diisopropylethylamine (2.0 eq). Tetrakis palladium (15 mol%) was added and the reaction was sealed and heated at 100 ° C. for 1 hour in a microwave reactor. The reaction was cooled and then 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 silica gel chromatography (ethyl acetate / hexane gradient). This material was then dissolved in methanol (0.07M) and the TMS group was deprotected by adding potassium carbonate (3.0 eq). After stirring at room temperature for 4 hours, 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 silica gel chromatography (ethyl acetate / hexane gradient). The resulting alkyne is then first dissolved in undiluted trimethylsilyl azide (80 eq), the reaction mixture purged with argon and heated in a microwave reactor at 110 ° C. for 3 hours. Converted to the desired triazole. 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 silica gel chromatography (methanol / methylene chloride gradient) to give the desired racemate. This gave triazole I-236. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.9 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-237a及びI-237bを、ラセミ化合物I-148から、最初に方法5を使用し化合物I-148を6-(メチルチオ)ピリジン-3-オール(6-(メチルチオ)ピリジン-3-イルボロン酸から方法11を使用して調整)と反応させ、引き続き実施例130と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝396.6m/z。活性：A。 (Example 233)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-237a and I-237b are obtained from racemic compound I-148, first using method 5 to convert compound I-148 to 6- (methylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11) followed by oxidation under conditions similar to Example 130. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 396.6 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-238a及びI-238bを、1-(トリフルオロメチル)-4-ビニルベンゼンから、方法1からの付加環化条件を使用する2工程で調製した。得られたブロモ-4,5-ジヒドロイソオキサゾールを、方法5を使用し、6-(メチルチオ)ピリジン-3-オール(方法11を使用し6-(メチルチオ)ピリジン-3-イルボロン酸から調製)と反応させ、化合物I-238を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝355.3m/z。活性：A。 (Example 234)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-238a and I-238b from 1- (trifluoromethyl) -4-vinylbenzene using cycloaddition conditions from Method 1 Prepared in two steps. The resulting bromo-4,5-dihydroisoxazole was prepared using method 5 and 6- (methylthio) pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using method 11). To give compound I-238. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 355.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-240a及びI-240bを、以下の手順に従い2工程で調製した：6-ブロモピリジン-3-オール(1.0当量)及び炭酸ナトリウム(10.0当量)を、マイクロ波用バイアルに添加した。トルエン、エタノール、及び水(0.16M、2:2:1v/v)を添加し、引き続き1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(1.5当量)を添加した。この混合物を、アルゴンで15分間パージし、引き続きテトラキスパラジウム(4mol％)を添加した。次にこの反応チューブを、アルミ箔で覆い、かつ油浴中で80℃で17時間加熱した。冷却後、この反応物を、過剰な水及び酢酸エチルと共に、分液漏斗に移した。次に有機層を、水(1×)、飽和塩化アンモニウム(1×)及びブライン(1×)で洗浄した。水層を一緒にし、酢酸エチル(1×)で洗浄した。次に有機層を一緒にし、硫酸ナトリウム上で乾燥し、濃縮し、フラッシュシリカゲルクロマトグラフィー(メタノール/塩化メチレン勾配)を用いて精製し、6-(1-メチル-1H-ピラゾール-4-イル)ピリジン-3-オールI-239を白色固形物として生じた。この化合物を次に、方法5を使用し、ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-75と反応させ、所望のラセミ化合物I-240を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝419.3m/z。活性：A。 (Example 235)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-240a and I-240b were prepared in two steps according to the following procedure: 6-bromopyridin-3-ol (1.0 eq) and carbonic acid Sodium (10.0 equiv) was added to the microwave vial. Toluene, ethanol, and water (0.16M, 2: 2: 1 v / v) were added followed by 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -1H-pyrazole (1.5 eq) was added. The mixture was purged with argon for 15 minutes, followed by the addition of tetrakis palladium (4 mol%). The reaction tube was then covered with aluminum foil and heated in an oil bath at 80 ° C. for 17 hours. After cooling, the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with water (1 ×), saturated ammonium chloride (1 ×) and brine (1 ×). The aqueous layers were combined and washed with ethyl acetate (1 ×). The organic layers are then combined, dried over sodium sulfate, concentrated and purified using flash silica gel chromatography (methanol / methylene chloride gradient) to give 6- (1-methyl-1H-pyrazol-4-yl). Pyridin-3-ol I-239 was produced as a white solid. This compound was then reacted with racemic 3-bromo-4,5-dihydroisoxazole I-75 using Method 5 to yield the desired racemic compound I-240. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 419.3 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-241a及びI-241bは、1-メチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールを、最初の工程におけるボロン酸エステル(boronoate)として1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールの代わりに使用する以外は、実施例235と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.2m/z。活性：A。 (Example 236)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-241a and I-241b are 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) -1H-pyrazole as 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 as boronate ester in the first step -Yl) Prepared using a procedure similar to that in Example 235 except that it was used instead of 1H-pyrazole. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.2 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-242a及びI-242bは、ラセミ化合物I-75を、出発物質として化合物I-14の代わりに使用する以外は、実施例188と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝406.3m/z。活性：A。 (Example 237)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole I-242a and I-242b are examples except that racemic compound I-75 is used instead of compound I-14 as starting material. Prepared using a procedure similar to 188. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 406.3 m / z. Activity: A.

2-(4,5-ジヒドロイソオキサゾール-3-イルアミノ)エタノールI-243a及びI-243bを、以下の手順に従い2工程で調製した：ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-10(1.0当量)を、n-ブタノール(0.57M)中に溶解し、引き続き(tert-ブチルジメチルシリルオキシ)メタンアミン(1.2当量)及び炭酸ナトリウム(2.5当量)を添加した。この反応物を密封し、マイクロ波反応で、150℃で1時間加熱し、この時点の後、LC/MS分析により、生成物の形成はごくわずかであった。次にこの反応物を再度密封し、マイクロ波で120℃で更に24時間加熱し、この後過剰な水及びtert-ブチルメチルエーテルと共に、分液漏斗に移した。水層を、tert-ブチルメチルエーテル(2×)で洗浄し、一緒にした有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥し、濃縮し、オレンジ色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)を用いて精製し、所望のシリルエーテルを生じた。この化合物(1.0当量)を次にメタノール(0.02M)中に溶解し、氷浴内で0℃に冷却した。塩化アセチル(50当量)を滴加し、その後この反応物を0℃で30分間攪拌させた。その後溶媒及び残存する塩化アセチルを、窒素流れ下で除去し、この後粗物質をフラッシュシリカゲルクロマトグラフィー(酢酸エチル/メタノール勾配)により精製し、ラセミ体I-243を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝300.2m/z。活性：B。 (Example 238)

2- (4,5-Dihydroisoxazol-3-ylamino) ethanol I-243a and I-243b were prepared in two steps according to the following procedure: Racemic 3-bromo-4,5-dihydroisoxazole I- 10 (1.0 eq) was dissolved in n-butanol (0.57 M) followed by addition of (tert-butyldimethylsilyloxy) methanamine (1.2 eq) and sodium carbonate (2.5 eq). The reaction was sealed and heated in a microwave reaction at 150 ° C. for 1 hour, after which time product formation was negligible by LC / MS analysis. The reaction was then resealed and heated in the microwave at 120 ° C. for an additional 24 hours before being transferred to a separatory funnel with excess water and tert-butyl methyl ether. The aqueous layer is washed with tert-butyl methyl ether (2 ×) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated to give an orange solid which is flash silica gel chromatographed. Purification using chromatography (ethyl acetate / hexane gradient) yielded the desired silyl ether. This compound (1.0 eq) was then dissolved in methanol (0.02M) and cooled to 0 ° C. in an ice bath. Acetyl chloride (50 eq) was added dropwise, after which the reaction was allowed to stir at 0 ° C. for 30 minutes. The solvent and residual 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 give racemic I-243. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 300.2 m / z. Activity: B.

2-((4,5-ジヒドロイソオキサゾール-3-イル)(メチル)アミノ)酢酸I-244a及びI-244bを、以下の手順に従い、2工程で調製した：ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-10を、実施例238と同じ条件下でサルコシンエチルエステルと反応させることにより、これを対応する3-アミノ-4,5-ジヒドロイソオキサゾールに変換した。このエチルエステルを次に、実施例119と類似の条件を使用し加水分解し、ラセミ体I-244の混合物を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝327.5m/z。活性：B。 (Example 239)

2-((4,5-Dihydroisoxazol-3-yl) (methyl) amino) acetic acid I-244a and I-244b were prepared in two steps according to the following procedure: Racemic 3-bromo-4, 5-Dihydroisoxazole I-10 was converted to the corresponding 3-amino-4,5-dihydroisoxazole by reacting with sarcosine ethyl ester under the same conditions as in Example 238. This ethyl ester was then hydrolyzed using conditions similar to Example 119 to give a mixture of racemic I-244. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 327.5 m / z. Activity: B.

2-(4,5-ジヒドロイソオキサゾール-3-イルアミノ)アルコールI-245a及びI-245bを、以下の手順に従い、1工程で調製した：ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-10(1.0当量)を、n-ブタノール(0.64M)中に溶解し、引き続き(S)-2-アミノ-1-フェニルエタノール(1.2当量)及び炭酸ナトリウム(2.5当量)を添加した。この反応物を密封し、油浴で120℃で18時間加熱し、この後冷却し、その後過剰な水及びtert-ブチルメチルエーテルと共に、分液漏斗に移した。水層を、tert-ブチルメチルエーテル(2×)で洗浄し、一緒にした有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥し、濃縮し、オレンジ色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(トルエン/ヘキサンからトルエン/酢酸エチルへの勾配)を用いて精製し、ラセミ体I-245を白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝374.20m/z。活性：C。 (Example 240)

2- (4,5-Dihydroisoxazol-3-ylamino) alcohols I-245a and I-245b were prepared in one step according to the following procedure: Racemic 3-bromo-4,5-dihydroisoxazole I -10 (1.0 eq) was dissolved in n-butanol (0.64 M) followed by addition of (S) -2-amino-1-phenylethanol (1.2 eq) and sodium carbonate (2.5 eq). The reaction was sealed and heated in an oil bath at 120 ° C. for 18 hours, then cooled and then transferred to a separatory funnel with excess water and tert-butyl methyl ether. The aqueous layer is washed with tert-butyl methyl ether (2 ×) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated to give an orange solid which is flash silica gel chromatographed. Purification using chromatography (gradient from toluene / hexane to toluene / ethyl acetate) gave racemic I-245 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 374.20 m / z. Activity: C.

2-(4,5-ジヒドロイソオキサゾール-3-イルアミノ)アルコールI-246a及びI-246bは、ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-14を出発物質として3-ブロモ-4,5-ジヒドロイソオキサゾールI-10の代わりに使用し、かつ(R)-2-アミノ-1-フェニルエタノールを(S)-2-アミノ-1-フェニルエタノールの代わりに使用する以外は、実施例240と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝365.6m/z。活性：C。 (Example 241)

2- (4,5-dihydroisoxazol-3-ylamino) alcohols I-246a and I-246b are prepared from racemic 3-bromo-4,5-dihydroisoxazole I-14 as a starting material. , 5-dihydroisoxazole I-10, except that (R) -2-amino-1-phenylethanol is used instead of (S) -2-amino-1-phenylethanol Prepared using a procedure similar to Example 240. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 365.6 m / z. Activity: C.

3-(フェニルチオ)-4,5-ジヒドロイソオキサゾールI-248a及びI-248bを、以下の手順に従い、2工程で調製した：N,N-ジブロモホルムアルドキシム(1.0当量)を、テトラヒドロフラン中に溶解した。チオフェノール(2.0当量)を添加し、引き続き水素化ナトリウム(1.98当量)を添加した。1時間攪拌した後、この反応物を濃縮し、かつフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)により精製し、所望のジフェニルヒドロキシカーボンイミドチオエートI-247を生じた。その後ジチオエート(1.0当量)をアセトニトリル(1.0M)中に溶解し、引き続き1-(トリフルオロメトキシ)-4-ビニルベンゼン(2.4当量)、硝酸銀(1.0当量)及び炭酸カリウム(1.0当量)を添加した。この反応物を、室温で3日間攪拌し、この時点の後、これを濃縮し、かつフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)により精製し、ラセミ体3-(フェニルチオ)-4,5-ジヒドロイソオキサゾールI-248を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝339.9m/z。活性：C。 (Example 242)

3- (Phenylthio) -4,5-dihydroisoxazole I-248a and I-248b were prepared in two steps according to the following procedure: N, N-dibromoformaldoxime (1.0 eq) was added in tetrahydrofuran. Dissolved. Thiophenol (2.0 eq) was added followed by sodium hydride (1.98 eq). After stirring for 1 hour, the reaction was concentrated and purified by flash silica gel chromatography (ethyl acetate / hexane gradient) to yield the desired diphenylhydroxycarbonimidothioate I-247. Dithioate (1.0 eq) was then dissolved in acetonitrile (1.0 M) followed by the addition of 1- (trifluoromethoxy) -4-vinylbenzene (2.4 eq), silver nitrate (1.0 eq) and potassium carbonate (1.0 eq). . The reaction was stirred at room temperature for 3 days after which it was concentrated and purified by flash silica gel chromatography (ethyl acetate / hexane gradient) to give racemic 3- (phenylthio) -4,5- Dihydroisoxazole I-248 was produced. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 339.9m / z. Activity: C.

3-(フェニルスルフィニル)-4,5-ジヒドロイソオキサゾールI-249a及びI-249bを、ラセミ体3-(フェニルチオ)-4,5-ジヒドロイソオキサゾールI-248の酸化により調製した。3-(フェニルチオ)-4,5-ジヒドロイソオキサゾールI-248(1.0当量)を、エタノール(0.15M)中に溶解し、引き続き過剰な水を溶媒とする過酸化水素(30重量％、＞50当量)及び1N HCl(0.29M)を添加した。この反応物を室温で14時間攪拌し、その後これを過剰な水及び塩化メチレンと共に分液漏斗に移した。水層を、塩化メチレン(1×)により抽出し、硫酸マグネシウム上で乾燥し、かつ濃縮し、粗生成物を生じ、これをヘキサンから再結晶し、所望のラセミ体3-(フェニルスルフィニル)-4,5-ジヒドロイソオキサゾールI-249を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝355.5m/z。活性：C。 (Example 243)

3- (Phenylsulfinyl) -4,5-dihydroisoxazole I-249a and I-249b were prepared by oxidation of racemic 3- (phenylthio) -4,5-dihydroisoxazole I-248. 3- (Phenylthio) -4,5-dihydroisoxazole I-248 (1.0 eq) was dissolved in ethanol (0.15M) followed by hydrogen peroxide (30 wt%,> 50 with excess water as solvent). Eq.) And 1N HCl (0.29M) were added. The reaction was stirred at room temperature for 14 hours, after which it was transferred to a separatory funnel with excess water and methylene chloride. The aqueous layer is extracted with methylene chloride (1 ×), dried over magnesium sulfate and concentrated to give the crude product, which is recrystallized from hexane to give the desired racemic 3- (phenylsulfinyl)- This gave 4,5-dihydroisoxazole I-249. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 355.5 m / z. Activity: C.

3-(フェニルスルホニル)-4,5-ジヒドロイソオキサゾールI-250a及びI-250bを、ラセミ体3-(フェニルスルフィニル)-4,5-ジヒドロイソオキサゾールI-249の酸化により調製した。3-(フェニルスルフィニル)-4,5-ジヒドロイソオキサゾールI-249を、塩化メチレン(0.03M)中に溶解した。m-クロロ過安息香酸(77重量％、2.95当量)を2部分で添加し、かつこの反応物を、室温で14時間攪拌し、その後これを過剰な水及び塩化メチレンと共に分液漏斗に移した。有機層を、飽和炭酸水素ナトリウム(2×)で洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、粗固形物を生じ、これを塩化メチレン/ヘキサンから再結晶し、所望のラセミ体3-(フェニルスルホニル)-4,5-ジヒドロイソオキサゾールI-250を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝371.7m/z。活性：C。 (Example 244)

3- (Phenylsulfonyl) -4,5-dihydroisoxazole I-250a and I-250b were prepared by oxidation of racemic 3- (phenylsulfinyl) -4,5-dihydroisoxazole I-249. 3- (Phenylsulfinyl) -4,5-dihydroisoxazole I-249 was dissolved in methylene chloride (0.03M). m-Chloroperbenzoic acid (77 wt%, 2.95 eq) was added in two portions and the reaction was stirred at room temperature for 14 hours before it was transferred to a separatory funnel with excess water and methylene chloride. . The organic layer is washed with saturated sodium bicarbonate (2 ×), dried over magnesium sulfate and concentrated to give a crude solid which is recrystallized from methylene chloride / hexane to give the desired racemic 3- This yielded (phenylsulfonyl) -4,5-dihydroisoxazole I-250. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 371.7 m / z. Activity: C.

3-(フェニルチオ)-4,5-ジヒドロイソオキサゾールI-251a及びI-251bは、4-メルカプト安息香酸メチルをチオフェノールの代わりに使用し、必要なヒドロキシカーボンイミドチオエートを形成する以外は、実施例242と同様の手順を使用し、調製した。その後得られたメチルエステル環状付加物を、実施例94と類似の条件を使用し加水分解し、ラセミ体3-(フェニルチオ)-4,5-ジヒドロイソオキサゾールI-251を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝384.1m/z。活性：C。 (Example 245)

3- (phenylthio) -4,5-dihydroisoxazole I-251a and I-251b, except that methyl 4-mercaptobenzoate is used in place of thiophenol to form the required hydroxycarbonimidothioate Prepared using a procedure similar to that in Example 242. The resulting methyl ester cycloadduct was then hydrolyzed using conditions similar to Example 94 to give racemic 3- (phenylthio) -4,5-dihydroisoxazole I-251. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 384.1 m / z. Activity: C.

N-エチル-N-フェニル-4,5-ジヒドロイソオキサゾール-3-アミンI-253a及びI-253bを、以下の手順に従い、2工程で調製した：N,N-ジブロモホルムアルドキシム(1.05当量)を、アセトニトリル中に溶解した。チオフェノール(1.0当量)及びN-エチルアニリン(1.0当量)を添加し、かつ反応物を室温で2.5時間攪拌し、この時点の後トリエチルアミン(5.0当量)を添加した。1時間攪拌した後、この時点で反応液から沈殿した固形物を濾過し、濾液を濃縮し、かつフラッシュシリカゲルクロマトグラフィー(酢酸エチル/1％トリエチルアミンを含むヘキサンの勾配)により直接精製し、所望のカルバムイミドチオエートI-252を生じた。次にこのカルバムイミドチオエート(1.0当量)を、アセトニトリル(1.0M)中に溶解し、引き続き1-(トリフルオロメトキシ)-4-ビニルベンゼン(2.4当量)、硝酸銀(1.07当量)及び炭酸カリウム(1.17当量)を添加した。この反応物を、室温で1日攪拌し、この時点の後これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/1％トリエチルアミンを含むヘキサンの勾配)により精製し、ラセミ体4,5-ジヒドロイソオキサゾール-3-アミンI-253を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+ 352.1m/z。活性：C。 (Example 246)

N-ethyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-253a and I-253b were prepared in two steps according to the following procedure: N, N-dibromoformaldoxime (1.05 eq. ) Was dissolved in acetonitrile. Thiophenol (1.0 eq) and N-ethylaniline (1.0 eq) were added and the reaction was stirred at room temperature for 2.5 hours, after which time triethylamine (5.0 eq) was added. After stirring for 1 hour, the solid precipitated from the reaction at this point was filtered, the filtrate was concentrated and directly purified by flash silica gel chromatography (gradient of ethyl acetate / 1% hexanes containing triethylamine) to give the desired This gave carbamimidothioate I-252. The carbamimidothioate (1.0 eq) was then dissolved in acetonitrile (1.0 M) followed by 1- (trifluoromethoxy) -4-vinylbenzene (2.4 eq), silver nitrate (1.07 eq) and potassium carbonate. (1.17 eq) was added. The reaction was stirred at room temperature for 1 day after which time it was purified by flash silica gel chromatography (gradient of ethyl acetate / 1% hexane with triethylamine) to give racemic 4,5-dihydroisoxazole-3. -Yielded amine I-253. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + 352.1m / z. Activity: C.

N-メチル-N-フェニル-4,5-ジヒドロイソオキサゾール-3-アミンI-255a及びI-255bを、以下の手順に従い、3工程で調製した：N,N-ジブロモホルムアルドキシム(1.05当量)を、アセトニトリル中に溶解した。チオフェノール(1.0当量)及び4-(メチルアミノ)安息香酸メチルエステル(1.0当量)を添加し、この時点の後トリエチルアミン(3.0当量)を3部分で添加した。3時間攪拌した後、この反応物を、過剰な水及び塩化メチレンと共に分液漏斗に移した。有機層を、1N HCl(2×)で洗浄し、硫酸マグネシウム上で乾燥し、濃縮し、かつフラッシュシリカゲルクロマトグラフィー(酢酸エチル/0.5％トリエチルアミンを含むヘキサンの勾配、引き続きメタノール/0.5％トリエチルアミンを含む塩化メチレンの勾配)を用い精製し、所望のカルバムイミドチオエートI-254を生じた。次にカルバムイミドチオエート(1.0当量)を、アセトニトリル(1.0M)中に再溶解し、引き続き1-(トリフルオロメトキシ)-4-ビニルベンゼン(1.8当量)、硝酸銀(2.3当量)及び炭酸カリウム(2.1当量)を添加した。この反応物を、室温で1日攪拌させ、この時点の後これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/0.5％トリエチルアミンを含むヘキサンの勾配、引き続きメタノール/0.5％トリエチルアミンを含む塩化メチレンの勾配)により精製した。次に得られたラセミ体メチルエステル環状付加物を、実施例94と類似の条件を用いて加水分解し、ラセミ体N-メチル-N-フェニル-4,5-ジヒドロイソオキサゾール-3-アミンI-255を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝381.5m/z。活性：C。 (Example 247)

N-methyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-255a and I-255b were prepared in 3 steps according to the following procedure: N, N-dibromoformaldoxime (1.05 eq. ) Was dissolved in acetonitrile. Thiophenol (1.0 eq) and 4- (methylamino) benzoic acid methyl ester (1.0 eq) were added, after which point triethylamine (3.0 eq) was added in three portions. After stirring for 3 hours, the reaction was transferred to a separatory funnel with excess water and methylene chloride. The organic layer is washed with 1N HCl (2 ×), dried over magnesium sulfate, concentrated, and flash silica gel chromatography (gradient of hexane with ethyl acetate / 0.5% triethylamine followed by methanol / 0.5% triethylamine) Purification using a methylene chloride gradient) gave the desired carbamimidothioate I-254. Carbamimidothioate (1.0 eq) was then redissolved in acetonitrile (1.0 M) followed by 1- (trifluoromethoxy) -4-vinylbenzene (1.8 eq), silver nitrate (2.3 eq) and potassium carbonate. (2.1 eq) was added. The reaction was allowed to stir at room temperature for 1 day after which it was purified by flash silica gel chromatography (gradient of ethyl acetate / hexane with 0.5% triethylamine followed by gradient of methylene chloride with methanol / 0.5% triethylamine). did. The resulting racemic methyl ester cycloadduct is then hydrolyzed using conditions similar to Example 94 to give racemic N-methyl-N-phenyl-4,5-dihydroisoxazol-3-amine I. Yielded -255. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 381.5 m / z. Activity: C.

3-(ピロリジン-1-イル)-4,5-ジヒドロイソオキサゾールI-256a及びI-256bを、ピロリジンを(S)-2-アミノ-1-フェニルエタノールの代わりに使用する以外は、実施例238と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝310.3m/z。活性：C。 (Example 248)

Examples except that 3- (pyrrolidin-1-yl) -4,5-dihydroisoxazole I-256a and I-256b were used, except that pyrrolidine was used instead of (S) -2-amino-1-phenylethanol. Prepared using a procedure similar to 238. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 310.3 m / z. Activity: C.

3-(1-メチル-3-(トリフルオロメチル)-1H-ピラゾール-5-イルオキシ)-4,5-ジヒドロイソオキサゾールI-257a及びI-257bを、化合物I-10及び1-メチル-3-(トリフルオロメチル)-1H-ピラゾール-5-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝403.7m/z。活性：B。 (Example 249)

3- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) -4,5-dihydroisoxazole I-257a and I-257b were converted to compound I-10 and 1-methyl-3 Prepared from-(trifluoromethyl) -1H-pyrazol-5-ol in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 403.7 m / z. Activity: B.

3-(フェノキシ)-4,5-ジヒドロイソオキサゾールI-258a及びI-258bを、ラセミ化合物I-14及び3-(1,3,4-オキサジアゾール-2-イル)フェノールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝392.4m/z。活性：A。 (Example 250)

3- (phenoxy) -4,5-dihydroisoxazole I-258a and I-258b were prepared from racemic compounds I-14 and 3- (1,3,4-oxadiazol-2-yl) phenol by method 5 And prepared in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 392.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-259a及びI-259bを、ラセミ化合物I-170を出発酸として使用する以外は、実施例152と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝390.7m/z。活性：A。 (Example 251)

A procedure similar to that of Example 152 was used, except that 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-259a and I-259b were used as racemic compound I-170 as the starting acid. Prepared. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 390.7 m / z. Activity: A.

4,5-ジヒドロイソオキサゾール-3-イルアセテートI-260a及びI-260bを、以下の手順に従い、3工程で調製した：ラセミ体ブロモイソオキサゾールI-10(1.0当量)を、テトラヒドロフラン(1.0M)中に溶解した。1N 水酸化ナトリウム溶液(4.0当量)を添加し、引き続きアリルアルコール(45当量)を添加した。この反応物を密封し、60℃で3時間加熱した。この反応混合物を冷却し、この後過剰な水及び酢酸エチルと共に、分液漏斗に移した。有機層を水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)を使用し精製した。次に得られたアリルエーテル(1.0当量)を、テトラヒドロフラン(0.2M)中に溶解した。ギ酸(5.0当量)を添加し、引き続きテトラキスパラジウム(10mol％)を添加し、その後この反応物を室温で2時間攪拌させた。反応混合物を、過剰な水及び酢酸エチルと共に、分液漏斗に移した。有機層を、飽和炭酸水素ナトリウム及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)を用いて精製した。得られたイソオキサゾリジン-3-オン(1.0当量)を、塩化メチレン(0.3M)中に溶解し、その後N,N-ジメチルアミノピリジン(1.0当量)及び無水酢酸(1.0当量)を添加した。室温で14時間攪拌後、この反応物を、過剰な水及び酢酸エチルと共に、分液漏斗に移した。有機層を、1N HCl及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、濃縮し、所望のラセミ体酢酸エステルI-260を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝297.8m/z。活性：D。 (Example 252)

4,5-Dihydroisoxazol-3-yl acetate I-260a and I-260b were prepared in 3 steps according to the following procedure: Racemic bromoisoxazole I-10 (1.0 eq) was added to tetrahydrofuran (1.0 M ). 1N sodium hydroxide solution (4.0 eq) was added followed by allyl alcohol (45 eq). The reaction was sealed and heated at 60 ° C. for 3 hours. The reaction mixture was cooled 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 give the crude material which was purified using flash silica gel chromatography (ethyl acetate / hexane gradient). The resulting allyl ether (1.0 eq) was then dissolved in tetrahydrofuran (0.2M). Formic acid (5.0 eq) was added followed by tetrakis palladium (10 mol%), after which the reaction was allowed to stir at room temperature for 2 hours. 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 silica gel chromatography (ethyl acetate / hexane gradient). The resulting isoxazolidine-3-one (1.0 eq) was dissolved in methylene chloride (0.3 M), followed by the addition of N, N-dimethylaminopyridine (1.0 eq) and acetic anhydride (1.0 eq). After stirring at room temperature for 14 hours, 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 yield the desired racemic acetate I-260. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 297.8 m / z. Activity: D.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールI-261a及びI-261bを、最初に6-(メチルチオ)ピリジン-3-オールを6-(メチルチオ)ピリジン-3-イルボロン酸から方法11を使用し調製した後、ラセミ化合物I-75及び6-(メチルチオ)ピリジン-3-オールから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝386.2m/z。活性：A。 (Example 253)

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-261a and I-261b, first 6- (methylthio) pyridin-3-ol to 6- (methylthio) pyridin-3-ylboronic acid Was prepared in 1 step from racemic compound I-75 and 6- (methylthio) pyridin-3-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 386.2 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-1a及びII-1bを、4-ビニルピリジンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝226.0m/z。活性：C。 Example 254

3-Bromo-4,5-dihydroisoxazole II-1a and II-1b were prepared from 4-vinylpyridine in one step using Method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 226.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-2a及びII-2bを、3-ビニルピリジンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝226.0m/z。活性：C。 (Example 255)

3-Bromo-4,5-dihydroisoxazole II-2a and II-2b were prepared from 3-vinylpyridine using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 226.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-3a及びII-3bを、2-ビニルピリジンから、方法2を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝226.0m/z。活性：C。 (Example 256)

3-Bromo-4,5-dihydroisoxazole II-3a and II-3b were prepared from 2-vinylpyridine using Method 2 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 226.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-4a及びII-4bを、方法8を使用する1-フェニル-1H-ピラゾール-4-カルボアルデヒドからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝291.0m/z。活性：B。 (Example 257)

3-Bromo-4,5-dihydroisoxazole II-4a and II-4b were started with alkene formation from 1-phenyl-1H-pyrazole-4-carbaldehyde using Method 8, followed by Method 2. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 291.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-5a及びII-5bを、方法8を使用する2-フェニル-1,3-チアゾール-4-カルボアルデヒドからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝308.0m/z。活性：C。 Example 258

3-bromo-4,5-dihydroisoxazole II-5a and II-5b starting with alkene formation from 2-phenyl-1,3-thiazole-4-carbaldehyde using method 8, followed by method Prepared in 2 steps of cycloaddition using 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 308.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-6a及びII-6bを、方法8を使用する2-フェニル-1,3-チアゾール-5-カルボアルデヒドからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝308.0m/z。活性：A。 (Example 259)

3-bromo-4,5-dihydroisoxazole II-6a and II-6b starting with alkene formation from 2-phenyl-1,3-thiazole-5-carbaldehyde using method 8, followed by method Prepared in 2 steps of cycloaddition using 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 308.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-7a及びII-7bを、方法8を使用する5-フェニルチオフェン-2-カルボアルデヒドからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝309.6m/z。活性：A。 (Example 260)

3-Bromo-4,5-dihydroisoxazole II-7a and II-7b starting with alkene formation from 5-phenylthiophene-2-carbaldehyde using Method 8, followed by addition using Method 1 Prepared in 2 steps of cyclization. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 309.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-8a及びII-8bを、方法8を使用する4-フェニルチオフェン-2-カルボアルデヒドからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝307.0m/z。活性：A。 (Example 261)

3-Bromo-4,5-dihydroisoxazole II-8a and II-8b starting with alkene formation from 4-phenylthiophene-2-carbaldehyde using Method 8, followed by addition using Method 2 Prepared in 2 steps of cyclization. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 307.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-9a及びII-9bを、方法8を使用する6-キノリンカルボアルデヒドからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝276.0m/z。活性：A。 (Example 262)

3-Bromo-4,5-dihydroisoxazole II-9a and II-9b were started with alkene formation from 6-quinolinecarbaldehyde using Method 8, followed by cycloaddition 2 using Method 2. Prepared in process. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 276.0m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-10a及びII-10bを、方法8を使用する3-キノリンカルボアルデヒドからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝276.0m/z。活性：A。 (Example 263)

3-Bromo-4,5-dihydroisoxazole II-10a and II-10b were started with alkene formation from 3-quinolinecarbaldehyde using Method 8, followed by cycloaddition 2 using Method 2. Prepared in process. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 276.0m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-11a及びII-11bを、方法10を使用する6-ブロモキノキサリンからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝277.0m/z。活性：A。 Example 264

2-Bromo-4,5-dihydroisoxazole II-11a and II-11b starting with alkene formation from 6-bromoquinoxaline using Method 10 followed by two steps of cycloaddition using Method 2 It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 277.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-12a及びII-12bを、方法9を使用する5-ブロモ-1-メチル-1H-インドールからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝278.0m/z。活性：A。 Example 265

3-Bromo-4,5-dihydroisoxazole II-12a and II-12b starting with alkene formation from 5-bromo-1-methyl-1H-indole using Method 9 followed by Method 2 Prepared in 2 steps of cycloaddition. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 278.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-13a及びII-13bを、下記のように2-アミノ-6-ブロモベンゾチアゾールのBoc-保護で出発する2工程で調製した：ベンゾチアゾール(1.0当量)を、塩化メチレン(チアゾールに対して0.12M)中に溶解した。その後二炭酸ジ-tert-ブチル(3.0当量)を添加し、引き続きDMAP(0.20当量)を5部分で添加した。この反応物を、23℃で2時間攪拌し、この時点の後、TLC分析により最早出発物質(SM)は存在しなかった。この反応物を、メタノール(75当量)の添加によりクエンチし、かつ10分間攪拌させ、その後この反応物を、水と塩化メチレンの間で分配し、かつ有機層を0.5Mクエン酸溶液(2×)及び飽和炭酸水素ナトリウム溶液(1×)で洗浄し、硫酸マグネシウム上で乾燥し、かつ真空中で濃縮し、粗固形物を生じ、これを方法9、引き続き方法2を使用し、所望の3-ブロモ-4,5-ジヒドロイソオキサゾールに直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝397.0m/z。活性：B。 (Example 266)

3-Bromo-4,5-dihydroisoxazole II-13a and II-13b were prepared in two steps starting with the Boc-protection of 2-amino-6-bromobenzothiazole as follows: benzothiazole (1.0 Eq) was dissolved in methylene chloride (0.12M relative to thiazole). Then di-tert-butyl dicarbonate (3.0 eq) was added followed by 5 portions of DMAP (0.20 eq). The reaction was stirred at 23 ° C. for 2 hours, after which time no starting material (SM) was present by TLC analysis. The reaction was quenched by the addition of methanol (75 eq) and allowed to stir for 10 minutes, after which the reaction was partitioned between water and methylene chloride and the organic layer was diluted with 0.5 M citric acid solution (2 × ) And saturated sodium bicarbonate solution (1 ×), dried over magnesium sulfate and concentrated in vacuo to give a crude solid which was obtained using Method 9 followed by Method 2 to obtain the desired 3 Direct conversion to -bromo-4,5-dihydroisoxazole. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 397.0 m / z. Activity: B.

1-アリルピペラジンを、塩化メチレン(ピペラジンに対して1.1M)中に溶解した。炭酸カリウム(1.5当量)を添加し、引き続き二炭酸ジ-tert-ブチル(1.1当量)を添加した。この反応物を16時間攪拌させ、その後水とtert-ブチルメチルエーテルの間で分配し、有機層をブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮し、粗アルケンを生じ、これを方法1を使用する1工程で、所望の3-ブロモ-4,5-ジヒドロイソオキサゾールII-14a及びII-14bに直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝347.1m/z。活性：A。 (Example 267)

1-allyl piperazine was dissolved in methylene chloride (1.1M for piperazine). Potassium carbonate (1.5 eq) was added followed by di-tert-butyl dicarbonate (1.1 eq). The reaction was allowed to stir for 16 hours, then partitioned between water and tert-butyl methyl ether, the organic layer washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude alkene. This was converted directly to the desired 3-bromo-4,5-dihydroisoxazoles II-14a and II-14b in one step using Method 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 347.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-15a及びII-15bを、方法8を使用する4-ホルミルピペリジン-1-カルボン酸ベンジルからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝366.1m/z。活性：B。 Example 268

3-Bromo-4,5-dihydroisoxazole II-15a and II-15b are started with alkene formation from benzyl 4-formylpiperidine-1-carboxylate using Method 8, followed by Method 2. Prepared in 2 steps of cycloaddition. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 366.1m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-16a及びII-16bを、方法8を使用する4-ホルミルピペリジン-1-カルボン酸tert-ブチルからのアルケン形成で出発し、それに続き方法2を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝332.1m/z。活性：A。 (Example 269)

3-Bromo-4,5-dihydroisoxazole II-16a and II-16b were started with alkene formation from tert-butyl 4-formylpiperidine-1-carboxylate using Method 8, followed by Method 2. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 332.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-17a及びII-17bを、方法8を使用する2-(4-クロロフェニル)チアゾール-5-カルボアルデヒドからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝342.5m/z。活性：A。 (Example 270)

3-Bromo-4,5-dihydroisoxazole II-17a and II-17b were started with alkene formation from 2- (4-chlorophenyl) thiazole-5-carbaldehyde using Method 8, followed by Method 1. Prepared in 2 steps of cycloaddition using These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 342.5 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-18a及びII-18bを、方法8を使用する1-(2-フェニルチアゾール-5-イル)エタノンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝322.3m/z。活性：A。 (Example 271)

3-Bromo-4,5-dihydroisoxazole II-18a and II-18b were started with alkene formation from 1- (2-phenylthiazol-5-yl) ethanone using Method 8, followed by Method 1. Prepared in 2 steps of cycloaddition using These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 322.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-19a及びII-19bを、エチルトリフェニルホスホニウムブロミドをメチルトリフェニルホスホニウムブロミドの代わりに使用する以外は方法8を使用し、2-フェニルチアゾール-5-カルボアルデヒドからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。[M+H]+＝325.1m/z。活性：A。 (Example 272)

Using method 8 except 3-bromo-4,5-dihydroisoxazole II-19a and II-19b, using ethyltriphenylphosphonium bromide instead of methyltriphenylphosphonium bromide, 2-phenylthiazole-5 -Prepared in 2 steps of cycloaddition using method 1 starting with alkene formation from carbaldehyde. [M + H] + = 325.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-20a及びII-20bを、同じく実施例272の付加環化時に形成されたtrans-ジアステレオ異性体として単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝324.9m/z。活性：C。 (Example 273)

3-Bromo-4,5-dihydroisoxazole II-20a and II-20b were also isolated as trans-diastereoisomers formed during the cycloaddition of Example 272. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 324.9 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-21a及びII-21bを、ラセミ化合物II-6及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝325.1m/z。活性：A。 (Example 274)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole II-21a and II-21b were prepared from racemic compound II-6 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 325.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-22a及びII-22bを、ラセミ化合物II-18及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝340.4m/z。活性：A。 (Example 275)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole II-22a and II-22b were prepared from racemic compound II-18 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 340.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-23a及びII-23bを、ラセミ化合物II-18及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝339.3m/z。活性：A。 (Example 276)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole II-23a and II-23b were prepared from racemic II-18 and 3-hydroxypyridine using Method 5 in one step. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 339.3 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-24a及びII-24bを、方法8を使用する1-(4-メチル-2-フェニルチアゾール-5-イル)エタノンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝339.0m/z。活性：B。 (Example 277)

3-bromo-4,5-dihydroisoxazole II-24a and II-24b starting with alkene formation from 1- (4-methyl-2-phenylthiazol-5-yl) ethanone using method 8; This was followed by two steps of cycloaddition using Method 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 339.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールII-25a及びII-25bを、方法8を使用する5-ピリジン-3-イルチオフェン-2-カルボアルデヒドからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝310.3m/z。活性：A。 (Example 278)

3-Bromo-4,5-dihydroisoxazole II-25a and II-25b were started with alkene formation from 5-pyridin-3-ylthiophene-2-carbaldehyde using Method 8, followed by Method 1. Prepared in 2 steps of cycloaddition using These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 310.3 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールII-26a及びII-26bを、ラセミ化合物II-25及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝325.1m/z。活性：A。 (Example 279)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole II-26a and II-26b were prepared from racemic II-25 and 5-hydroxypyrimidine in one step using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 325.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-27a及びII-27bを、以下の手順に従い、ラセミ化合物II-25から、2工程で調製した：5-ヒドロキシピコリン酸メチルエステルを、方法5の使用、引き続きメチルエステル加水分解により反応させた。ラセミ体3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-27のメチルエステル(1.0当量)を、1:1テトラヒドロフラン/水(0.06M)中に溶解し、かつ水酸化リチウム(8.0当量)を添加した。この反応物を、室温で1時間攪拌し、この時点の後テトラヒドロフランを窒素流れ下で除去し、残存する溶液を、1N HClによりpH＜2まで酸性とし、所望の酸II-27a及びII-27bを白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝367.5m/z。活性：A。 (Example 280)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole II-27a and II-27b were prepared from racemic compound II-25 in two steps according to the following procedure: Methyl 5-hydroxypicolinate The ester was reacted by use of Method 5 followed by methyl ester hydrolysis. Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole II-27 methyl ester (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 equiv) was added. The reaction was stirred at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the desired acids II-27a and II-27b. As a white solid, which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 367.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-28a及びII-28bを、ラセミ化合物II-6から、最初に方法5を使用し化合物II-6を6-(メチルチオ)ピリジン-3-オール(6-(メチルチオ)ピリジン-3-イルボロン酸から方法11を使用して調製)と反応させ、引き続き以下の手順に従い酸化する、2工程で調製した：ラセミ体3-(6-(メチルチオ)ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールを、塩化メチレン(イソオキサゾールに対して0.5M)中に溶解し、この時点の後m-クロロ過安息香酸(2.0当量)を1部で添加し、かつこの反応物を室温で1時間攪拌した。LC/MSによりこの反応が完了したことを決定した後、溶媒を蒸発させた。次に粗混合物を、tert-ブチルメチルエーテル(0.5M)中に再度溶解し、その後ヘキサンを、固形物が沈殿するまで、ゆっくり添加した。次に固形物を、真空濾過により収集し、1:1ヘキサン/MTBEで洗浄し、所望の3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-29a及びII-29bを白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝404.1m/z。活性：A。 (Example 281)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole II-28a and II-28b are prepared from racemic compound II-6, first using method 5 to convert compound II-6 to 6- (methylthio). Prepared in 2 steps, reacted with pyridin-3-ol (prepared using method 11 from 6- (methylthio) pyridin-3-ylboronic acid) and subsequently oxidized according to the following procedure: Racemic 3- (6 -(Methylthio) pyridin-3-yloxy) -4,5-dihydroisoxazole is dissolved in methylene chloride (0.5 M relative to isoxazole), after which point m-chloroperbenzoic acid (2.0 eq) Was added in 1 part and the reaction was stirred at room temperature for 1 hour. After determining that the reaction was complete by LC / MS, the solvent was evaporated. The crude mixture was then redissolved in tert-butyl methyl ether (0.5M), after which hexane was added slowly until a solid precipitated. The solid is then collected by vacuum filtration and washed with 1: 1 hexane / MTBE to give the desired 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole II-29a and II-29b in white It occurred as a solid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 404.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールII-29a及びII-29bを、ラセミ化合物II-18から、最初に方法5を使用し化合物II-18を6-(メチルチオ)ピリジン-3-オール(方法11を使用し6-(メチルチオ)ピリジン-3-イルボロン酸から調整)と反応させ、引き続き実施例281と類似の条件下で酸化する、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝417.9m/z。活性：A。 (Example 282)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole II-29a and II-29b are prepared from racemic compound II-18, first using method 5 to convert compound II-18 to 6- (methylthio) Prepared in two steps by reacting with pyridin-3-ol (prepared from 6- (methylthio) pyridin-3-ylboronic acid using Method 11) followed by oxidation under conditions similar to Example 281. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 417.9 m / z. Activity: A.

2-(4,5-ジヒドロイソオキサゾール-3-イルアミノ)アルコールII-30a及びII-30bを、以下の手順に従い、1工程で調製した：ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールI-8(1.0当量)を、n-ブタノール(0.64M)中に溶解し、引き続き(S)-2-アミノ-1-フェニルエタノール(1.2当量)及び炭酸ナトリウム(2.5当量)を添加した。この反応物を密封し、かつ油浴中で120℃3fで18時間加熱し、その後これを冷却し、この後過剰な水及びtert-ブチルメチルエーテルと共に、分液漏斗に移した。水層を、tert-ブチルメチルエーテル(2×)で洗浄し、かつ一緒にした有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、オレンジ色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(トルエン/ヘキサンからトルエン/酢酸エチルの勾配)を用いて精製し、ラセミ体II-30を白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝374.20m/z。活性：C。 (Example 283)

2- (4,5-Dihydroisoxazol-3-ylamino) alcohol II-30a and II-30b were prepared in one step according to the following procedure: Racemic 3-bromo-4,5-dihydroisoxazole I -8 (1.0 eq) was dissolved in n-butanol (0.64 M) followed by addition of (S) -2-amino-1-phenylethanol (1.2 eq) and sodium carbonate (2.5 eq). The reaction was sealed and heated in an oil bath at 120 ° C. 3 f for 18 hours, after which it was cooled and then transferred to a separatory funnel with excess water and tert-butyl methyl ether. The aqueous layer is washed with tert-butyl methyl ether (2 ×) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated to give an orange solid that is flushed Purification using silica gel chromatography (toluene / hexane to toluene / ethyl acetate gradient) gave racemic II-30 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 374.20 m / z. Activity: C.

2-(4,5-ジヒドロイソオキサゾール-3-イルアミノ)アルコールII-31a及びII-31bを、(R)-2-アミノ-1-フェニルエタノールを(S)-2-アミノ-1-フェニルエタノールの代わりに使用する以外は、実施例283と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝366.4m/z。活性：C。 (Example 284)

2- (4,5-dihydroisoxazol-3-ylamino) alcohol II-31a and II-31b, (R) -2-amino-1-phenylethanol (S) -2-amino-1-phenylethanol Prepared using a procedure similar to that in Example 283 except using in place of These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 366.4 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-1を、メチレンシクロヘキサンから、方法1を使用し、1工程で調製した。[M-H]-＝217.0m/z。活性：A。 (Example 285)

3-Bromo-4,5-dihydroisoxazole III-1 was prepared from methylenecyclohexane using Method 1 in one step. [MH]-= 217.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-2a及びIII-2bを、方法6を使用する4-tert-ブチルシクロヘキサノンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝273.1m/z。活性：B。 (Example 286)

3-Bromo-4,5-dihydroisoxazole III-2a and III-2b was started with alkene formation from 4-tert-butylcyclohexanone using Method 6 followed by cycloaddition using Method 1. Prepared in 2 steps. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 273.1 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-3a及びIII-3bを、方法6を使用する4-フェニルシクロヘキサノンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝293.0m/z。活性：A。 (Example 287)

2-Bromo-4,5-dihydroisoxazole III-3a and III-3b starting with alkene formation from 4-phenylcyclohexanone using Method 6 followed by two steps of cycloaddition using Method 1 It was prepared with. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 293.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-4を、方法6を使用する1,4-ジオキサスピロ[4.5]デカン-8-オンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。[M-H]-＝275.0m/z。活性：C。 (Example 288)

3-Bromo-4,5-dihydroisoxazole III-4 starting with alkene formation from 1,4-dioxaspiro [4.5] decan-8-one using method 6 followed by addition using method 1 Prepared in 2 steps of cyclization. [MH]-= 275.0 m / z. Activity: C.

4-メチレンシクロヘキサンカルボン酸エチルエステルを、方法3を使用し、4-オキソシクロヘキサンカルボン酸エチルに対するウィティッヒ反応から調製した。このエステルは、以下の手順に従い、化合物III-5に還元した：ジエチルエーテル(水素化物に対して1.0M)中の水素化リチウムアルミニウム(4.0当量)の溶液へ、ジエチルエーテル(エステルに対して2.0M)中の4-オキソシクロヘキサンカルボン酸エチルを添加した。この反応物を2時間還流加熱し、その後氷浴中で冷却し、かつイソプロパノール、水を溶媒とする50％のNaOH、及び水の連続添加によりクエンチした。次にこの混合物を濾過し、フィルターケーキを、過剰なジエチルエーテルで洗浄した。次に濾液を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空中で濃縮し、透明な油状物を生じ、これを更に精製することなく使用した。 Example 289

4-Methylenecyclohexanecarboxylic acid ethyl ester was prepared from the Wittig reaction on ethyl 4-oxocyclohexanecarboxylate using Method 3. This ester was reduced to compound III-5 according to the following procedure: To a solution of lithium aluminum hydride (4.0 eq) in diethyl ether (1.0 M relative to the hydride), diethyl ether (2.0 relative to the ester). Ethyl 4-oxocyclohexanecarboxylate in M) was added. The reaction was heated at reflux for 2 hours, then cooled in an ice bath and quenched by sequential addition of isopropanol, 50% NaOH in water, and water. The mixture was then filtered and the filter cake was washed with excess diethyl ether. The filtrate was then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a clear oil that was used without further purification.

  Compound III-5 (1.0 eq) was then dissolved in pyridine (0.90M with respect to alcohol). p-Toluenesulfonyl chloride (1.1 eq) was added and the reaction was allowed to stir for 16 hours before being quenched with a few drops of water, diluted with excess methylene chloride and washed with water, dilute HCl and brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to yield a yellowish white solid that was used directly without further purification.

  Phenol (1.2 eq) was then dissolved in N, N-dimethylformamide (0.20 M relative to tosylate). Cesium carbonate (1.3 eq) was added, followed by compound III6 (1.0 eq) and TBAI (0.10 eq). The reaction was heated at 40 ° C. for 19 hours, after which time it was diluted with tert-butyl methyl ether and washed with dilute NaOH, water and brine, then dried over sodium sulfate. Concentration under vacuum yielded compound III-7 as a clear oil that was used without further purification.

この粗アルケンを、方法2を使用する1工程で、所望のジアステレオ異性体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-8a及びIII-8bに、直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝323.6m/z。活性：A。

This crude alkene was converted directly to the desired diastereoisomers 3-bromo-4,5-dihydroisoxazole III-8a and III-8b in one step using Method 2. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 323.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII9を、方法7を使用する1-(tert-ブトキシカルボニル)-4-ピペリドンからのアルケン形成で出発し、それに続き方法1又は方法2を使用する付加環化の2工程で調製した。[M-H]-＝318.1m/z。活性：A。 (Example 290)

3-Bromo-4,5-dihydroisoxazole III9 starts with alkene formation from 1- (tert-butoxycarbonyl) -4-piperidone using Method 7 followed by addition using Method 1 or Method 2 Prepared in 2 steps of cyclization. [MH]-= 318.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-10a及びIII-10bを、方法7を使用する1-(tert-ブトキシカルボニル)-3-ピペリドンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝318.1m/z。活性：C。 (Example 291)

3-Bromo-4,5-dihydroisoxazole III-10a and III-10b were started with alkene formation from 1- (tert-butoxycarbonyl) -3-piperidone using Method 7, followed by Method 1. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 318.1 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-11a及びIII-11bを、方法7を使用するN-(tert-ブトキシカルボニル)-3-ピロリジノンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝304.7m/z。活性：B。 (Example 292)

3-Bromo-4,5-dihydroisoxazole III-11a and III-11b were started with alkene formation from N- (tert-butoxycarbonyl) -3-pyrrolidinone using Method 7, followed by Method 1. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 304.7 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-12a及びIII-12bを、方法7を使用する1-(tert-ブトキシカルボニル)-4-オキソアゼパンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝332.1m/z。活性：A。 (Example 293)

3-Bromo-4,5-dihydroisoxazole III-12a and III-12b were started with alkene formation from 1- (tert-butoxycarbonyl) -4-oxoazepane using Method 7, followed by Method 1. Prepared in 2 steps of cycloaddition used. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 332.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-13a及びIII-13bを、方法7を使用するN-(tert-ブトキシカルボニル)-ノルトロピオンからのアルケン形成で出発し、それに続き方法1を使用する付加環化の2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝344.1m/z。活性：C。 (Example 294)

3-Bromo-4,5-dihydroisoxazole III-13a and III-13b are started with alkene formation from N- (tert-butoxycarbonyl) -nortropion using Method 7, followed by Method 1. Prepared in 2 steps of cycloaddition. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 344.1 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII9を、トリフルオロ酢酸(イソオキサゾールに対して0.20M)中に溶解し、かつ室温で1時間攪拌した。その後溶媒を真空下で除去し、粗残渣をトルエン(2×)と共沸し、化合物III14をTFA塩(白色固形物)として生じた。[M-H]-＝218.0m/z。活性：C。 (Example 295)

3-Bromo-4,5-dihydroisoxazole III9 was dissolved in trifluoroacetic acid (0.20M relative to isoxazole) and stirred at room temperature for 1 hour. The solvent was then removed under vacuum and the crude residue was azeotroped with toluene (2 ×) to yield compound III14 as a TFA salt (white solid). [MH]-= 218.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、塩化メチレン(イソオキサゾールに対して0.03M)中に溶解し、その後トリエチルアミン(4.0当量)及び無水酢酸(3.0当量)を添加した。この反応物を16時間攪拌させ、この時点の後酢酸エチルで希釈し、かつ希HCl、希NaOH、次にブラインで洗浄した。その後有機層を硫酸ナトリウム上で乾燥し、真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、酢酸塩III15を白色固形物として生じた。[M-H]-＝260.0m/z。活性：C。 Example 296

3-Bromo-4,5-dihydroisoxazole III14 was dissolved in methylene chloride (0.03M relative to isoxazole) followed by the addition of triethylamine (4.0 eq) and acetic anhydride (3.0 eq). The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute HCl, dilute NaOH, then brine. The organic layer was then dried over sodium sulfate and concentrated in vacuo to yield a crude material that was purified using flash silica gel chromatography (ethyl acetate / hexanes) to yield acetate III15 as a white solid. . [MH]-= 260.0 m / z. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、塩化メチレン(イソオキサゾールに対して0.05M)中に溶解し、その後トリエチルアミン(4.0当量)及び塩化ベンゾイル(1.25当量)を添加した。この反応物を、16時間攪拌させ、この時点の後酢酸エチルで希釈し、かつ希HCl、希NaOH、その後ブラインで洗浄した。次に有機層を硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、酢酸塩III16を白色フィルム状物として生じた。[M-H]-＝332.0m/z。活性：A。 (Example 297)

3-Bromo-4,5-dihydroisoxazole III14 was dissolved in methylene chloride (0.05M relative to isoxazole) followed by addition of triethylamine (4.0 eq) and benzoyl chloride (1.25 eq). The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute HCl, dilute NaOH, then brine. The organic layer was then dried over sodium sulfate and concentrated under vacuum to yield acetate III16 as a white film. [MH]-= 332.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、塩化メチレン(イソオキサゾールに対して0.05M)中に溶解し、その後トリエチルアミン(4.0当量)及びベンゼンスルホニルクロリド(1.25当量)を添加した。この反応物を、16時間攪拌させ、この時点の後酢酸エチルで希釈し、かつ希HCl、希NaOH、その後ブラインで洗浄した。次に有機層を硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、スルホンアミドIII17を白色固形物として生じた。[M-H]-＝358.0m/z。活性：B。 (Example 298)

3-Bromo-4,5-dihydroisoxazole III14 was dissolved in methylene chloride (0.05M relative to isoxazole) followed by addition of triethylamine (4.0 eq) and benzenesulfonyl chloride (1.25 eq). The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute HCl, dilute NaOH, then brine. The organic layer was then dried over sodium sulfate and concentrated under vacuum to yield sulfonamide III17 as a white solid. [MH]-= 358.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、塩化メチレン(イソオキサゾールに対して0.05M)中に溶解し、その後トリエチルアミン(4.0当量)及びクロロギ酸ベンジル(1.25当量)を添加した。この反応物を、16時間攪拌させ、この時点の後酢酸エチルで希釈し、かつ希HCl、希NaOH、その後ブラインで洗浄した。次に有機層を硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、カルバメートIII18を白色固形物として生じた。[M-H]-＝352.0m/z。活性：A。 (Example 299)

3-Bromo-4,5-dihydroisoxazole III14 was dissolved in methylene chloride (0.05M relative to isoxazole) followed by the addition of triethylamine (4.0 eq) and benzyl chloroformate (1.25 eq). The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute HCl, dilute NaOH, then brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to yield a crude material that is purified using flash silica gel chromatography (ethyl acetate / hexanes) to yield carbamate III18 as a white solid. It was. [MH]-= 352.0 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、塩化メチレン(イソオキサゾールに対して0.06M)中に溶解し、その後トリエチルアミン(2.5当量)及びベンズアルデヒド(1.25当量)を添加し、引き続きトリアセトキシ水素化ホウ素ナトリウム(1.5当量)を添加した。この反応物を、16時間攪拌させ、この時点の後酢酸エチルで希釈し、かつ希NaOH、その後ブラインで洗浄した。次に有機層を硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、N-ベンジルピペリジンIII19を白色固形物として生じた。[M-H]-＝308.1m/z。活性：A。 (Example 300)

3-Bromo-4,5-dihydroisoxazole III14 is dissolved in methylene chloride (0.06M relative to isoxazole) followed by addition of triethylamine (2.5 eq) and benzaldehyde (1.25 eq) followed by triacetoxyhydrogen. Sodium borohydride (1.5 eq) was added. The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute NaOH followed by brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to give a crude material which is purified using flash silica gel chromatography (ethyl acetate / hexane) to give N-benzylpiperidine III19 as a white solid It happened as a thing. [MH]-= 308.1 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-20は、4-クロロベンズアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝342.6m/z。活性：A。 (Example 301)

3-Bromo-4,5-dihydroisoxazole III-20 was prepared using a procedure similar to Example 300, except that 4-chlorobenzaldehyde was used in place of benzaldehyde. [M + H] + = 342.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII21は、4-メトキシベンズアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝338.7m/z。活性：A。 (Example 302)

3-Bromo-4,5-dihydroisoxazole III21 was prepared using a procedure similar to Example 300, except that 4-methoxybenzaldehyde was used in place of benzaldehyde. [M + H] + = 338.7 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-22は、2-ピリジンカルボキシアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝312.1m/z。活性：B。 (Example 303)

3-Bromo-4,5-dihydroisoxazole III-22 was prepared using a procedure similar to Example 300, except that 2-pyridinecarboxaldehyde was used in place of benzaldehyde. [M + H] + = 312.1 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-23は、3-ピリジンカルボキシアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝312.4m/z。活性：B。 (Example 304)

3-Bromo-4,5-dihydroisoxazole III-23 was prepared using a procedure similar to Example 300, except that 3-pyridinecarboxaldehyde was used in place of benzaldehyde. [M + H] + = 312.4 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-24は、4-メチルベンズアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝322.5m/z。活性：A。 (Example 305)

3-Bromo-4,5-dihydroisoxazole III-24 was prepared using a procedure similar to Example 300, except that 4-methylbenzaldehyde was used in place of benzaldehyde. [M + H] + = 322.5 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-25は、3,4-ジクロロベンズアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝378.6m/z。活性：A。 (Example 306)

3-Bromo-4,5-dihydroisoxazole III-25 was prepared using a procedure similar to Example 300, except that 3,4-dichlorobenzaldehyde was used in place of benzaldehyde. [M + H] + = 378.6 m / z. Activity: A.

ブロモ-4,5-ジヒドロイソオキサゾールIII-26は、4-トリフルオロメチルベンズアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝376.6m/z。活性：A。 (Example 307)

Bromo-4,5-dihydroisoxazole III-26 was prepared using a procedure similar to Example 300, except that 4-trifluoromethylbenzaldehyde was used in place of benzaldehyde. [M + H] + = 376.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-27は、3-クロロベンズアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝342.6m/z。活性：A。 (Example 308)

3-Bromo-4,5-dihydroisoxazole III-27 was prepared using a procedure similar to Example 300, except that 3-chlorobenzaldehyde was used in place of benzaldehyde. [M + H] + = 342.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-28は、ヒドロシンナムアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝336.7m/z。活性：A。 (Example 309)

3-Bromo-4,5-dihydroisoxazole III-28 was prepared using a procedure similar to Example 300, except that hydrocinnamaldehyde was used in place of benzaldehyde. [M + H] + = 336.7 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、N,N-ジメチルホルムアミド(イソオキサゾールに対して0.05M)中に溶解し、その後炭酸カリウム(3.0当量)を添加し、引き続きヨウ化カリウム(0.2当量)及び2-ブロモエチルベンゼン(3.0当量)を添加した。この反応物を、油浴中で70℃で16時間加熱し、この時点の後、フラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を使用し直接精製し、アミンIII-29を油状物として生じた。[M+H]+＝324.6m/z。活性：A。 (Example 310)

3-Bromo-4,5-dihydroisoxazole III14 is dissolved in N, N-dimethylformamide (0.05M relative to isoxazole), followed by the addition of potassium carbonate (3.0 eq) followed by potassium iodide ( 0.2 eq) and 2-bromoethylbenzene (3.0 eq) were added. The reaction was heated in an oil bath at 70 ° C. for 16 hours, after which time it was purified directly using flash silica gel chromatography (ethyl acetate / hexanes) to yield amine III-29 as an oil. [M + H] + = 324.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-30は、1-フェニル-4-ピペリドンを1-(tert-ブトキシカルボニル)-4-ピペリドンの代わりに使用する以外は、実施例290と同様の手順を使用し、調製した。[M+H]+＝297.0m/z。活性：B。 (Example 311)

3-Bromo-4,5-dihydroisoxazole III-30 is the same as Example 290 except that 1-phenyl-4-piperidone is used instead of 1- (tert-butoxycarbonyl) -4-piperidone. The procedure was used and prepared. [M + H] + = 297.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-30を、クロロホルム(イソオキサゾールに対して0.01M)中に溶解し、その後臭素(1.0当量)を添加した。この反応物を16時間攪拌させ、この時点の後、水で希釈し、かつ飽和Na₂CO₃で洗浄した。その後有機層を硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、化合物III31を黄色固形物として生じた。[M+H]+＝377.0m/z。活性：B。 (Example 312)

3-Bromo-4,5-dihydroisoxazole III-30 was dissolved in chloroform (0.01 M relative to isoxazole) followed by addition of bromine (1.0 eq). The reaction was allowed to stir for 16 hours after which time it was diluted with water and washed with saturated Na ₂ CO ₃ . The organic layer was then dried over sodium sulfate and concentrated under vacuum to yield compound III31 as a yellow solid. [M + H] + = 377.0 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-32は、シクロヘキサンカルボキシアルデヒドをベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝390.5m/z。活性：A。 (Example 313)

3-Bromo-4,5-dihydroisoxazole III-32 was prepared using a procedure similar to Example 300, except that cyclohexanecarboxaldehyde was used in place of benzaldehyde. [M + H] + = 390.5 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-33は、ピバルアルデヒド(pivaldehyde)をベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝290.5m/z。活性：B。 (Example 314)

3-Bromo-4,5-dihydroisoxazole III-33 was prepared using a procedure similar to Example 300 except that pivalaldehyde was used instead of benzaldehyde. [M + H] + = 290.5 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-34は、ヒドロシンナムアルデヒドを塩化ベンゾイルの代わりに使用する以外は、実施例297と同様の手順を使用し、調製した。[M+H]+＝352.8m/z。活性：A。 (Example 315)

3-Bromo-4,5-dihydroisoxazole III-34 was prepared using a procedure similar to Example 297, except that hydrocinnamaldehyde was used instead of benzoyl chloride. [M + H] + = 352.8 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-35は、クロロギ酸メチルをクロロギ酸ベンジルの代わりに使用する以外は、実施例299と同様の手順を使用し、調製した。[M+H]+＝378.8m/z。活性：B。 (Example 316)

3-Bromo-4,5-dihydroisoxazole III-35 was prepared using a procedure similar to Example 299 except that methyl chloroformate was used in place of benzyl chloroformate. [M + H] + = 378.8 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-36は、クロロギ酸iso-ブチルをクロロギ酸ベンジルの代わりに使用する以外は、実施例299と同様の手順を使用し、調製した。[M+H]+＝318.7m/z。活性：A。 (Example 317)

3-Bromo-4,5-dihydroisoxazole III-36 was prepared using a procedure similar to Example 299 except that iso-butyl chloroformate was used in place of benzyl chloroformate. [M + H] + = 318.7 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-37は、クロロギ酸フェニルをクロロギ酸ベンジルの代わりに使用する以外は、実施例299と同様の手順を使用し、調製した。[M+H]+＝340.7m/z。活性：A。 (Example 318)

3-Bromo-4,5-dihydroisoxazole III-37 was prepared using a procedure similar to Example 299 except that phenyl chloroformate was used instead of benzyl chloroformate. [M + H] + = 340.7 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-38は、クロロギ酸2,2,2-トリクロロエチルをクロロギ酸ベンジルの代わりに使用する以外は、実施例299と同様の手順を使用し、調製した。[M+H]+＝394.5m/z。活性：B。 (Example 319)

3-Bromo-4,5-dihydroisoxazole III-38 was prepared using a procedure similar to Example 299, except that 2,2,2-trichloroethyl chloroformate was used instead of benzyl chloroformate. did. [M + H] + = 394.5 m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII14を、塩化メチレン(イソオキサゾールに対して0.05M)中に溶解し、その後トリエチルアミン(5.0当量)及びカルボニルジイミダゾール(1.25当量)を添加した。この反応物を2時間攪拌させ、この時点の後、アニシルアルコール(2.5当量)を添加し、引き続き触媒の硫酸水素テトラブチルアンモニウム及び50％水酸化ナトリウム水溶液(イソオキサゾールに対して0.10M)を添加した。この不均一な混合物を、16時間攪拌させ、この時点の後、酢酸エチルで希釈した。水層を、酢酸エチルで更に2回洗浄し、その後これらの有機層を一緒にし、硫酸ナトリウム上で乾燥し、真空下で濃縮し、粗物質を提供し、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、カルバメートIII-39を白色固形物として生じた。[M+H]+＝382.9m/z。活性：A。 (Example 320)

3-Bromo-4,5-dihydroisoxazole III14 was dissolved in methylene chloride (0.05M relative to isoxazole) followed by addition of triethylamine (5.0 eq) and carbonyldiimidazole (1.25 eq). The reaction was allowed to stir for 2 hours after which time anisyl alcohol (2.5 eq) was added followed by the catalyst tetrabutylammonium hydrogen sulfate and 50% aqueous sodium hydroxide (0.10 M relative to isoxazole). Added. The heterogeneous mixture was allowed to stir for 16 hours after which time it was diluted with ethyl acetate. The aqueous layer is washed twice more with ethyl acetate, after which these organic layers are combined, dried over sodium sulfate and concentrated in vacuo to provide the crude material which is purified by flash silica gel chromatography (ethyl acetate). / Hexane) to give carbamate III-39 as a white solid. [M + H] + = 382.9 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-40は、4-クロロベンジルアルコールをアニシルアルコールの代わりに使用する以外は、実施例320と同様の手順を使用し、調製した。[M+H]+＝388.8m/z。活性：A。 (Example 321)

3-Bromo-4,5-dihydroisoxazole III-40 was prepared using a procedure similar to Example 320, except that 4-chlorobenzyl alcohol was used in place of anisyl alcohol. [M + H] + = 388.8m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-41a及びIII-41bは、ラセミ体sec-フェネチルアルコールをアニシルアルコールの代わりに使用する以外は、実施例320と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝368.8m/z。活性：A。 (Example 322)

3-Bromo-4,5-dihydroisoxazole III-41a and III-41b were prepared using a procedure similar to Example 320, except that racemic sec-phenethyl alcohol was used in place of anisyl alcohol. did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 368.8 m / z. Activity: A.

3-シクロペンテン-1-オール(1.0当量)を、N,N-ジメチルホルムアミド(アルコールに対して0.80M)中に溶解し、かつTBAI(0.10当量)、引き続き粉砕した水酸化ナトリウム(2.0当量)で処理した。その後臭化ベンジル(1.2当量)を添加し、この反応物を室温で48時間攪拌させた。次にこの反応物を、tert-ブチルメチルエーテルで希釈し、かつ希Na₂S₂O₃及びブラインで洗浄した。その後有機層を硫酸ナトリウム上で乾燥し、真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、所望のシクロアルケンを無色の油状物として生じた。この化合物を次に、方法1に概説した付加環化手順を使用し、所望の3-ブロモ-4,5-ジヒドロイソオキサゾールIII-42に変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝295.0m/z。活性：B。 (Example 323)

3-Cyclopenten-1-ol (1.0 eq) was dissolved in N, N-dimethylformamide (0.80 M relative to alcohol) and TBAI (0.10 eq) followed by ground sodium hydroxide (2.0 eq). Processed. Benzyl bromide (1.2 eq) was then added and the reaction was allowed to stir at room temperature for 48 hours. The reaction was then diluted with tert-butyl methyl ether and washed with dilute Na ₂ S ₂ O ₃ and brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to give a crude material that is purified using flash silica gel chromatography (ethyl acetate / hexanes) to give the desired cycloalkene as a colorless oil. occured. This compound was then converted to the desired 3-bromo-4,5-dihydroisoxazole III-42 using the cycloaddition procedure outlined in Method 1. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 295.0m / z. Activity: B.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-43a及びIII-43bを、N-(tert-ブトキシカルボニル)-2,5-ジヒドロ-1H-ピロールから、方法1を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M-H]-＝290.0m/z。活性：B。 (Example 324)

3-Bromo-4,5-dihydroisoxazole III-43a and III-43b prepared from N- (tert-butoxycarbonyl) -2,5-dihydro-1H-pyrrole in one step using Method 1 did. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [MH]-= 290.0 m / z. Activity: B.

ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-43を、トリフルオロ酢酸(イソオキサゾールに対して0.20M)中に溶解し、かつ室温で1時間攪拌した。その後溶媒を真空下で除去し、かつこの粗残渣を、トルエン(2×)と共沸し、トリフルオロ酢酸塩を白色固形物として生じ、これを塩化メチレン(イソオキサゾール(isozaole)に対して0.05M)中に溶解し、その後トリエチルアミン(4.0当量)及びクロロギ酸ベンジル(1.25当量)を添加した。この反応物を16時間攪拌させ、この時点の後、酢酸エチルで希釈し、かつ希HCl、希NaOH、その後ブラインで洗浄した。次にこの有機層を硫酸ナトリウム上で乾燥し、真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、カルバメートIII-44を白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝324.6m/z。活性：A。 (Example 325)

Racemic 3-bromo-4,5-dihydroisoxazole III-43 was dissolved in trifluoroacetic acid (0.20M relative to isoxazole) and stirred at room temperature for 1 hour. The solvent is then removed in vacuo and the crude residue is azeotroped with toluene (2 ×) to yield the trifluoroacetate salt as a white solid, which is methylene chloride (0.05% relative to isozaole). M), then triethylamine (4.0 eq) and benzyl chloroformate (1.25 eq) were added. The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute HCl, dilute NaOH, then brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to yield a crude material that is purified using flash silica gel chromatography (ethyl acetate / hexanes) to give carbamate III-44 as a white solid. As a result. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 324.6 m / z. Activity: A.

ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-43を、トリフルオロ酢酸(イソオキサゾールに対して0.20M)中に溶解し、室温で1時間攪拌した。その後溶媒を真空下で除去し、かつ粗残渣をトルエン(2×)と共沸し、トリフルオロ酢酸塩を白色固形物として生じ、これを次に塩化メチレン(イソオキサゾールに対して0.06M)中に溶解し、その後トリエチルアミン(2.5当量)及び4-クロロベンズアルデヒド(1.25当量)を添加し、引き続きトリアセトキシ水素化ホウ素ナトリウム(1.5当量)を添加した。この反応物を16時間攪拌させ、この時点の後酢酸エチルで希釈し、希NaOH、その後ブラインで洗浄した。次に有機層を硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)を用いて精製し、N-ベンジルピペリジンIII-45を白色固形物として生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝316.6m/z。活性：C。 (Example 326)

Racemic 3-bromo-4,5-dihydroisoxazole III-43 was dissolved in trifluoroacetic acid (0.20M relative to isoxazole) and stirred at room temperature for 1 hour. The solvent is then removed under vacuum and the crude residue is azeotroped with toluene (2 ×) to yield the trifluoroacetate salt as a white solid, which is then in methylene chloride (0.06M for isoxazole) Then triethylamine (2.5 eq) and 4-chlorobenzaldehyde (1.25 eq) were added followed by sodium triacetoxyborohydride (1.5 eq). The reaction was allowed to stir for 16 hours, after which time it was diluted with ethyl acetate and washed with dilute NaOH followed by brine. The organic layer is then dried over sodium sulfate and concentrated in vacuo to yield a crude material that is purified using flash silica gel chromatography (ethyl acetate / hexanes) to give N-benzylpiperidine III-45. Occurs as a white solid. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 316.6 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-46を、化合物III18及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。[M+H]+＝369.4m/z。活性：A。 (Example 327)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-46 was prepared from compound III18 and 3-hydroxypyridine using Method 5 in one step. [M + H] + = 369.4 m / z. Activity: A.

3-クロロ-4,5-ジヒドロイソオキサゾールIII-47を、方法6を使用する1-(tert-ブトキシカルボニル)-4-ピペリドンからのアルケン形成で出発し、それに続きN-クロロスクシンアミドをN-ブロモスクシンアミドの代わりに使用する以外は、方法2を使用する付加環化の2工程で調製した。[M+H]+＝274.9m/z。活性：A。 Example 328

3-Chloro-4,5-dihydroisoxazole III-47 was started with alkene formation from 1- (tert-butoxycarbonyl) -4-piperidone using Method 6, followed by N-chlorosuccinamide. Prepared in two steps of cycloaddition using method 2, except used instead of N-bromosuccinamide. [M + H] + = 274.9 m / z. Activity: A.

3-クロロ-4,5-ジヒドロイソオキサゾールIII-48を、3-クロロ-4,5-ジヒドロイソオキサゾールIII-47を、3-ブロモ-4,5-ジヒドロイソオキサゾールIII9の代わりに使用する以外は、実施例301と同様の手順を使用し、調製した。[M+H]+＝298.6m/z。活性：A。 (Example 329)

Other than using 3-chloro-4,5-dihydroisoxazole III-48 and 3-chloro-4,5-dihydroisoxazole III-47 instead of 3-bromo-4,5-dihydroisoxazole III9 Was prepared using the same procedure as Example 301. [M + H] + = 298.6 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-49を、4-エチニルカルボキシアルデヒドを、ベンズアルデヒドの代わりに使用する以外は、実施例300と同様の手順を使用し、調製した。[M+H]+＝335.1m/z。活性：A。 (Example 330)

3-Bromo-4,5-dihydroisoxazole III-49 was prepared using a procedure similar to Example 300 except that 4-ethynylcarboxaldehyde was used in place of benzaldehyde. [M + H] + = 335.1 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-50を、化合物III-49及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。[M+H]+＝348.6m/z。活性：A。 (Example 331)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-50 was prepared from compound III-49 and 3-hydroxypyridine using Method 5 in one step. [M + H] + = 348.6 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII51を、化合物III-20及び3-ヒドロキシピリジンから、方法5を使用し、1工程で調製した。[M-H]-＝358.1m/z。活性：A。 (Example 332)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III51 was prepared from compound III-20 and 3-hydroxypyridine using Method 5 in one step. [MH]-= 358.1m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-52を、化合物III-20及び5-ヒドロキシピリミジンから、方法5を使用し、1工程で調製した。[M+H]+＝360.2m/z。活性：A。 (Example 333)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole III-52 was prepared from compound III-20 and 5-hydroxypyrimidine in one step using Method 5. [M + H] + = 360.2 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-54は、化合物III9から3工程で調製し、方法5を使用する、化合物III9及び5-ヒドロキシピリミジンからの3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII53の合成により出発する。次に化合物III-53を、実施例295と類似の条件を使用し脱保護し、その後ヒドロシンナムアルデヒドを塩化ベンゾイルの代わりに使用する以外は、実施例297と同様の手順を使用し、所望の生成物III54に変換した。[M+H]+＝367.6m/z。活性：B。 (Example 334)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole III-54 was prepared in 3 steps from compound III9 and 3- (pyridine from 5-hydroxypyrimidine using method 5 using method 5. Starting with the synthesis of -3-yloxy) -4,5-dihydroisoxazole III53. Compound III-53 is then deprotected using conditions similar to Example 295, followed by the same procedure as Example 297, except that hydrocinnamaldehyde is used in place of benzoyl chloride and the desired Conversion to product III54. [M + H] + = 367.6 m / z. Activity: B.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-55を、化合物III9から、4-クロロベンゾイルクロリドを、ヒドロシンナムアルデヒドの代わりに使用する以外は、実施例334と同様の手順を使用し、3工程で調製した。[M-H]-＝372.9m/z。活性：A。 (Example 335)

Similar to Example 334 except that 3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole III-55 was used from compound III9 and 4-chlorobenzoyl chloride was used instead of hydrocinnamaldehyde. The procedure was used and prepared in 3 steps. [MH]-= 372.9m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-56を、化合物III-53から、実施例295に類似の条件を使用する脱保護から出発し、2工程で合成した。次に得られたトリフルオロ酢酸塩(1.0当量)を、塩化メチレン(イソオキサゾールに対して0.11M)中に溶解し、その後イソシアン酸フェニル(1.5当量)を添加し、引き続きピリジン(5.0当量)を添加した。この反応物を室温で一晩攪拌させ、この時点の後反応物を、過剰な水及び塩化メチレンと共に分液漏斗に移した。有機層を、飽和炭酸水素ナトリウム(2×)で洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、白色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/メタノール勾配)により精製した。[M+H]+＝353.6m/z。活性：C。 (Example 336)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole III-56 was synthesized from compound III-53 starting in deprotection using conditions similar to Example 295 in two steps. The resulting trifluoroacetate salt (1.0 eq) is then dissolved in methylene chloride (0.11 M with respect to isoxazole) followed by the addition of phenyl isocyanate (1.5 eq) followed by pyridine (5.0 eq). Added. The reaction was allowed to stir overnight at room temperature, after which time 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 give a white solid that was purified by flash silica gel chromatography (ethyl acetate / methanol gradient). [M + H] + = 353.6 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-57を、化合物III-53から、実施例295に類似の条件を使用する脱保護から出発し、2工程で合成した。次に得られたトリフルオロ酢酸塩(1.0当量)を、塩化メチレン(イソオキサゾールに対して0.11M)中に溶解し、その後5,5,5-トリフルオロペンタン酸(1.5当量)、EDC(1.5当量)及びトリエチルアミン(3.0当量)を添加した。この反応物を室温で14時間攪拌させ、この時点の後反応物を、過剰な水及び塩化メチレンと共に分液漏斗に移した。有機層を、飽和炭酸水素ナトリウム(2×)で洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、白色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/メタノール勾配)により精製した。[M+H]+＝373.7m/z。活性：C。 (Example 337)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-57 was synthesized from compound III-53 starting from deprotection using conditions similar to Example 295 in two steps. The resulting trifluoroacetate salt (1.0 eq) was then dissolved in methylene chloride (0.11 M with respect to isoxazole) followed by 5,5,5-trifluoropentanoic acid (1.5 eq), EDC (1.5 eq) Eq) and triethylamine (3.0 eq) were added. The reaction was allowed to stir at room temperature for 14 hours, after which time 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 give a white solid that was purified by flash silica gel chromatography (ethyl acetate / methanol gradient). [M + H] + = 373.7 m / z. Activity: C.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-58を、化合物III16から、以下の手順に従い3工程で合成した：6-(メチルチオ)ピリジン-3-オールを、方法11を使用し、6-(メチルチオ)ピリジン-3-イルボロン酸から調製した。その後、3-ブロモ-4,5-ジヒドロキシオキサゾールIII16を、6-(メチルチオ)ピリジン-3-オールと、方法5を用いて反応させた。得られた3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールを、塩化メチレン(イソオキサゾールに対して0.5M)中に溶解し、この時点の後、m-クロロ過安息香酸(2.0当量)を1部分で添加し、かつこの反応物を室温で1時間攪拌させた。LC/MSにより反応が完了したことを決定した後、この反応物を、過剰な水及び塩化メチレンと共に分液漏斗に移した。有機層を、飽和炭酸水素ナトリウム(2×)及び1N NaOH(1×)で洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、白色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/メタノール勾配)により精製した。[M+H]+＝415.8m/z。活性：B。 (Example 338)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-58 was synthesized from compound III16 in three steps according to the following procedure: 6- (Methylthio) pyridin-3-ol was synthesized in Method 11 Was prepared from 6- (methylthio) pyridin-3-ylboronic acid. Subsequently, 3-bromo-4,5-dihydroxyoxazole III16 was reacted with 6- (methylthio) pyridin-3-ol using Method 5. The resulting 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole is dissolved in methylene chloride (0.5M relative to isoxazole), after which time m-chloroperbenzoic acid ( 2.0 equivalents) was added in one portion and the reaction was allowed to stir at room temperature for 1 hour. After determining that the reaction was complete 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 (2 ×) and 1N NaOH (1 ×), dried over magnesium sulfate and concentrated to give a white solid which was purified by flash silica gel chromatography (ethyl acetate / (Methanol gradient). [M + H] + = 415.8m / z. Activity: B.

3-(ピロリジン-1-イル)-4,5-ジヒドロイソオキサゾールIII-59を、以下の手順に従い1工程で調製した：3-ブロモ-4,5-ジヒドロイソオキサゾールIII18(1.0当量)を、n-ブタノール(0.64M)中に溶解し、引き続きピロリジン(1.2当量)及び炭酸ナトリウム(2.5当量)を添加した。この反応物を密封し、油浴中で120℃で18時間加熱し、その後これを冷却し、次に過剰な水及びtert-ブチルメチルエーテルと共に分液漏斗に移した。水層を、tert-ブチルメチルエーテル(2×)で洗浄し、一緒にした有機層を、ブラインで洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、オレンジ色固形物を生じ、これをフラッシュシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン勾配)により精製し、化合物III-59を白色固形物として生じた。[M+H]+＝345.4m/z。活性：C。 (Example 339)

3- (Pyrrolidin-1-yl) -4,5-dihydroisoxazole III-59 was prepared in one step according to the following procedure: 3-Bromo-4,5-dihydroisoxazole III18 (1.0 equiv.) Dissolved in n-butanol (0.64M) followed by addition of pyrrolidine (1.2 eq) and sodium carbonate (2.5 eq). The reaction was sealed and heated in an oil bath at 120 ° C. for 18 hours, after which it was cooled and then transferred to a separatory funnel with excess water and tert-butyl methyl ether. The aqueous layer is washed with tert-butyl methyl ether (2 ×) and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated to give an orange solid that is flushed Purification by silica gel chromatography (ethyl acetate / hexane gradient) gave compound III-59 as a white solid. [M + H] + = 345.4 m / z. Activity: C.

ヨウ化1-(4,5-ジヒドロイソオキサゾール-3-イル)-1-メチルピロリジニウムIII-60を、以下の手順に従い合成した：3-(ピロリジン-1-イル)-4,5-ジヒドロイソオキサゾールIII-59を、メタノール(0.044M)中に溶解し、引き続きヨウ化メチル(0.022M)を添加した。この反応物を、72時間静置させ、その後これを濃縮し、高圧液体クロマトグラフィー(0.1％ギ酸)を用いて精製した。所望の画分を凍結乾燥し、所望の生成物と若干の不純物を生じ、この固形物をヘキサンで洗浄することにより不純物を除去した。活性：C。 (Example 340)

1- (4,5-Dihydroisoxazol-3-yl) -1-methylpyrrolidinium III-60 iodide was synthesized according to the following procedure: 3- (Pyrrolidin-1-yl) -4,5- Dihydroisoxazole III-59 was dissolved in methanol (0.044M) followed by addition of methyl iodide (0.022M). The reaction was allowed to stand for 72 hours, after which it was concentrated and purified using high pressure liquid chromatography (0.1% formic acid). The desired fraction was lyophilized to yield the desired product and some impurities, which were removed by washing the solid with hexane. Activity: C.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-62a及びIII-62bを、以下の手順に従い、3工程で合成した：フェニルボロン酸(2.0当量)を、トルエン(ボロン酸に対して0.23M)中に懸濁し、溶液が生じるまで加熱した。溶媒を蒸発させ、このプロセスを繰り返した。次に得られた無水物を、塩化メチレン(0.23M)中に再度溶解した。6-ヒドロキシ-3,4-ジヒドロナフタレン-1(2H)-オン(1.0当量)、トリエチルアミン(5.0当量)及び酢酸銅(0.95当量)を添加し、この反応物を密封し、かつ室温で16時間攪拌した。次にこの混合物を、過剰な塩化メチレン及び水と共に分液漏斗に移した。その後有機層を、水、希水酸化ナトリウム、及びブラインで洗浄した。有機層を硫酸ナトリウムで乾燥し、かつ濃縮し、化合物III61を茶色油状物として生じ、これを方法5、引き続き方法1を使用し、ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-62に直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝359.5m/z。活性：A。 (Example 341)

3-Bromo-4,5-dihydroisoxazole III-62a and III-62b were synthesized in 3 steps according to the following procedure: Phenylboronic acid (2.0 eq) was added to toluene (0.23M relative to boronic acid) Suspended in and heated until a solution formed. The solvent was evaporated and the process was repeated. The resulting anhydride was then redissolved in methylene chloride (0.23M). 6-Hydroxy-3,4-dihydronaphthalen-1 (2H) -one (1.0 eq), triethylamine (5.0 eq) and copper acetate (0.95 eq) were added and the reaction was sealed and at room temperature for 16 h. Stir. The mixture was then transferred to a separatory funnel with excess methylene chloride and water. The organic layer was then washed with water, dilute sodium hydroxide, and brine. The organic layer is dried over sodium sulfate and concentrated to yield compound III61 as a brown oil, which is obtained using Method 5, followed by Method 1, to give racemic 3-bromo-4,5-dihydroisoxazole III-62. Converted directly to These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 359.5 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-63a及びIII-63bは、5-ヒドロキシ-2,3-ジヒドロ-1H-インデン-1-オンを、第一工程の出発物質として6-ヒドロキシ-3,4-ジヒドロナフタレン-1(2H)-オンの代わりに使用する以外は、実施例341と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝343.7m/z。活性：A。 (Example 342)

3-Bromo-4,5-dihydroisoxazole III-63a and III-63b are 5-hydroxy-2,3-dihydro-1H-inden-1-one as the starting material for the first step, 6-hydroxy- Prepared using a procedure similar to that in Example 341 except that it was used instead of 3,4-dihydronaphthalen-1 (2H) -one. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 343.7 m / z. Activity: A.

3-(ピリミジン-5-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-60a及びIII-60bを、方法5を使用し、ラセミ化合物III-63及び5-ヒドロキシピリミジンから、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝361.2m/z。活性：A。 (Example 343)

3- (Pyrimidin-5-yloxy) -4,5-dihydroisoxazole III-60a and III-60b were prepared in one step from racemic compound III-63 and 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 361.2 m / z. Activity: A.

3-ブロモ-4,5-ジヒドロイソオキサゾールIII-66a及びIII-66bを、以下の手順に従い、4工程で合成した：10/30温度計挿入口を備えた250mLの丸底フラスコに、攪拌棒、アナログ式温度計、及びAllihn冷却器を装着した。3-(3-(トリフルオロメトキシ)フェニル)プロパン酸(0.22mol, 1.0当量)を添加し、塩化チオニル(6.0当量)中に溶解し、かつ油浴中で1時間還流し、この間その内部温度は1時間にわたり78〜82℃であった。この時点で、冷却器を短いヘッド(short-path head)と、及び温度計を乾燥アルゴンの流入口と交換し、かつ揮発物を蒸留により除去した。蒸留が完了した時点で、このポットにシクロヘキサン(100mL)を添加し、同じ方式で蒸留除去させ、所望の酸塩化物を定量的収率で茶色油状物として生じ、これを直接使用した。次に2Lの3首丸底フラスコに、機械式攪拌子、熱電対プローブ、及び250-mLの側管付き滴下ロートを装着した。これに、三塩化アルミニウム(0.233mol, 1.08当量)及び塩化メチレン(0.24M)を充填し、次に可能な限り多く溶解するよう、45分間攪拌した。その後この反応物を氷浴中で、内部温度＜2.5℃まで冷却した。塩化メチレン200ml中の酸塩化物(1.0当量, 0.215mol)の溶液を、15分間かけて、滴下ロートを介して添加した。添加が完了した後、氷を浴から取り外し、室温の水と交換し(浴の温度18℃)、かつ反応を2時間以上進行させ、この時点でTLC及びLC/MS分析により反応が完了したことが示された。次にこの反応混合物を、氷(500g)、次に水(600mL)で処理し、その後この混合物を、全ての固形物が溶解するまで、1時間攪拌した。これらの層を分離し、水層を、ジエチルエーテル(350mL)で抽出した。一緒にした有機物を、水(250mL、1×)、半飽和炭酸水素ナトリウム(250mL、1×)、ブライン(250mL、1×)で洗浄し、硫酸マグネシウム上で乾燥し、かつ濃縮し、5-(トリフルオロメトキシ)-2,3-ジヒドロ-1H-インデン-1-オンIII-65をピンク色固形物として定量的収率で生じた。この物質を次に、方法5、引き続き方法1を使用し、ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-66へ直接変換した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝335.6m/z。活性：A。 Example 344

3-Bromo-4,5-dihydroisoxazole III-66a and III-66b were synthesized in 4 steps according to the following procedure: In a 250 mL round bottom flask equipped with a 10/30 thermometer inlet, stir bar An analog thermometer and an Allihn cooler were installed. Add 3- (3- (trifluoromethoxy) phenyl) propanoic acid (0.22 mol, 1.0 eq), dissolve in thionyl chloride (6.0 eq) and reflux in an oil bath for 1 h, during which the internal temperature Was 78-82 ° C over 1 hour. At this point, the condenser was replaced with a short-path head, and the thermometer replaced with a dry argon inlet, and volatiles were removed by distillation. When distillation was complete, cyclohexane (100 mL) was added to the pot and distilled off in the same manner, yielding the desired acid chloride as a brown oil in quantitative yield, which was used directly. Next, a 2 L 3-neck round bottom flask was equipped with a mechanical stirrer, thermocouple probe, and 250-mL dropping funnel with side tube. This was charged with aluminum trichloride (0.233 mol, 1.08 equivalents) and methylene chloride (0.24M) and then stirred for 45 minutes to dissolve as much as possible. The reaction was then cooled to an internal temperature <2.5 ° C. in an ice bath. A solution of acid chloride (1.0 eq, 0.215 mol) in 200 ml of methylene chloride was added via a dropping funnel over 15 minutes. After the addition was complete, the ice was removed from the bath, replaced with room temperature water (bath temperature 18 ° C.), and the reaction was allowed to proceed for at least 2 hours, at which point the reaction was complete by TLC and LC / MS analysis It has been shown. The reaction mixture was then treated with ice (500 g) followed by water (600 mL), after which the mixture was stirred for 1 hour until all solids dissolved. The layers were separated and the aqueous layer was extracted with diethyl ether (350 mL). The combined organics were washed with water (250 mL, 1 ×), half-saturated sodium bicarbonate (250 mL, 1 ×), brine (250 mL, 1 ×), dried over magnesium sulfate and concentrated, 5- (Trifluoromethoxy) -2,3-dihydro-1H-inden-1-one III-65 was produced as a pink solid in quantitative yield. This material was 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. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 335.6 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-67a及びIII-67bを、最初に6-(メチルチオ)ピリジン-3-オールを、6-(メチルチオ)ピリジン-3-イルボロン酸から、方法11を使用し調製した後、ラセミ化合物III-66及び6-(メチルチオ)ピリジン-3-オールから、方法5を使用し、2工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝396.7m/z。活性：A。 (Example 345)

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole III-67a and III-67b, first 6- (methylthio) pyridin-3-ol, 6- (methylthio) pyridin-3-ylboron Prepared from the acid using Method 11 and then from racemic III-66 and 6- (methylthio) pyridin-3-ol using Method 5 and prepared in two steps. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 396.7 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-68a及びIII-68bを、ラセミ化合物III-67から、実施例338と類似の酸化条件を使用し、1工程で調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝429.4m/z。活性：A。 (Example 346)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-68a and III-68b were prepared from racemic compound III-67 in one step using oxidation conditions similar to Example 338. . These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 429.4 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-70a及びIII-70bを、以下の手順に従い、2工程で調製した：6-ブロモピリジン-3-オール(1.0当量)及び炭酸ナトリウム(10.0当量)を、マイクロ波用バイアルに添加した。トルエン、エタノール、及び水(0.16M、2:2:1v/v)を添加し、引き続き1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(1.5当量)を添加した。この混合物を、アルゴンで15分間パージし、引き続きテトラキスパラジウム(4mol％)を添加した。その後この反応チューブを、アルミ箔で覆い、油浴中で80℃で17時間加熱した。冷却後、反応物を、過剰な水及び酢酸エチルと共に分液漏斗に移した。その後有機層を、水(1×)、飽和塩化アンモニウム(1×)及びブライン(1×)で洗浄した。水層を一緒にし、酢酸エチル(1×)で洗浄した。有機層をその後一緒にし、硫酸ナトリウムで乾燥し、かつ濃縮し、フラッシュシリカゲルクロマトグラフィー(メタノール/塩化メチレン勾配)により精製し、6-(1-メチル-1H-ピラゾール-4-イル)ピリジン-3-オールIII-69を白色固形物として生じた。この化合物を次に、方法5を使用し、ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII66と反応させ、所望のラセミ化合物III-70を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝430.0m/z。活性：A。 (Example 347)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-70a and III-70b were prepared in two steps according to the following procedure: 6-bromopyridin-3-ol (1.0 eq) and Sodium carbonate (10.0 equiv) was added to the microwave vial. Toluene, ethanol, and water (0.16M, 2: 2: 1 v / v) were added followed by 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -1H-pyrazole (1.5 eq) was added. The mixture was purged with argon for 15 minutes, followed by the addition of tetrakis palladium (4 mol%). The reaction tube was then covered with aluminum foil and heated in an oil bath at 80 ° C. for 17 hours. After cooling, the reaction was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with water (1 ×), saturated ammonium chloride (1 ×) and brine (1 ×). The aqueous layers were combined and washed with ethyl acetate (1 ×). The organic layers are then combined, dried over sodium sulfate and concentrated, purified by flash silica gel chromatography (methanol / methylene chloride gradient) to give 6- (1-methyl-1H-pyrazol-4-yl) pyridine-3. -All III-69 was produced as a white solid. This compound was then reacted with racemic 3-bromo-4,5-dihydroisoxazole III66 using Method 5 to yield the desired racemic compound III-70. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 430.0 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-71a及びIII-71bは、1-メチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールを第一工程におけるボロン酸塩(boronoate)として1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾールの代わりに使用する以外は、実施例347と同様の手順を使用し、調製した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝430.0m/z。活性：A。 (Example 348)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-71a and III-71b are 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2- 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- (dioxaborolan-2-yl) -1H-pyrazole as the boronate in the first step Yl) Prepared using a procedure similar to that in Example 347 except that it was used instead of 1H-pyrazole. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 430.0 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-73a及びIII-73bを、以下の手順に従い、3工程で調製した：5-ヒドロキシニコチン酸メチルエステル(1.0当量)を、メタノール(0.08M)中に溶解し、その後ヒドラジン(50当量、水中50重量％)を添加し、この反応物を14時間攪拌させた。次に反応混合物を、真空下で濃縮し、かつ次工程で直接使用した。オルトギ酸トリエチル(8.0当量)を添加し、かつこの反応物を密封し、14時間還流加熱した。次にこの反応物を、過剰な酢酸エチル及び水と共に分液漏斗に移した。有機層を、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥し、かつ真空下で濃縮し、粗物質を生じ、これをフラッシュシリカゲルクロマトグラフィー(メタノール/塩化メチレン勾配)により精製し、所望のオキサジアゾールIII-72を生じた。この化合物を次に、方法5を使用し、ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-66と反応させ、所望のラセミ化合物III-73を生じた。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝419.5m/z。活性：A。 (Example 349)

3- (Pyridin-3-yloxy) -4,5-dihydroisoxazole III-73a and III-73b were prepared in 3 steps according to the following procedure: 5-Hydroxynicotinic acid methyl ester (1.0 equiv.) Dissolved in methanol (0.08M), then hydrazine (50 eq, 50 wt% in water) was added and the reaction was allowed to stir for 14 hours. The reaction mixture was then concentrated under vacuum and used directly in the next step. Triethylorthoformate (8.0 eq) was added and the reaction was sealed and heated to reflux for 14 hours. The reaction was then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a crude material which is purified by flash silica gel chromatography (methanol / methylene chloride gradient) to give the desired oxa Diazole III-72 was produced. This compound was then reacted with racemic 3-bromo-4,5-dihydroisoxazole III-66 using Method 5 to yield the desired racemic compound III-73. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 419.5 m / z. Activity: A.

3-(ピリジン-3-イルオキシ)-4,5-ジヒドロイソオキサゾールIII-74a及びIII-74bの鏡像異性体を、以下の手順に従い、2工程で調製した：ラセミ体3-ブロモ-4,5-ジヒドロイソオキサゾールIII-66を、方法5を使用し、5-ヒドロキシニコチン酸メチルエステルと反応させた。得られたエステル(1.0当量)を、1:1テトラヒドロフラン/水(0.06M)中に溶解し、水酸化リチウム(8.0当量)を添加した。この反応物を、室温で1時間攪拌させ、この時点の後、テトラヒドロフランを、窒素流れ下で除去し、残存する溶液を、1N HClによりpH＜2まで酸性とし、ラセミ体の所望の酸III-74を白色固形物として生じ、これを真空濾過により単離した。これらの化合物は、当該技術分野において公知のキラルHPLC法を用いて分離することができる。例えば、本明細書に開示されたキラルHPLC法を参照のこと。[M+H]+＝395.5m/z。活性：A。 (Example 350)

The enantiomers of 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole III-74a and III-74b were prepared in two steps according to the following procedure: Racemic 3-bromo-4,5 -Dihydroisoxazole III-66 was reacted with 5-hydroxynicotinic acid methyl ester using Method 5. The resulting ester (1.0 eq) was dissolved in 1: 1 tetrahydrofuran / water (0.06M) and lithium hydroxide (8.0 eq) was added. The reaction was allowed to stir at room temperature for 1 hour after which time the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified with 1N HCl to pH <2 to give the racemic desired acid III- 74 was produced as a white solid which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. See, for example, the chiral HPLC method disclosed herein. [M + H] + = 395.5 m / z. Activity: A.

(Example 351)
(Inhibition of human FAAH)
(Preparation of human FAAH): COS-7 cells were split 1: 5 the day before and loaded into a 150 mm × 25 mm cell culture dish (Corning, catalog number 430599). FuGENE 6 transfection reagent (Roche, catalog number 11814443001) resulted in transient transfection at 30-40% confluence.

  (Transfection procedure): FuGENE transfection 6 reagent (45 uL) was added to 1410 μL of medium (DMEM, serum-free penicillin / streptomycin free) in a 15 mL conical tube, incubated for 5 min at room temperature, then FAAH Plasmid DNA (15 μg) (OriGene catalog number TC119221, Genbank deposit number NM — 001441.1, 0.67 ug / uL) was added, and further incubated at room temperature for 15 minutes. The resulting solution was added dropwise to one dish of 30-40% confluent COS-7 cells. Subsequently, the COS-7 cell dish was incubated for 48 hours. Cells were then harvested.

  (Recovery procedure): The medium was aspirated from the dish and the cells were rinsed with 10 mL PBS. PBS was removed and 3 mL of PBS was added to the dish. The dish was rubbed to resuspend the cells and the subsequent cell suspension was collected in a 15 mL conical tube. Cells were pelleted by centrifugation at 1200 rpm for 5 minutes in a bench top centrifuge. PBS was removed and the cell pellet was snap frozen in liquid nitrogen and stored at -80 ° C.

(COS-7 cell-FAAH purification):
(1) Fractionation: Thaw frozen cell pellet from transient transfection on ice and resuspend in 12.5 mM Hepes (pH 8.0), 100 mM NaCl, 1 mM EDTA (10 mL / 0.2 g cell pellet) I let you. The pellet was dounce homogenized and then sonicated to produce a cell extract. Subsequently, the cell extract was centrifuged at 1000 g to remove cell debris. The pellet was discarded and the supernatant was centrifuged at 13000 g for 20 minutes. The pellet contained membrane bound FAAH. The supernatant was discarded and the pellet was redissolved.
(2) Redissolution: The fraction of interest (13000 g, membrane fraction) is reconstituted with 2.3 mL of resuspension buffer (20 mM Hepes (pH 7.8), 10% v / v glycerol, 1 mM EDTA, 1% Resuspended in Triton X-100), the sample was incubated on ice for 1 hour and then centrifuged to remove particulate matter. The supernatant containing dissolved human FAAH was aliquoted, snap frozen in liquid nitrogen and stored at -80 ° C until use.
(3) Characterization: Protein concentration was measured by Bradford assay.
SDS gel and Western blot to confirm the presence of FAAH.
FAAH activity assay.
K _m measured 96 Well Assays linear dependence 96 Well Assays standard compound K _i measured -384 well assay

  (Human FAAH assay: experimental procedure): A 0.1 mg / mL human FAAH solution was prepared in FAAH reaction buffer, and 24 ul was pipetted into a 384 well plate. To this was added 1 μL of the inhibitor serially diluted 3-fold from the DMSO stock solution. FAAH solution and inhibitor were incubated at room temperature for 30 minutes. FAAH reaction by adding 25 μL of 40 μM AMC arachidonoylamide in FAAH reaction buffer, final reaction human FAAH preparation concentration to 0.05 mg / mL, AMC-arachidonoyl substrate concentration to 20 μM, reaction volume to 50 μL Started. The reaction was allowed to proceed for 4 hours at room temperature. The reaction was stopped by adding 25 μL of 12 μM a-keto heterocycle (Cayman Chemicals, catalog # 10435). The microtiter plate was read with an Envision plate reader.

Original fluorescence was plotted on the y-axis and inhibitor concentration was plotted on the x-axis to obtain a dose response inhibition curve. The data was fitted to a single site competitive inhibition equation, respectively K _m of human enzyme was 12μM and 9 [mu] M.

Other assays that can be used to determine FAAH inhibition by compounds of the present invention are:
(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);
(2) High-throughput screening for the discovery of inhibitors of fatty acid amide hydrolase using a microsome-based fluorescence assay (Wang et al., Biomolecular Screening, (2006), 1-9).

(Example 352)
(Evidence for the formation of a covalent complex between serine-241 of FAAH and isoxazoline)
Treatment of rat FAAH protein with methoxy arachidonyl fluorophosphonate, an active site-directed irreversible inhibitor, resulted in a crystal structure in which methoxy arachidonyl phosphonate was covalently attached to the side chain of Ser-241 (Bracey Et al., Science (2002) 298: 1793-1796).

  Based on this data, it was postulated that the isoxazoline compound of the present invention formed a covalent complex with the nucleophilic side chain of Ser-241. This hypothesis is consistent with kinetic data, where the proposed binding involved nucleophilic attack of the isoxazoline electrophile by the active site Ser-241, followed by elimination of the leaving group from the cytosolic port. This results in the formation of a covalent enzyme-isoxazoline adduct. The restoration of activity involves a subsequent deacylation reaction, which may occur inefficiently if not all of the covalent enzyme-isoxazoline adduct.

Experimental activity recovery, enzymatic - rapidly diluted inhibitor complex below 5 times a K _i of its apparent, and the jump dilution method to measure the activity as a function of time was performed. Little or no enzyme activity was obtained again over 2 hours, indicating that inhibition is essentially irreversible or a very slow hydrolyzable complex, said hypothesis Is backed up.

(Other embodiments)
Those skilled in the art will recognize or be able to ascertain using no more routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Sequence identification number Sequence number 1 : Homo sapiens FAAH amino acid sequence:

Claims (86)

Compounds of formula (I), or pharmaceutically acceptable forms thereof:

(Where:
(i) each of R ^a , R ^b , and R ^c is independently selected from H, C _1-10 alkyl, and C _1-10 perhaloalkyl, R ^d is a group -LZ, and Z is , C _6-14 aryl;
(ii) each of R ^a , R ^b , and R ^c is independently selected from —H, C _1-10 alkyl, and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z Is selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl;
(iii) R ^a and R ^d are combined to form a C _3-10 carbocyclyl or 3-14 membered heterocyclyl fused ring, and R ^b and R ^c are -H, C _1-10 alkyl and C _1- Independently selected from ₁₀ perhaloalkyl; or
(iv) R ^c and R ^d combine to form a C _3-10 carbocyclyl or 3-14 membered heterocyclylspiro-fused ring, and R ^a and R ^b are —H, C _1-10 alkyl and C Independently selected from _1-10 perhaloalkyl;
L is a covalent bond or a divalent C _1-6 hydrocarbon group, wherein one, two or three methylene units of L are optionally and independently represented by one or more oxygen, sulfur or nitrogen atoms. Replaced by:
G _{is, -CN, -NO 2, -S (} = O) R e, -SO 2 R e, -SO 2 NR f R e, -PO 2 R e, -PO 2 OR e, -PO 2 NR f R ^e ,-(C = O) R ^e ,-(C = O) OR ^e ,-(C = O) NR ^f R ^e , -Br, -I, -F, -Cl, -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , -ONR ^f PO ₂ OR ^e , -SR ^e , -OSO ₂ R ^e ,- NR ^f SO ₂ R ^e , -OPO ₂ R ^e , -OPO ₂ OR ^e , -NR ^f PO ₂ R ^e , -NR ^f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e , -NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -O (C = NR ^f ) NR ^f R ^e , -NR ^f (C = NR ^f ) OR ^e ,-[N (R ^f ) ₂ R ^e ] ⁺ X ⁻ , wherein X ⁻ is a counter ion; and each R ^e is C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl. , C _6-14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each R ^f attached to the nitrogen atom is independently of the —H, C _1-10 alkyl or amino protecting group. Selected Or R ^e and R ^f are joined to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring. ). Each of R ^a , R ^b , and R ^c is independently selected from H, C _1-10 alkyl and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z is C _{6— 2.} A compound according to claim 1 selected from ₁₄ aryl. Each of R ^a , R ^b , and R ^c is independently selected from H, C _1-10 alkyl and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z is 3-14 2. The compound of claim 1 selected from a member heterocyclyl. Each of R ^a , R ^b , and R ^c is independently selected from H, C _1-10 alkyl and C _1-10 perhaloalkyl, R ^d is a group —LZ, and Z is 5-14 2. The compound of claim 1 selected from membered heteroaryl. L is a covalent bond, or L is a divalent C _1-6 hydrocarbon group, wherein 1, 2 or 3 methylene units of L are substituted by one or more oxygen atoms. 2. The compound of claim 1, wherein:   6. The compound of claim 5, wherein L is a covalent bond. 6. The compound according to claim 5, wherein L is an unsubstituted divalent C _1-6 hydrocarbon group, wherein one methylene unit of L is substituted with an oxygen atom.   6. The compound according to claim 5, wherein L is —O—. 2. The compound of claim 1, wherein R ^a , R ^b , and R ^c are independently selected from —H, C _1-3 alkyl, and C _1-3 perhaloalkyl. 10. The compound of claim 9, wherein each of R ^a , R ^b , and R ^c is independently selected from —H, —CH _3, and —CF ₃ . 11. The compound of claim 10, wherein R ^a and R ^b are —H, and R ^c is selected from —CH ₃ and —CF ₃ . Wherein R ^b and R ^c are -H, and R ^a is selected from -CH ₃ and -CF _3, wherein compound of claim 10. 11. The compound of claim 10, wherein each of R ^a , R ^b , and R ^c is —H. R ^a and R ^d are combined to form a C _3-10 carbocyclyl fused ring, and R ^b and R ^c are independently selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl. 2. The compound according to claim 1. Wherein both R ^b and R ^c are -H, claim 14 A compound according. R ^a and R ^d combine to form a 3-14 membered heterocyclyl fused ring, and R ^b and R ^c are independently selected from -H, C _1-10 alkyl and C _1-10 perhaloalkyl 2. The compound of claim 1, wherein Wherein both R ^b and R ^c is -H, 16. A compound according. R ^c and R ^d are combined to form a C _3-10 carbocyclylspiro-fused ring, and R ^a and R ^b are independently -H, C _1-10 alkyl and C _1-10 per 2. A compound according to claim 1 selected from haloalkyl. 19. The compound of claim 18, wherein R ^a and R ^b are both —H. R ^c and R ^d combine to form a 3-14 membered heterocyclylspiro-fused ring, and R ^a and R ^b are independently -H, C _1-10 alkyl and C _1-10 perhaloalkyl. 2. The compound of claim 1, wherein the compound is selected from: 21. The compound of claim 20, wherein R ^a and R ^b are both —H.   3. A compound according to claim 2, wherein Z is phenyl. 23. The compound of claim 22, wherein the compound is of the following formula or a pharmaceutically acceptable form thereof:

(Where:
z is 0, 1, 2, 3, 4 or 5; and each R ¹⁵ is fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN , -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ¹⁶ , -ON (R ¹⁸ ) ₂ , -N (R ¹⁸ ) ₂ , -N (R ¹⁸ ) ₃ ^{+ X -, -N (OR 17)} R 18, -SH, -SR 16, -SSR 17, -C (= O) R 16, -CO 2 H, -CHO, -C (OR 17) 2, -CO ₂ R ¹⁶ , -OC (= O) R ¹⁶ , -OCO ₂ R ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -OC (= O) N (R ¹⁸ ) ₂ , -NR ¹⁸ C ( = O) R ¹⁶ , -NR ¹⁸ CO ₂ R ¹⁶ , -NR ¹⁸ C (= O) N (R ¹⁸ ) ₂ , -C (= NR ¹⁸ ) R ¹⁶ , -C (= NR ¹⁸ ) OR ¹⁶ ,- OC (= NR ¹⁸ ) R ¹⁶ , -OC (= NR ¹⁸ ) OR ¹⁶ , -C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -OC (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -C (= O) NR ¹⁸ SO ₂ R ¹⁶ , -NR ¹⁸ SO ₂ R ¹⁶ , -SO ₂ N (R ¹⁸ ) ₂ , -SO ₂ R ¹⁶ , -SO ₂ OR ¹⁶ , -OSO ₂ R ¹⁶ , -S (= O) R ¹⁶ , -OS (= O) R ¹⁶ , -Si (R ¹⁶ ) ₃ , -OSi (R ¹⁶ ) ₃ -C (= S ) N (R ¹⁸ ) ₂ , -C (= O) SR ¹⁶ , -C (= S) SR ¹⁶ , -SC (S) SR ¹⁶ , -P (= O) ₂ R ¹⁶ , -OP (= O) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -OP (= O) (R ¹⁶ ) ₂ , -OP (= O) (OR ¹⁷ ) ₂ , -P (= O) ₂ N (R ¹⁸ ) ₂ , -OP (= O) ₂ N (R ¹⁸ ) ₂ , -P (= O) (NR ¹⁸ ) ₂ , -OP (= O) (NR ¹⁸ ) ₂ , -NR ¹⁸ P (= O) (OR _{^{17) 2, -NR 18 P (}} = O) (NR 18) 2, -P (R 17) 2, -P (R 17) 3, -OP (R 17) 2, -OP (R 17) 3, -B (OR ¹⁷ ) ₂ , -BR ¹⁶ (OR ¹⁷ ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 Independently selected from membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0 , 1, 2, 3, 4, or 5 R ¹⁹ groups; or two adjacent R ¹⁵ groups are replaced by a group —O (C (R ² ) ₂ ) _1-2 O— Substituted, wherein each R ² is independently —H, C _1-6 alkyl or halogen;
Each instance of R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ¹⁹ groups;
Each example of R ¹⁸ is independently hydrogen, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -CN, -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁷ , -SO ₂ OR ¹⁷ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁷ , -C (= S) SR ¹⁷ , -P (= O ) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -P (= O) ₂ N (R ¹⁷ ) ₂ , -P (= O) (NR ¹⁷ ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ¹⁷ groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently 0,1,2,3,4 or 5 of R ^19, It is substituted by;
Each instance of R ¹⁷ is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ¹⁷ groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups Is;
Each example of R ¹⁹ is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ²⁰ , -ON (R ²¹ ) ₂ , -N _{^{(R 21) 2, -N (}} R 21) 3 + X -, -N (OR 20) R 21, -SH, -SR 20, -SSR 20, -C (= O) R 20, -CO 2 H , -CO ₂ R ²⁰ , -OC (= O) R ²⁰ , -OCO ₂ R ²⁰ , -C (= O) N (R ²¹ ) ₂ , -OC (= O) N (R ²¹ ) ₂ , -NR ²¹ C (= O) R ²⁰ , -NR ²¹ CO ₂ R ²⁰ , -NR ²¹ C (= O) N (R ²¹ ) ₂ , -C (= NR ²¹ ) OR ²⁰ , -OC (= NR ²¹ ) R ²⁰ , -OC (= NR ²¹ ) OR ²⁰ , -C (= NR ²¹ ) N (R ²¹ ) ₂ , -OC (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ C (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ SO ₂ R ²⁰ , -SO ₂ N (R ²¹ ) ₂ , -SO ₂ R ²⁰ , -SO ₂ OR ²⁰ , -OSO ₂ R ²⁰ , -S (= O) R ²⁰ , -Si (R ²⁰ ) ₃ , -OSi (R ²⁰ ) ₃ , -C (= S) N (R ²¹ ) ₂ , -C (= O) SR ²⁰ , -C (= S) SR ²⁰ , -SC (= S) SR ²⁰ , -P (= O) ₂ R ²⁰ , -P (= O) (R ²⁰ ) ₂ , -OP (= O) (R ²⁰ ) ₂ , -OP (= O) (OR ²⁰ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member heteroa It is selected from Lumpur, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted by 1, 2, 3, 4, or 5 R ²² groups Or two geminal R ¹⁹ substituents can be joined to form ═O or ═S;
Each example of R ²⁰ is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ²² groups;
Each example of R ²¹ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Two R ²¹ groups selected from C _6-10 aryl and 5-10 membered heteroaryl or bonded to the N atom are bonded together to form a 3-14 membered heterocyclyl ring or a 5-14 membered heterocycle Forms an aryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups ;And
Each example of R ²² is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH ( C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1- 6} alkyl), - NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), - NHC (= O) NH 2, -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1- 6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1- 6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ²² substituents are attached and = O or = S can be formed;
Here, X ⁻ is a counter ion. ). R ¹⁵ is fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -OR ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -SO ₂ Selected from N (R ¹⁸ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-14 aryl, and 5-14 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl, and each heteroaryl is independently 0, 1, 2, 3, or 5 amino substituted by R ¹⁹ groups, 23. a compound according.   24. The compound of claim 23, wherein z is 1 or 2.   26. The compound of claim 25, wherein z is 1. 27. The compound of claim 26, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. 28. The compound of claim 27, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

(Where:
R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl. , And 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or 5 Substituted by the R ¹⁹ group. ). 29. The compound of claim 28, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. 29. The compound of claim 28, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. 28. The compound of claim 27, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

.   26. The compound of claim 25, wherein z is 2. 35. The compound of claim 32, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. 34. The compound of claim 33, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

.   5. A compound according to claim 4, wherein Z is 5-membered heteroaryl. 36. The compound of claim 35, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

Wherein Y ¹ , Y ² , Y ³ and Y ⁴ are independently selected from CH, CR ¹⁵ , O, S, N, or NR ¹⁸ provided that Y ¹ , Y ² , Y ³ and Y ⁴ At least one of is selected from O, S, N, or NR ¹⁸ ; and each R ¹⁵ is independently fluoro (-F), bromo (-Br), chloro (-Cl) , And iodine (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ¹⁶ , -ON (R ¹⁸ ) ₂ , -N (R ¹⁸ ) _{^{2, -N (R 18) 3}} + X -, -N (OR 17) R 18, -SH, -SR 16, -SSR 17, -C (= O) R 16, -CO 2 H, -CHO, -C (OR ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -OC (= O) R ¹⁶ , -OCO ₂ R ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -OC (= O) N ( R ¹⁸ ) ₂ , -NR ¹⁸ C (= O) R ¹⁶ , -NR ¹⁸ CO ₂ R ¹⁶ , -NR ¹⁸ C (= O) N (R ¹⁸ ) ₂ , -C (= NR ¹⁸ ) R ¹⁶ ,- C (= NR ¹⁸ ) OR ¹⁶ , -OC (= NR ¹⁸ ) R ¹⁶ , -OC (= NR ¹⁸ ) OR ¹⁶ , -C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -OC (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -C (= O) NR ¹⁸ SO ₂ R ¹⁶ , -NR ¹⁸ SO ₂ R ¹⁶ , -SO ₂ N (R _{^{18) 2, -SO 2 R 16}} , -SO 2 OR 16, -OSO 2 R 16, -S (= O) R 16, -OS (= O) R 16 _{^{-Si (R 16) 3, -OSi}} (R 16) 3, -C (= S) N (R 18) 2, -C (= O) SR 16, -C (= S) SR 16, -SC ( S) SR ¹⁶ , -P (= O) ₂ R ¹⁶ , -OP (= O) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -OP (= O) (R ¹⁶ ) ₂ ,- OP (= O) (OR ¹⁷ ) ₂ , -P (= O) ₂ N (R ¹⁸ ) ₂ , -OP (= O) ₂ N (R ¹⁸ ) ₂ , -P (= O) (NR ¹⁸ ) ₂ , -OP (= O) (NR ¹⁸ ) ₂ , -NR ¹⁸ P (= O) (OR ¹⁷ ) ₂ , -NR ¹⁸ P (= O) (NR ¹⁸ ) ₂ , -P (R ¹⁷ ) ₂ ,- P (R ¹⁷ ) ₃ , -OP (R ¹⁷ ) ₂ , -OP (R ¹⁷ ) ₃ , -B (OR ¹⁷ ) ₂ , -BR ¹⁶ (OR ¹⁷ ), C _1-10 alkyl, C _1-10 pel Selected from haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein alkyl, alkenyl , Alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups; or two adjacent R ¹⁵ location group is a group _{^{-O (C (R 2) 2}} ) 1-2 O- by It is, wherein each R ² is independently, -H, be a C _1-6 alkyl or halogen;
Each instance of R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ¹⁹ groups;
Each example of R ¹⁸ is independently hydrogen, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -CN, -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁷ , -SO ₂ OR ¹⁷ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁷ , -C (= S) SR ¹⁷ , -P (= O ) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -P (= O) ₂ N (R ¹⁷ ) ₂ , -P (= O) (NR ¹⁷ ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ¹⁷ groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently 0,1,2,3,4 or 5 of R ^19, It is substituted by;
Each instance of R ¹⁷ is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ¹⁷ groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups Is;
Each example of R ¹⁹ is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ²⁰ , -ON (R ²¹ ) ₂ , -N _{^{(R 21) 2, -N (}} R 21) 3 + X -, -N (OR 20) R 21, -SH, -SR 20, -SSR 20, -C (= O) R 20, -CO 2 H , -CO ₂ R ²⁰ , -OC (= O) R ²⁰ , -OCO ₂ R ²⁰ , -C (= O) N (R ²¹ ) ₂ , -OC (= O) N (R ²¹ ) ₂ , -NR ²¹ C (= O) R ²⁰ , -NR ²¹ CO ₂ R ²⁰ , -NR ²¹ C (= O) N (R ²¹ ) ₂ , -C (= NR ²¹ ) OR ²⁰ , -OC (= NR ²¹ ) R ²⁰ , -OC (= NR ²¹ ) OR ²⁰ , -C (= NR ²¹ ) N (R ²¹ ) ₂ , -OC (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ C (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ SO ₂ R ²⁰ , -SO ₂ N (R ²¹ ) ₂ , -SO ₂ R ²⁰ , -SO ₂ OR ²⁰ , -OSO ₂ R ²⁰ , -S (= O) R ²⁰ , -Si (R ²⁰ ) ₃ , -OSi (R ²⁰ ) ₃ , -C (= S) N (R ²¹ ) ₂ , -C (= O) SR ²⁰ , -C (= S) SR ²⁰ , -SC (= S) SR ²⁰ , -P (= O) ₂ R ²⁰ , -P (= O) (R ²⁰ ) ₂ , -OP (= O) (R ²⁰ ) ₂ , -OP (= O) (OR ²⁰ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member of hetero ants Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups. Or two geminal R ¹⁹ substituents can be joined to form ═O or ═S;
Each example of R ²⁰ is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ²² groups;
Each example of R ²¹ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Two R ²¹ groups selected from C _6-10 aryl and 5-10 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups Is; and
Each example of R ²² is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH ( C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1- 6} alkyl), - NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), - NHC (= O) NH 2, -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1- 6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1- 6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ²² substituents are attached and = O or = S can be formed;
Here, X ⁻ is a counter ion. ). R ¹⁵ is fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -OR ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -SO ₂ Selected from N (R ¹⁸ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _6-14 aryl, and 5-14 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl, and each heteroaryl is independently 0, 1, 2, 3, or 5 amino substituted by R ¹⁹ groups, claim 36 a compound according. Wherein Y ¹ is S, Y ³ is N, and Y ² and Y ⁴ is CH or CR ¹⁵ independently is 36. A compound according. 39. The compound of claim 38, wherein the compound is of the following formula, or a pharmaceutically acceptable form thereof:

. Wherein Y ¹ is S, and Y ^2, each of Y ³ and Y ⁴ are independently CH or CR ^15, claim 36 A compound according. 41. The compound of claim 40, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. 2. The compound of claim 1, wherein the compound is of the following formula or a pharmaceutically acceptable form thereof:

(Where:
W ²⁰ , W ²¹ , W ²² , and W ²³ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ ;
s is 0, 1 or 2; and each R ¹⁵ is fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO ₂ , — _{N 3, -SO 2 H, -SO} 3 H, -OH, -OR 16, -ON (R 18) 2, -N (R 18) 2, -N (R 18) 3 + X -, -N ( OR ¹⁷ ) R ¹⁸ , -SH, -SR ¹⁶ , -SSR ¹⁷ , -C (= O) R ¹⁶ , -CO ₂ H, -CHO, -C (OR ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -OC (= O) R ¹⁶ , -OCO ₂ R ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -OC (= O) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= O) R ¹⁶ , -NR ¹⁸ CO ₂ R ¹⁶ , -NR ¹⁸ C (= O) N (R ¹⁸ ) ₂ , -C (= NR ¹⁸ ) R ¹⁶ , -C (= NR ¹⁸ ) OR ¹⁶ , -OC (= NR ¹⁸ ) R ¹⁶ , -OC (= NR ¹⁸ ) OR ¹⁶ , -C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -OC (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -C (= O) NR ¹⁸ SO ₂ R ¹⁶ , -NR ¹⁸ SO ₂ R ¹⁶ , -SO ₂ N (R ¹⁸ ) ₂ , -SO ₂ R ¹⁶ , -SO ₂ OR ¹⁶ , -OSO ₂ R ¹⁶ , -S (= O) R ¹⁶ , -OS (= O) R ¹⁶ , -Si (R ¹⁶ ) ₃ , -OSi (R ¹⁶ ) ₃ , -C (= S) N (R ¹⁸ ) ₂ , -C (= O) SR ¹⁶ , -C (= S) SR ¹⁶ , -SC (S) SR ¹⁶ , -P (= O) ₂ R ¹⁶ , -OP (= O) ₂ R ¹⁶ ,- ^{P (= O) (R 16} ) 2, -OP (= O) (R 16) 2, -OP (= O) (OR 17) 2, -P (= O) 2 N (R 18) 2 _{-OP (= O) 2 N (} R 18) 2, -P (= O) (NR 18) 2, -OP (= O) (NR 18) 2, -NR 18 P (= O) (OR 17) ₂ , -NR ¹⁸ P (= O) (NR ¹⁸ ) ₂ , -P (R ¹⁷ ) ₂ , -P (R ¹⁷ ) ₃ , -OP (R ¹⁷ ) ₂ , -OP (R ¹⁷ ) ₃ , -B (OR ¹⁷ ) ₂ , —BR ¹⁶ (OR ¹⁷ ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 membered Independently selected from heterocyclyl, C _6-14 -aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, Substituted by 1, 2, 3, 4, or 5 R ¹⁹ groups; or two adjacent R ¹⁵ groups are substituted by the group —O (C (R ² ) ₂ ) _1-2 O— Wherein each R ² is independently —H, C _1-6 alkyl or halogen;
Each instance of R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ¹⁹ groups;
Each example of R ¹⁸ is independently hydrogen, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -CN, -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁷ , -SO ₂ OR ¹⁷ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁷ , -C (= S) SR ¹⁷ , -P (= O ) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -P (= O) ₂ N (R ¹⁷ ) ₂ , -P (= O) (NR ¹⁷ ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ¹⁷ groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently 0,1,2,3,4 or 5 of R ^19, It is substituted by;
Each instance of R ¹⁷ is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ¹⁷ groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups Is;
Each example of R ¹⁹ is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ²⁰ , -ON (R ²¹ ) ₂ , -N _{^{(R 21) 2, -N (}} R 21) 3 + X -, -N (OR 20) R 21, -SH, -SR 20, -SSR 20, -C (= O) R 20, -CO 2 H , -CO ₂ R ²⁰ , -OC (= O) R ²⁰ , -OCO ₂ R ²⁰ , -C (= O) N (R ²¹ ) ₂ , -OC (= O) N (R ²¹ ) ₂ , -NR ²¹ C (= O) R ²⁰ , -NR ²¹ CO ₂ R ²⁰ , -NR ²¹ C (= O) N (R ²¹ ) ₂ , -C (= NR ²¹ ) OR ²⁰ , -OC (= NR ²¹ ) R ²⁰ , -OC (= NR ²¹ ) OR ²⁰ , -C (= NR ²¹ ) N (R ²¹ ) ₂ , -OC (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ C (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ SO ₂ R ²⁰ , -SO ₂ N (R ²¹ ) ₂ , -SO ₂ R ²⁰ , -SO ₂ OR ²⁰ , -OSO ₂ R ²⁰ , -S (= O) R ²⁰ , -Si (R ²⁰ ) ₃ , -OSi (R ²⁰ ) ₃ , -C (= S) N (R ²¹ ) ₂ , -C (= O) SR ²⁰ , -C (= S) SR ²⁰ , -SC (= S) SR ²⁰ , -P (= O) ₂ R ²⁰ , -P (= O) (R ²⁰ ) ₂ , -OP (= O) (R ²⁰ ) ₂ , -OP (= O) (OR ²⁰ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member of hetero ants Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups. Or two geminal R ¹⁹ substituents can be joined to form ═O or ═S;
Each example of R ²⁰ is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ²² groups;
Each example of R ²¹ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Two R ²¹ groups selected from C _6-10 aryl and 5-10 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups Is; and
Each example of R ²² is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH ( C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1- 6} alkyl), - NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), - NHC (= O) NH 2, -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1- 6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1- 6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ²² substituents are attached and = O or = S can be formed;
Here, X ⁻ is a counter ion. ).   43. The compound of claim 42, wherein s is 0. Wherein W ^20, W ²¹ and W ²² are ^{_{independently, CH 2, CHR 15, C}} (R 15) 2, or NR ^18, claim 42 A compound according. 45. The compound of claim 44, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. 2. The compound of claim 1, wherein the compound is of the following formula or a pharmaceutically acceptable form thereof:

Wherein W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ are independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , or NR ¹⁸ , or optional here W ²⁵ and W ²⁶ are substituted by a fused C ₆ aryl ring or a fused 6-membered heteroaryl ring; t and v are independently 0 or 1; and each R ¹⁵ is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -N 3, -SO 2 H, -SO 3 H, -OH, -OR _{^{16, -ON (R 18) 2}} , -N (R 18) 2, -N (R 18) 3 + X -, -N (OR 17) R 18, -SH, -SR 16, -SSR 17, - C (= O) R ¹⁶ , -CO ₂ H, -CHO, -C (OR ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -OC (= O) R ¹⁶ , -OCO ₂ R ¹⁶ , -C (= O ) N (R ¹⁸ ) ₂ , -OC (= O) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= O) R ¹⁶ , -NR ¹⁸ CO ₂ R ¹⁶ , -NR ¹⁸ C (= O) N ( R ¹⁸ ) ₂ , -C (= NR ¹⁸ ) R ¹⁶ , -C (= NR ¹⁸ ) OR ¹⁶ , -OC (= NR ¹⁸ ) R ¹⁶ , -OC (= NR ¹⁸ ) OR ¹⁶ , -C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -OC (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -C (= O) NR ¹⁸ SO ₂ R ¹⁶ , -NR ¹⁸ SO ₂ R ¹⁶ , -SO ₂ N (R ¹⁸ ) ₂ , -SO ₂ R ¹⁶ , -SO ₂ OR ¹⁶ , -OSO ₂ R ¹⁶ , -S (= O) R ¹⁶ , -OS (= O) R ¹⁶ , -Si (R ¹⁶ ) ₃ , -OSi (R ¹⁶ ) ₃ , -C (= S) N (R ¹⁸ ) ₂ , -C (= O) SR ¹⁶ , -C (= S) SR ¹⁶ , -SC (S) SR ¹⁶ , -P (= O) ₂ R ¹⁶ , -OP (= O) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -OP (= O) (R ¹⁶ ) ₂ , -OP (= O ) (OR ¹⁷ ) ₂ , -P (= O) ₂ N (R ¹⁸ ) ₂ , -OP (= O) ₂ N (R ¹⁸ ) ₂ , -P (= O) (NR ¹⁸ ) ₂ , -OP ( = O) (NR ¹⁸ ) ₂ , -NR ¹⁸ P (= O) (OR ¹⁷ ) ₂ , -NR ¹⁸ P (= O) (NR ¹⁸ ) ₂ , -P (R ¹⁷ ) ₂ , -P (R ¹⁷ ) ₃ , -OP (R ¹⁷ ) ₂ , -OP (R ¹⁷ ) ₃ , -B (OR ¹⁷ ) ₂ , -BR ¹⁶ (OR ¹⁷ ), C _1-10 alkyl, C _1-10 perhaloalkyl, C ₂ Selected from _-10 alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl , heterocyclyl, aryl, and each heteroaryl is independently 0, 1, 2, 3, or the five R ¹⁹ groups Either conversion; or, the two adjacent groups R ¹⁵ is substituted by O- group _{^{-O (C (R 2) 2}} ) 1-2, wherein each R ² is independently, -H, C _1-6 alkyl or halogen;
Each instance of R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ¹⁹ groups;
Each example of R ¹⁸ is independently hydrogen, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -CN, -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁷ , -SO ₂ OR ¹⁷ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁷ , -C (= S) SR ¹⁷ , -P (= O ) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -P (= O) ₂ N (R ¹⁷ ) ₂ , -P (= O) (NR ¹⁷ ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ¹⁷ groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , Aryl, and heteroaryl are each independently 0, 1, 2, 3, 4, or 5 R Substituted by ¹⁹ groups;
Each instance of R ¹⁷ is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ¹⁷ groups selected from C _6-14 aryl and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently represented by 0, 1, 2, 3, 4, or 5 R ¹⁹ groups. Replaced;
Each example of R ¹⁹ is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ²⁰ , -ON (R ²¹ ) ₂ , -N _{^{(R 21) 2, -N (}} R 21) 3 + X -, -N (OR 20) R 21, -SH, -SR 20, -SSR 20, -C (= O) R 20, -CO 2 H , -CO ₂ R ²⁰ , -OC (= O) R ²⁰ , -OCO ₂ R ²⁰ , -C (= O) N (R ²¹ ) ₂ , -OC (= O) N (R ²¹ ) ₂ , -NR ²¹ C (= O) R ²⁰ , -NR ²¹ CO ₂ R ²⁰ , -NR ²¹ C (= O) N (R ²¹ ) ₂ , -C (= NR ²¹ ) OR ²⁰ , -OC (= NR ²¹ ) R ²⁰ , -OC (= NR ²¹ ) OR ²⁰ , -C (= NR ²¹ ) N (R ²¹ ) ₂ , -OC (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ C (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ SO ₂ R ²⁰ , -SO ₂ N (R ²¹ ) ₂ , -SO ₂ R ²⁰ , -SO ₂ OR ²⁰ , -OSO ₂ R ²⁰ , -S (= O) R ²⁰ , -Si (R ²⁰ ) ₃ , -OSi (R ²⁰ ) ₃ , -C (= S) N (R ²¹ ) ₂ , -C (= O) SR ²⁰ , -C (= S) SR ²⁰ , -SC (= S) SR ²⁰ , -P (= O) ₂ R ²⁰ , -P (= O) (R ²⁰ ) ₂ , -OP (= O) (R ²⁰ ) ₂ , -OP (= O) (OR ²⁰ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member heteroa It is selected from Lumpur, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted by 1, 2, 3, 4, or 5 R ²² groups Or two geminal R ¹⁹ substituents can be joined to form ═O or ═S;
Each example of R ²⁰ is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ²² groups;
Each example of R ²¹ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Selected from C _6-10 aryl, and 5-10 membered heteroaryl, or two R ²¹ groups bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently represented by 0, 1, 2, 3, 4, or 5 R ²² groups. Substituted; and
Each example of R ²² is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH ( C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1- 6} alkyl), - NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), - NHC (= O) NH 2, -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1- 6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1- 6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ²² substituents are attached and = O or = S can be formed;
Here, X ⁻ is a counter ion. ). 47. The compound of claim 46, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. Wherein t is 0, v is 1 and W ²⁵ and W ²⁶ are substituted by a fused C ₆ aryl ring, wherein W ²⁷ and W ²⁸ are independently CH ₂ , CHR ¹⁵ , and C (R ¹⁵⁾ is _2, 46. a compound according. 49. The compound of claim 48, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

(Wherein z is 0, 1, 2, 3 or 4; and each R ¹⁵ is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (- I), -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ¹⁶ , -ON (R ¹⁸ ) ₂ , -N (R ¹⁸ ) ₂ , -N ( _{^{R 18) 3 + X -,}} -N (OR 17) R 18, -SH, -SR 16, -SSR 17, -C (= O) R 16, -CO 2 H, -CHO, -C (OR 17 ) ₂ , -CO ₂ R ¹⁶ , -OC (= O) R ¹⁶ , -OCO ₂ R ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , -OC (= O) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= O) R ¹⁶ , -NR ¹⁸ CO ₂ R ¹⁶ , -NR ¹⁸ C (= O) N (R ¹⁸ ) ₂ , -C (= NR ¹⁸ ) R ¹⁶ , -C (= NR ¹⁸ ) OR ¹⁶ , -OC (= NR ¹⁸ ) R ¹⁶ , -OC (= NR ¹⁸ ) OR ¹⁶ , -C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -OC (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -NR ¹⁸ C (= NR ¹⁸ ) N (R ¹⁸ ) ₂ , -C (= O) NR ¹⁸ SO ₂ R ¹⁶ , -NR ¹⁸ SO ₂ R ¹⁶ , -SO ₂ N (R ¹⁸ ) ₂ ,- SO ₂ R ¹⁶ , -SO ₂ OR ¹⁶ , -OSO ₂ R ¹⁶ , -S (= O) R ¹⁶ , -OS (= O) R ¹⁶ , -Si (R ¹⁶ ) ₃ , -OSi (R ¹⁶ ) ₃ , -C (= S) N (R ¹⁸ ) ₂ , -C (= O) SR ¹⁶ , -C (= S) SR ¹⁶ , -SC (S) SR ¹⁶ , -P (= O) ₂ R ¹⁶ , -OP (= O) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -OP (= O) (R ¹⁶ ) ₂ , -OP (= O) (OR ¹⁷ ) ₂ , -P (= O) ₂ N (R ¹⁸ ) ₂ , -OP (= O) ₂ N (R ¹⁸ ) ₂ , -P (= O) (NR ¹⁸ ) ₂ , -OP (= O) (NR ¹⁸ ) ₂ , -NR ¹⁸ P (= O) (OR ¹⁷ ) ₂ , -NR ¹⁸ P (= O) (NR ¹⁸ ) ₂ , -P (R ¹⁷ ) ₂ , -P (R ¹⁷ ) ₃ , -OP ( R ¹⁷ ) ₂ , -OP (R ¹⁷ ) ₃ , -B (OR ¹⁷ ) ₂ , -BR ¹⁶ (OR ¹⁷ ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and Each heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups; or two adjacent R ¹⁵ groups are group —O (C (R ² ) ₂ ) substituted by _1-2 O-, wherein each R ² is independently -H, C _1-6 alkyl, or halogen;
Each instance of R ¹⁶ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ¹⁹ groups;
Each example of R ¹⁸ is independently hydrogen, -OH, -OR ¹⁶ , -N (R ¹⁷ ) ₂ , -CN, -C (= O) R ¹⁶ , -C (= O) N (R ¹⁷ ) ₂ , -CO ₂ R ¹⁶ , -SO ₂ R ¹⁶ , -C (= NR ¹⁷ ) OR ¹⁶ , -C (= NR ¹⁷ ) N (R ¹⁷ ) ₂ , -SO ₂ N (R ¹⁷ ) ₂ , -SO ₂ R ¹⁷ , -SO ₂ OR ¹⁷ , -SOR ¹⁶ , -C (= S) N (R ¹⁷ ) ₂ , -C (= O) SR ¹⁷ , -C (= S) SR ¹⁷ , -P (= O ) ₂ R ¹⁶ , -P (= O) (R ¹⁶ ) ₂ , -P (= O) ₂ N (R ¹⁷ ) ₂ , -P (= O) (NR ¹⁷ ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ¹⁷ groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , Aryl, and heteroaryl are each independently 0, 1, 2, 3, 4, or 5 R Substituted by ¹⁹ groups;
Each instance of R ¹⁷ is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two R ¹⁷ groups selected from C _6-14 aryl and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently represented by 0, 1, 2, 3, 4, or 5 R ¹⁹ groups. Replaced;
Each example of R ¹⁹ is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ²⁰ , -ON (R ²¹ ) ₂ , -N _{^{(R 21) 2, -N (}} R 21) 3 + X -, -N (OR 20) R 21, -SH, -SR 20, -SSR 20, -C (= O) R 20, -CO 2 H , -CO ₂ R ²⁰ , -OC (= O) R ²⁰ , -OCO ₂ R ²⁰ , -C (= O) N (R ²¹ ) ₂ , -OC (= O) N (R ²¹ ) ₂ , -NR ²¹ C (= O) R ²⁰ , -NR ²¹ CO ₂ R ²⁰ , -NR ²¹ C (= O) N (R ²¹ ) ₂ , -C (= NR ²¹ ) OR ²⁰ , -OC (= NR ²¹ ) R ²⁰ , -OC (= NR ²¹ ) OR ²⁰ , -C (= NR ²¹ ) N (R ²¹ ) ₂ , -OC (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ C (= NR ²¹ ) N (R ²¹ ) ₂ , -NR ²¹ SO ₂ R ²⁰ , -SO ₂ N (R ²¹ ) ₂ , -SO ₂ R ²⁰ , -SO ₂ OR ²⁰ , -OSO ₂ R ²⁰ , -S (= O) R ²⁰ , -Si (R ²⁰ ) ₃ , -OSi (R ²⁰ ) ₃ , -C (= S) N (R ²¹ ) ₂ , -C (= O) SR ²⁰ , -C (= S) SR ²⁰ , -SC (= S) SR ²⁰ , -P (= O) ₂ R ²⁰ , -P (= O) (R ²⁰ ) ₂ , -OP (= O) (R ²⁰ ) ₂ , -OP (= O) (OR ²⁰ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 Member heteroa It is selected from Lumpur, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted by 1, 2, 3, 4, or 5 R ²² groups Or two geminal R ¹⁹ substituents can be joined to form ═O or ═S;
Each example of R ²⁰ is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ²² groups;
Each example of R ²¹ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Selected from C _6-10 aryl, and 5-10 membered heteroaryl, or two R ²¹ groups bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently represented by 0, 1, 2, 3, 4, or 5 R ²² groups. Substituted; and
Each example of R ²² is independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 Alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, -NH (C _1-6 alkyl) ₂ X, -NH ₂ (C _1-6 alkyl) X , -NH ₃ X, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), - C (= O) (C 1-6 _{alkyl), - CO 2 H, -CO} 2 (C 1-6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH ( C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _{1- 6} alkyl), - NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), - NHC (= O) NH 2, -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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 (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _{1- 6 alkyl), - SO 2 N (C} 1-6 _{alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), - SO 2 NH 2,} -SO 2 C 1-6 alkyl, -SO ₂ OC _{1- 6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) 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) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) O (C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-10 carbocyclyl, C _3-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ²² substituents are attached and = O Or = S can be formed;
Here, X ⁻ is a counter ion. ). Wherein W ²⁷ and W ²⁸ are both CH ₂ groups, according to claim 49 A compound according. 51. The compound of claim 50, wherein the compound is of the following formula: or a pharmaceutically acceptable form thereof:

. G is -Cl, -Br, -I, -OR ^e , -ONR ^f R ^e , -ONR ^f (C = O) R ^e , -ONR ^f SO ₂ R ^e , -ONR ^f PO ₂ R ^e , _{^{-ONR f PO 2 OR e, -SR}} e, -OSO 2 R e, -NR f SO 2 R e, -OPO 2 R e, -OPO 2 OR e, -NR f PO 2 R e, -NR f PO ₂ OR ^e , -OPO ₂ NR ^f R ^e , -O (C = O) R ^e , -O (C = O) OR ^e , -NR ^f R ^e , -NR ^f (C = O) R ^e ,- NR ^f (C = O) OR ^e , -O (C = O) NR ^f R ^e , -NR ^f (C = NR ^f ) NR ^f R ^e , -O (C = NR ^f ) NR ^f R ^e ,- ^{NR f (C = NR f)} oR e, and _{^{- [N (R f) 2}} R e] + X - is selected from wherein X ^- is a counter ion, one of the claims 1 to 51 The described compound. Wherein G is -OR ^e, claim 52 A compound according. Wherein R ^e is a C _6-14 aryl, claim 53 A compound according. 55. The compound of claim 54, wherein ^Re is phenyl. 56. The compound of claim 55, wherein ^Re is monosubstituted phenyl. 55. The compound of claim 54, wherein R ^e is a phenyl group of the formula:

(Where:
x is 0, 1, 2, 3, 4 or 5, and each R ^h is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I) , -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ⁱ , -ON (R ^k ) ₂ , -N (R ^k ) ₂ , -N (R ^{k _{) 3 + X -, -N (}} OR j) R k, -SH, -SR i, -SSR j, -C (= O) R i, -CO 2 H, -CHO, -CO 2 R i, - OC (= O) R ⁱ , -OCO ₂ R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -NR ^k C (= O) N (R ^k ) ₂ , -C (= NR ^k ) R ⁱ , -C (= NR ^k ) OR ⁱ , -OC (= NR ^k ) R ⁱ , -OC (= NR ^k ) OR ⁱ , -C (= NR ^k ) N (R ^k ) ₂ , -OC (= NR ^k ) N (R ^k ) ₂ , -NR ^k C (= NR ^k ) N (R ^k ) ₂ , -C (= O) NR ^k SO ₂ R ⁱ , -NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , -SO ₂ OR ⁱ , -OSO ₂ R ⁱ , -S (= O) R ⁱ , -OS (= O) R ⁱ , -Si (R ⁱ ) ₃ , -OSi (R ⁱ ) ₃ , -C (= S) N (R ^k ) ₂ , -C (= O) SR ⁱ , -C (= S) SR ⁱ , -SC (S) SR ⁱ , -P (= O) ₂ R ⁱ , -OP (= O) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -OP (= O) (R ⁱ ) ₂ , -OP (= O) (OR ^j ) ₂ , -P (= O) ₂ N (R ^k ) ₂ , -OP (= O) ₂ N (R ^k ) ₂ , -P (= O) (NR ^k ) ₂ , -OP (= O) (NR ^k ) ₂ , -NR ^k P (= O) (OR ^j ) ₂ , -NR ^k P (= O) (NR ^k ) ₂ , -P (R ^j ) ₂ , -P (R ^j ) ₃ , -OP ( R ^j ) ₂ , -OP (R ^j ) ₃ , -B (OR ^j ) ₂ , -BR ⁱ (OR ^j ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and Each heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups;
Each example of R ⁱ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ^m groups;
Each example of R ^k is independently hydrogen, -OH, -OR ⁱ , -N (R ^j ) ₂ , -CN, -C (= O) R ⁱ , -C (= O) N (R ^j ) ₂ , -CO ₂ R ⁱ , -SO ₂ R ⁱ , -C (= NR ^j ) OR ⁱ , -C (= NR ^j ) N (R ^j ) ₂ , -SO ₂ N (R ^j ) ₂ , -SO ₂ R ^j , -SO ₂ OR ^j , -SOR ⁱ , -C (= S) N (R ^j ) ₂ , -C (= O) SR ^j , -C (= S) SR ^j , -P (= O ) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -P (= O) ₂ N (R ^j ) ₂ , -P (= O) (NR ^j ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two R ^j groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl It is substituted aryl, and each heteroaryl is independently 0, 1, 2, 3, or the five R ^m groups ;
Each instance of R ^j is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two Rj groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups Is;
Each example of R ^m is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H _{, -SO 3 H, -OH, -OR} o, -ON (R n) 2, -N (R n) 2, -N (R n) 3 + X -, -N (OR o) R n, - ^{SH, -SR o, -SSR o,} -C (= O) R o, -CO 2 H, -CO 2 R o, -OC (= O) R o, -OCO 2 R o, -C (= O ) N (R ⁿ ) ₂ , -OC (= O) N (R ⁿ ) ₂ , -NR ⁿ C (= O) R ^o , -NR ⁿ CO ₂ R ^o , -NR ⁿ C (= O) N ( R ⁿ ) ₂ , -C (= NR ⁿ ) OR ^o , -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) OR ^o , -C (= NR ⁿ ) N (R ⁿ ) ₂ ,- ^{OC (= NR n) n (} R n) 2, -NR n C (= NR n) n (R n) 2, -NR n SO 2 R o, -SO 2 n (R n) 2, -SO 2 R ^o , -SO ₂ OR ^o , -OSO ₂ R ^o , -S (= O) R ^o , -Si (R ^o ) ₃ , -OSi (R ^o ) ₃ , -C (= S) N (R ⁿ _{) 2, -C (= O)} SR o, -C (= S) SR o, -SC (= S) SR o, -P (= O) 2 R o, -P (= O) (R o) ₂ , -OP (= O) (R ^o ) ₂ , -OP (= O) (OR ^o ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14 membered f It is selected from Roariru, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted 0,1,2,3,4, or by five R ^p group Or two geminal R ^m substituents can be joined to form ═O or ═S;
Each example of R ^o is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ^p groups;
Each example of R ⁿ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Selected from C _6-10 aryl, and 5-10 membered heteroaryl, or two R ⁿ groups bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently represented by 0, 1, 2, 3, 4, or 5 R ^p groups. Substituted; and
Each example of R ^p is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H , -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, --NH (C _1-6 alkyl) ₂ X, --NH ₂ (C _1-6 alkyl) X, --NH ₃ X, --N (OC _1-6 alkyl) (C _1-6 alkyl), --N (OH ) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (= O) (C _1-6 alkyl),- CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ ,- C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _{1- 6} alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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} (C 1-6 alkyl), - OC (NH) NH 2, - NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N (C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl,- Si (C _1-6 alkyl) 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) SC 1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) ( OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, 3-14 membered heterocyclyl, or a 5-14 membered heteroaryl; or two geminal R ^p substituent bonded, = O Wakashi It can form the = S;
Here, X ⁻ is a counter ion. ). Wherein R ^h is, fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -OH, -OR i, -SR i, -N _{^{(R k) 2, -N (}} R k) 3 + X -, -C (= O) R i, -CO 2 R i, -CO 2 H, -OC (= O) R i, -OCO 2 R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ -NR ^k C (= O) N (R ^k ) ₂ , -C (= O) NR ^k SO ₂ R ⁱ , -NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , C _{1 -10} alkyl, C ₆ aryl, and 5-6 membered heteroaryl, wherein the alkyl, aryl, and each heteroaryl is independently 0, 1, 2, 3, or 4 R ^m substituted by groups; and, wherein X ^- is a counter ion, claim 57 a compound according. Selected from —C (═O) R ⁱ , —CO ₂ H, —SO ₂ R ⁱ , and 5-membered heteroaryl, wherein R ^h is independently substituted with 0 or 1 R ^m group; 59. The compound of claim 58, wherein   60. The compound of claim 59, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. 58. The compound of claim 57, wherein the phenyl group is a monosubstituted phenyl group of any one of the following formulae:

. 58. The compound of claim 57, wherein the phenyl group is a disubstituted phenyl group of any one of the following formulae:

. Wherein G is a -OR ^e selected from the following, according to claim 53, wherein the compound:

. Wherein R ^e is a 5-14 membered heteroaryl, claim 53 A compound according. 65. The compound of claim 64, wherein ^Re is 6-membered heteroaryl. Wherein R ^e is a pyrindinyl group, Claim 65 A compound according. Wherein R ^e is a monosubstituted pyrindinyl group, Claim 66 A compound according. Wherein R ^e is 3-pyridinyl which is based, according to claim 66 A compound according. Wherein R ^e is a pyrindinyl group of the formula, according to claim 66, wherein the compound:

(Wherein x is 0, 1, 2, 3 or 4 and each R ^h is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (- I), -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ⁱ , -ON (R ^k ) ₂ , -N (R ^k ) ₂ , -N ( _{^{R k) 3 + X -,}} -N (OR j) R k, -SH, -SR i, -SSR j, -C (= O) R i, -CO 2 H, -CHO, -CO 2 R i , -OC (= O) R ⁱ , -OCO ₂ R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -NR ^k C (= O) N (R ^k ) ₂ , -C (= NR ^k ) R ⁱ , -C (= NR ^k ) OR ⁱ , -OC (= NR ^k ) R ⁱ , -OC (= NR ^k ) OR ⁱ , -C (= NR ^k ) N (R ^k ) ₂ , -OC (= NR ^k ) N (R ^k ) ₂ , -NR ^k C (= ^{NR k) N (R k)} 2, -C (= O) NR k SO 2 R i, -NR k SO 2 R i, -SO 2 N (R k) 2, -SO 2 R i, -SO 2 OR ⁱ , -OSO ₂ R ⁱ , -S (= O) R ⁱ , -OS (= O) R ⁱ , -Si (R ⁱ ) ₃ , -OSi (R ⁱ ) ₃ , -C (= S) N (R ^k ) ₂ , -C (= O) SR ⁱ , -C (= S) SR ⁱ , -SC (S) SR ⁱ , -P (= O) ₂ R ⁱ , -OP (= O) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -OP (= O) (R ⁱ ) ₂ , -OP (= O) (OR ^j ) ₂ , -P (= O) ₂ N (R ^k ) ₂ , -OP (= O) ₂ N (R ^k ) ₂ , -P (= O) (NR ^k ) ₂ , -OP (= O ) (NR ^k ) ₂ , -NR ^k P (= O) (OR ^j ) ₂ , -NR ^k P (= O) (NR ^k ) ₂ , -P (R ^j ) ₂ , -P (R ^j ) ₃ , -OP (R ^j ) ₂ , -OP (R ^j ) ₃ , -B (OR ^j ) ₂ , -BR ⁱ (OR ^j ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 Selected from alkenyl, C _2-10 alkynyl, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , Aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups;
Each example of R ⁱ is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl, and 5-14 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ^m groups;
Each example of R ^k is independently hydrogen, -OH, -OR ⁱ , -N (R ^j ) ₂ , -CN, -C (= O) R ⁱ , -C (= O) N (R ^j ) ₂ , -CO ₂ R ⁱ , -SO ₂ R ⁱ , -C (= NR ^j ) OR ⁱ , -C (= NR ^j ) N (R ^j ) ₂ , -SO ₂ N (R ^j ) ₂ , -SO ₂ R ^j , -SO ₂ OR ^j , -SOR ⁱ , -C (= S) N (R ^j ) ₂ , -C (= O) SR ^j , -C (= S) SR ^j , -P (= O ) ₂ R ⁱ , -P (= O) (R ⁱ ) ₂ , -P (= O) ₂ N (R ^j ) ₂ , -P (= O) (NR ^j ) ₂ , C _1-10 alkyl, C Whether selected from _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl Or two Rj groups attached to the N atom join to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently of substituted 0,1,2,3,4, or by five R ^m groups ;
Each instance of R ^j is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, Two Rj groups selected from C _6-14 aryl, and 5-14 membered heteroaryl, or bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Forms a heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups Is;
Each example of R ^m is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H _{, -SO 3 H, -OH, -OR} 0, -ON (R n) 2, -N (R n) 2, -N (R n) 3 + X -, -N (OR o) R n, - ^{SH, -SR o, -SSR o,} -C (= O) R o, -CO 2 H, -CO 2 R o, -OC (= O) R o, -OCO 2 R o, -C (= O ) N (R ⁿ ) ₂ , -OC (= O) N (R ⁿ ) ₂ , -NR ⁿ C (= O) R ^o , -NR ⁿ CO ₂ R ^o , -NR ⁿ C (= O) N ( R ⁿ ) ₂ , -C (= NR ⁿ ) OR ^o , -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) OR ^o , -C (= NR ⁿ ) N (R ⁿ ) ₂ ,- ^{OC (= NR n) n (} R n) 2, -NR n C (= NR n) n (R n) 2, -NR n SO 2 R o, -SO 2 n (R n) 2, -SO 2 R ^o , -SO ₂ OR ^o , -OSO ₂ R ^o , -S (= O) R ^o , -Si (R ^o ) ₃ , -OSi (R ^o ) ₃ , -C (= S) N (R ⁿ _{) 2, -C (= O)} SR o, -C (= S) SR o, -SC (= S) SR o, -P (= O) 2 R o, -P (= O) (R o) ₂ , -OP (= O) (R ^o ) ₂ , -OP (= O) (OR ^o ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14 membered f It is selected from Roariru, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and each heteroaryl is independently substituted 0,1,2,3,4, or by five R ^p group Or two geminal R ^m substituents can be joined to form ═O or ═S;
Each example of R ^o is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 Selected from membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, Or substituted by 5 R ^p groups;
Each example of R ⁿ is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, Selected from C _6-10 aryl, and 5-10 membered heteroaryl, or two R ⁿ groups bonded to the N atom are bonded to form a 3-14 membered heterocyclyl ring or 5-14 membered Wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently represented by 0, 1, 2, 3, 4, or 5 R ^p groups. Substituted; and
Each example of R ^p is independently fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H , -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ X, --NH (C _1-6 alkyl) ₂ X, --NH ₂ (C _1-6 alkyl) X, --NH ₃ X, --N (OC _1-6 alkyl) (C _1-6 alkyl), --N (OH ) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (= O) (C _1-6 alkyl),- CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ ,- C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _{1- 6} alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -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} (C 1-6 alkyl), - OC (NH) NH 2, - NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N (C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH _2, -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl,- Si (C _1-6 alkyl) 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) SC 1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) ₂ (C _1-6 alkyl), -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) ( OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, 3-14 membered heterocyclyl, or a 5-14 membered heteroaryl; or two geminal R ^p substituent bonded, = O Wakashi It can form the = S;
Here, X ⁻ is a counter ion. ). Wherein R ^h is, fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I), - CN, -NO 2, -OH, -OR i, -SR i, -N _{^{(R k) 2, -N (}} R k) 3 + X -, -C (= O) R i, -CO 2 R i, -CO 2 H, -OC (= O) R i, -OCO 2 R ⁱ , -C (= O) N (R ^k ) ₂ , -OC (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -NR ^k C (= O) N (R k) 2, -C (= O) NR k SO 2 R i, -NR k SO 2 R i, -SO 2 N (R k) 2, -SO 2 Ri, C 1 _-10 alkyl, C ₆ aryl, and 5-6 membered heteroaryl, wherein the alkyl, aryl, and each heteroaryl is independently 0, 1, 2, 3, or 4 R ^m 70. The compound of claim 69, wherein said compound is substituted by a group; and wherein X < ^- > is a counter ion. Selected from —C (═O) R ⁱ , —CO ₂ H, —SO ₂ R ⁱ , and 5-membered heteroaryl, wherein R ^h is independently substituted with 0 or 1 R ^m group; 71. The compound of claim 70, wherein   72. The compound of claim 71, wherein the 5-membered heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. 38. The compound of claim 36, wherein the pyridinyl group is a 3-pyridinyl group of the formula:

. Wherein G is a -OR ^e selected from the following, according to claim 66, wherein the compound:

.   75. The compound of claims 1-74, wherein the compound is substantially enantiomerically pure.   76. A pharmaceutical composition comprising a compound according to claims 1 to 75, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient.   Treating a FAAH-mediated disorder comprising administering to a subject in need of treatment of a FAAH-mediated disorder a therapeutically effective amount of a compound according to claims 1-75, or a pharmaceutically acceptable form thereof. Method.   78. The method of claim 77, wherein the FAAH-mediated disorder is selected from painful conditions, inflammatory conditions, immune disorders, central nervous system disorders, metabolic disorders, heart disease and glaucoma.   The FAAH-mediated disorder is neuropathic pain, central pain, afferent blocking pain, chronic pain, postoperative pain, preoperative pain, nociceptive pain, acute pain, non-inflammatory pain, inflammatory pain, cancer Pain associated with pain, trauma pain, pain associated with medical treatment, pain resulting from pruritus, bladder pain syndrome, pain associated with premenstrual dysphoric disorder, pain associated with premenstrual syndrome, pain associated with chronic fatigue syndrome, Pain associated with early childbirth, pain associated with withdrawal from drug addiction, joint pain, arthritic pain, lumbosacral pain, musculoskeletal pain, headache, migraine, muscle pain, low back pain, neck pain, toothache, dental / maxillofacial 79. The method of claim 78, wherein the pain condition is selected from pain and visceral pain.   79. The method of claim 78, wherein the FAAH mediated disorder is an inflammatory condition or an immune disorder.   81. The method of claim 80, wherein the inflammatory condition or immune disorder is a gastrointestinal disorder.   81. The method of claim 80, wherein the inflammatory condition or immune disorder is a skin condition.   The FAAH-mediated disorder is neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, mental disorder, sleep disorder, movement disorder, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer 79. The method of claim 78, wherein the disorder is a central nervous system disorder selected from disease and drug addiction.   79. The method of claim 78, wherein the FAAH-mediated disorder is a metabolic disorder selected from a debilitating condition or an obesity-related condition or a complication thereof.   79. The method of claim 78, wherein the FAAH mediated disorder is a heart disease selected from hypertension, circulatory shock, myocardial reperfusion injury, and atherosclerosis. 79. The method of claim 78, wherein the FAAH mediated disorder is glaucoma.