RU2539595C2 - Isoxazoline as fatty acid amide hydrolase inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula

(I) or their pharmaceutically acceptable forms, wherein each of G, R^a, R^b, R^c and R^d has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

Description

Cross reference to related applications

This application claims priority based on U.S. provisional patent applications serial numbers 61/179280, 61/179283, and 61/179285, filed May 18, 2009, the entire contents of each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Fatty acid amide hydrolase (FAAH), also called oleamide hydrolase and anandamidamidohydrolase, is a complete membrane protein responsible for the hydrolysis of some important endogenous neuromodulating fatty acid amides (FAA), including anadamide, oleoylethanolamide and palmitoyl ethanolamide, which are closely linked. Because these FAAs interact with cannabinoid and vanilloid receptors, they are often called "endocannabinoids" or "endovanilloids." Initially, interest in this area was focused on the development of FAAH inhibitors to enhance the effects of FAA and relieve pain. As a result of further studies, it was found that FAAH inhibitors, through interactions of FAA with specific extracellular and intracellular receptors, can be used to treat many different conditions that include, but are not limited to, inflammation, metabolic disorders (e.g., obesity-related and related with depletion of the condition, such as cachexia and anorexia), disorders of the central nervous system (for example, disorders associated with neurotoxicity and / or neurotrauma, oud p, multiple sclerosis, spinal cord injury, motor disorders such as disorders associated with the basal nuclei of the brain, amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, mental disorders such as anxiety, depression, learning disabilities and schizophrenia, sleep disorders, such as insomnia, nausea and / or vomiting, and drug addiction), heart disorders (e.g. hypertension, circulatory shock, myocardial reperfusion injury, and atherosclerosis) and glaucoma (Pacher et al, "The Endocannabinoid S ystem as Emerging Target of Pharmacotherapy "Pharmacological Reviews (2006) 58: 389-462; Pillarisetti et al, "Pain and Beyond: Fatty Acid Amides and Fatty Acid Amide Hydrolase Inhibitors in Cardiovascular and Metabolic Diseases" Drug Discovery Today (2009) 597: 1-14).

SUMMARY OF THE INVENTION

The present invention provides isoxazoline compounds that are FAAH inhibitors of formula (I):

or their pharmaceutically acceptable forms, where:

(i) each of R ^a , R ^b and R ^{c is} independently selected from —H, C _1-10 alkyl or C _1-10 perhaloalkyl, R ^d represents a —LZ group, 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, or C _1-10 perhaloalkyl, R ^d represents a —LZ group, and Z is selected from a 3-14 membered heterocyclyl or 5-14 membered heteroaryl;

(iii) R ^a and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic fused ring, and R ^b and R ^{c are} independently selected from —H, C _1-10 alkyl, or C _1-10 perhaloalkyl; or

(iv) R ^c and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic spiro-fused ring, and R ^a and R ^{b are} independently selected from —H, C _1-10 alkyl, or C _1-10 perhaloalkyl;

L represents a covalent bond or a divalent C _1-6 hydrocarbon group, where one, two or three methylene units in L are optionally and independently replaced by one or more oxygen, sulfur or nitrogen atoms;

G is selected from -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 ^- where X ^- represents a counterion; and

each R ^{e is} independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, C _6-14 aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl; each R ^f bonded to a nitrogen atom is independently selected from —H, C _1-10 alkyl or an amino protecting group; or R ^e and R ^{f are} combined to form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring.

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

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

A detailed description of additional embodiments of the present invention is presented below in the sections “Detailed description of the invention” “Illustrative examples”. Other features, objectives, and advantages of the present invention will be apparent from the present description and from the claims.

Definitions

The definitions of specific functional groups and chemical terms are presented in more detail below. Chemical elements are designated according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., On the inside of the cover, and specific functional groups are generally defined as described in this manual. In addition, the general principles of organic chemistry, as well as specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, University of Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 ^{th Edition, John Wiley & Sons,} Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987.

Some compounds of the present invention may include one or more asymmetric centers and, thus, can exist in various isomeric forms, for example, in the form of enantiomers and / or diastereomers. The compounds provided herein may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, the compounds of the present invention are enantiopure compounds. In some other embodiments, mixtures of stereoisomers are provided.

In addition, some of the compounds described in this application may contain one or more double bonds, which can exist either as cis or trans, or the E or Z isomer, unless otherwise indicated. The invention also encompasses compounds in the form of individual isomers, essentially free of other isomers, and, alternatively, in the form of mixtures of various isomers, for example, racemic mixtures of E / Z isomers or mixtures enriched in one E / Z isomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and “non-racemic,” as used interchangeably herein, refer to compositions in which the weight percent of one enantiomer is greater than the amount of such one enantiomer in the control mixture of the racemic composition (for example, more than 1 : 1 by weight). For example, an enantiomerically enriched (S) -enantiomer preparation means a preparation of a compound containing more than 50% by weight of (S) -enantiomer relative to the (R) -enantiomer, more preferably at least 75% by weight, and even more preferably at least 80% of the mass. In some embodiments, the enrichment can be much more than 80% by weight, providing a “substantially enantiomerically enriched”, “substantially enantiomerically pure” or “substantially non-racemic” preparation, and relates to the preparation of compositions that contain at least 85% mass of one enantiomer relative to another enantiomer, more preferably at least 90% by mass, and even more preferably at least 95% by mass. In preferred embodiments, the enantiomerically enriched composition has a higher activity in terms of therapeutic utility per unit mass, compared to such a racemic mixture composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be obtained by asymmetric synthesis. See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33: 2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN 1972).

When a range of values is indicated, it is assumed that it encompasses each value and sub-range within the specified range. For example, “C _1-6 alkyl” includes, 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 _{5 -6} alkyl.

As the term is used in this application, “single bond” or “covalent bond” refers to a single bond connecting two groups.

As the term is used in this application, separately or as part of another group, “halo” and “halogen” refer to fluoro (fluoro, —F), chloro (chloro, —Cl), bromo (bromo, —Br) or iodo ( iodine, -I).

As the term is used herein, individually or as part of another group, “alkyl” refers to a mono radical of a linear or branched saturated hydrocarbon group containing from 1 to 10 carbon atoms (“C _1-10 alkyl”). In some embodiments, the alkyl group contains from 1 to 9 carbon atoms ("C _1-9 alkyl"). In some embodiments, the alkyl group contains from 1 to 8 carbon atoms ("C _1-8 alkyl"). In some embodiments, the alkyl group contains from 1 to 7 carbon atoms ("C _1-7 alkyl"). In some embodiments, the alkyl group contains from 1 to 6 carbon atoms ("C _1-6 alkyl"). In some embodiments, the alkyl group contains from 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group contains from 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group contains from 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, the alkyl group contains from 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group contains 1 carbon atom (“C ₁ alkyl”). In some embodiments, the alkyl group contains from 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 ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentanyl (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. Unless otherwise specified, in each case, the alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") and contains 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the alkyl group is unsubstituted C _1-10 alkyl (e.g., -CH ₃ ). In some embodiments, the alkyl group is substituted C _1-10 alkyl.

"Perhaloalkyl," as defined herein, refers to an alkyl group containing from 1 to 10 carbon atoms, where all hydrogen atoms, each independently, are substituted with halogen, for example, selected from fluorine, bromine, chlorine or iodine ("C _{1 -10} perhaloalkyl "). In some embodiments, the alkyl group contains from 1 to 8 carbon atoms ("C _1-8 perhaloalkyl"). In some embodiments, the alkyl group contains from 1 to 6 carbon atoms ("C _1-6 perhaloalkyl"). In some embodiments, the alkyl group contains from 1 to 4 carbon atoms ("C _1-4 perhaloalkyl"). In some embodiments, the alkyl group contains from 1 to 3 carbon atoms ("C _1-3 perhaloalkyl"). In some embodiments, the alkyl group contains from 1 to 2 carbon atoms ("C _1-2 perhaloalkyl"). In some embodiments, each of the hydrogen atoms is replaced by fluorine. In some embodiments, each of the hydrogen atoms is replaced with chlorine. Examples of perhaloalkyl groups include —CF ₃ , —CF ₂ CF ₃ , —CF ₂ CF ₂ CF ₃ , —CCl ₃ , —CFCl ₂ , —CF ₂ Cl, and the like.

As the term is used herein, alone or as part of another group, “alkenyl” refers to a mono radical of a linear or branched hydrocarbon group containing from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (“C _2-10 alkenyl "). In some embodiments, the alkenyl group contains from 2 to 9 carbon atoms ("C _2-9 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 8 carbon atoms ("C _2-8 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 7 carbon atoms ("C _2-7 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 4 carbon atoms ("C _2-4 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 3 carbon atoms ("C _2-3 alkenyl"). In some embodiments, the alkenyl group contains 2 carbon atoms (“C ₂ alkenyl”). One or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 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 ) and the like. Examples of C _2-6 alkenyl groups include the above C _2-4 alkenyl groups, as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ) and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ) and the like. Unless otherwise indicated, in each case, the alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the alkenyl group is an unsubstituted C _2-10 alkenyl. In some embodiments, the alkenyl group is a substituted C _2-10 alkenyl.

As the term is used herein, individually or as part of another group, “alkynyl” refers to a mono radical of a linear or branched hydrocarbon group containing from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (“C _2-10 alkynyl "). In some embodiments, the alkynyl group contains from 2 to 9 carbon atoms ("C _2-9 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 8 carbon atoms ("C _2-8 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 7 carbon atoms ("C _2-7 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 5 carbon atoms ("C _2-5 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 4 carbon atoms ("C _2-4 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 3 carbon atoms ("C _2-3 alkynyl"). In some embodiments, the alkynyl group contains 2 carbon atoms (“C ₂ alkynyl”). One or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 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 ), 2-butynyl (C ₄ ), and like that. Examples of the C ₂ - ₆ alkenyl groups include the aforementioned C _2-4 alkynyl group, and pentynyl (C _5), hexynyl (C _6), and the like. Additional examples of alkynyl include heptinyl (C ₇ ), octynyl (C ₈ ) and the like. Unless otherwise indicated, in each case, the alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted (“substituted alkynyl”) with 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the alkynyl group is an unsubstituted C ₂ - ₁₀ alkynyl. In some embodiments, the alkynyl group is a substituted C ₂ - ₁₀ alkynyl.

A "divalent C _1-6 hydrocarbon group" is a divalent C _1-6 alkyl group, a divalent C _1-6 alkenyl group or a divalent C _1-6 alkynyl group, where one, two or three methylene units (-CH ₂ -) hydrocarbon the chains are optionally and independently replaced by one or more oxygen, sulfur, or nitrogen atoms. In some embodiments, the divalent C _1-6 hydrocarbon group is a divalent C _1-6 alkyl group. In some embodiments, a divalent C _1-6 hydrocarbon group is an unsubstituted divalent C _1-6 hydrocarbon group (for example, an unsubstituted divalent C _1-6 alkyl group).

As the term is used herein, alone or as part of another group, “alkoxy” refers to an alkyl group, as defined herein, substituted by an oxygen atom, where the attachment point is an oxygen atom. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms ("C _1-10 alkoxy"). In some embodiments, the alkyl group contains from 1 to 8 carbon atoms ("C _1-8 alkoxy"). In some embodiments, the alkyl group contains from 1 to 6 carbon atoms ("C _1-16 alkoxy"). In some embodiments, the alkyl group contains from 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 ) and the like. Examples of C _1-6 alkoxy groups include the above C _1-4 alkoxy groups, as well as pentyloxy (C ₅ ), isopentyloxy (C ₅ ), neopentyloxy (C ₅ ), hexyloxy (C ₆ ) and the like. Additional examples of alkoxy groups include heptyloxy (C ₇ ), octyloxy (C ₈ ) and the like. Unless otherwise specified, in each case, the alkyl group in the alkoxy group is independently unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy"), and may be substituted with 1, 2, 3, 4, or 5 substituents, as described herein . In some embodiments, the alkoxy group represents unsubstituted C ₂ - ₁₀ alkoxy (e.g., -OCH _3). In some embodiments, the alkoxy group is a substituted C _2-10 alkoxy (e.g., perhaloalkoxy as defined herein).

"Perhaloalkoxy" refers to an alkoxy group wherein all hydrogen atoms of an alkyl group, each independently, are replaced by halogen atoms selected from fluorine, chlorine, bromine and iodine. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms ("C _1-10 perhaloalkoxy"). In some embodiments, the alkyl group contains from 1 to 8 carbon atoms ("C _1-8 perhaloalkoxy"). In some embodiments, the alkyl group contains from 1 to 6 carbon atoms ("C _1-6 perhaloalkoxy"). In some embodiments, the alkyl group contains from 1 to 4 carbon atoms ("C _1-4 perhaloalkoxy"). In some embodiments, the alkyl group contains from 1 to 3 carbon atoms ("C _1-3 perhaloalkoxy"). In some embodiments, the alkyl group contains from 1 to 2 carbon atoms ("C _1-2 perhaloalkoxy"). In some embodiments, each of the hydrogen atoms present is replaced by fluorine. In some embodiments, each of the hydrogen atoms present is replaced with chlorine. 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 the term is used in this application, separately or as part of another group, “carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group containing from 3 to 10 carbon atoms in the ring (“C _3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group contains from 3 to 8 carbon atoms in the ring (“C _3-8 carbocyclyl”). In some embodiments, the carbocyclic group contains from 3 to 6 carbon atoms in the ring (“C _3-6 carbocyclyl”). In some embodiments, the carbocyclic group contains from 3 to 6 carbon atoms in the ring (“C _3-6 carbocyclyl”). In some embodiments, the carbocyclic group contains from 5 to 10 carbon atoms in the ring (“C _5-10 carbocyclyl”). Examples of C _3-6 carbocyclic groups include, without limitation, 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 C _3-8 carbocyclic groups include the above C _3-6 carbocyclic groups, 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 C _3-10 carbocyclic groups include the above C ₃ - ₈ carbocyclic group, and octahydro-1H-indenyl, decahydronaphthalene, spiro [4.5] decanyl, and the like. As illustrated by the above examples, in some embodiments, the carbocyclic group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (eg, containing a fused, bridged or spiro ring system, such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system ("tricyclic carbocyclyl")) and may be saturated or may contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems where the carbocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, where the attachment point is on the carbocyclic ring. Unless otherwise indicated, in each case, the carbocyclic group is independently unsubstituted (“unsubstituted carbocyclyl”) or substituted (“substituted carbocyclyl”) with 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the carbocyclic group is an unsubstituted C _3-10 carbocyclyl. In some embodiments, the carbocyclic group is a substituted C ₃ - ₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic saturated carbocyclic group containing from 3 to 10 carbon atoms in the ring (“C _3-10 cycloalkyl”). In some embodiments, the cycloalkyl group contains from 3 to 8 carbon atoms in the ring (“C _3-8 cycloalkyl”). In some embodiments, the cycloalkyl group contains from 3 to 6 carbon atoms in the ring (“C _3-6 cycloalkyl”). In some embodiments, the cycloalkyl group contains from 5 to 6 carbon atoms in the ring (“C _5-6 cycloalkyl”). In some embodiments, the cycloalkyl group contains from 5 to 10 carbon atoms in the ring (“C _5-10 cycloalkyl”). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include the above C _5-6 cycloalkyl groups, as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the above C _3-6 cycloalkyl groups, as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise indicated, in each case, the cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with 1, 2, 3, 4 or 5 substituents, as described herein. In some embodiments, the cycloalkyl group is an unsubstituted C _3-10 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C _3-10 cycloalkyl.

As the term is used in this application, individually or as part of another group, “heterocyclyl” refers to a radical of a 3-14 membered non-aromatic ring system containing carbon atoms in the ring and from 1 to 4 heteroatoms in the ring, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (“3-14 membered heterocyclyl”). In heterocyclic groups that contain one or more nitrogen atoms, the attachment point may be a carbon or nitrogen atom, as valency allows. The heterocyclic group may be either monocyclic (“monocyclic heterocyclyl”) or polycyclic (for example, a fused, bridged or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)) and be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic ring systems may include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems where the heterocyclic ring as defined above is fused with one or more carbocyclic groups, where the attachment point is either on a carbocyclic or heterocyclic ring, or ring systems where the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups where the attachment point is on the heterocyclic ring. In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heterocyclyl" ) In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl” ) In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl” ) In some embodiments, a 5-6 membered heterocyclyl contains 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl contains 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl contains 1 heteroatom in the ring selected from nitrogen, oxygen and sulfur. Examples of 3-membered heterocyclic groups containing 1 heteroatom include, without limitation, aziridinyl, oxiranyl, thiorenyl. Examples of 4-membered heterocyclic groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Examples of 5-membered heterocyclic groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Examples of 5 membered heterocyclic groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Examples of 5-membered heterocyclic groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl and thiadiazolinyl. Examples of 6-membered heterocyclic groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Examples of 6 membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianil, dioxanyl. Examples of 6 membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanil, oxepanyl, and tiepanyl. Examples of 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocanyl, oxane and thiocanil. Exemplary bicyclic heterocyclic groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetragidrobenzotienil, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinoline, oktagidrohromenil, oktagidroizohromenil, dekagidronaftiridinil, decahydro-1,8-naphthyridinyl, pyrrolo [3,2- -b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chranyl, chromenyl, 1H-benzo [e] [l, 4] diazepinyl, 1,4,5,7-tetrahydropyrano [3,4-b] pyrrolyl, 5,6- di idro-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 1,6-naphthyridinyl and the like. Unless otherwise indicated, in each case, heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the heterocyclic group is an unsubstituted 3-14 membered heterocyclyl. In some embodiments, the heterocyclic group is a substituted 3-14 membered heterocyclyl.

As the term is used in this application, separately or as part of another group, “aryl” refers to a radical of a monocyclic or polycyclic (eg, bicyclic or tricyclic) aromatic ring system (for example, containing 6, 10 or 14 π electrons common to these rings in cyclic arrangement) containing 6-14 carbon atoms in the ring and zero heteroatoms represented in the aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl group contains 6 carbon atoms in the ring (“C ₆ aryl,” for example phenyl). In some embodiments, the aryl group contains 10 carbon atoms in the ring (“C ₁₀ aryl”; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group contains 14 carbon atoms in the ring (“C ₁₄ aryl”; for example, anthracyl). “Aryl” also includes ring systems where the aryl ring, as defined above, is fused to one or more carbocyclic or heterocyclic groups, where the radical or attachment point is located on the aryl ring. Unless otherwise indicated, in each case, the aryl group is independently unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the aryl group is an unsubstituted C _6-14 aryl. In some embodiments, the aryl group is a substituted C _6-14 aryl.

“Aralkyl” is a subgroup of “alkyl” and refers to an alkyl group as defined herein, a substituted aryl group as defined herein, where the attachment point is on an alkyl group.

As the term is used in this application, separately or as part of another group, “heteroaryl” refers to the radical of a 5-14 membered monocyclic or polycyclic (eg, bicyclic or tricyclic) aromatic ring system (for example, containing 6, 10 or 14 common to of these rings are π electrons in a cyclic arrangement) containing carbon atoms in the ring and 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the attachment point may be a carbon or nitrogen atom, as valency allows. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems where the heteroaryl ring as defined above is fused to one or more aryl groups, where the attachment point is either on the aryl or heteroaryl ring, or where the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups where the attachment point is on the heteroaryl ring. As for polycyclic heteroaryl groups, where one ring does not contain a heteroatom (e.g. indolyl, quinolinyl, carbazolyl and the like), the attachment point can be on any ring, i.e. either on a ring containing a heteroatom (e.g., 2-indolyl), or on a ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5 10 membered heteroaryl "). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5 -8 membered heteroaryl "). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system containing carbon atoms in the ring and 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5 -6 membered heteroaryl "). In some embodiments, a 5-6 membered heteroaryl contains 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl contains 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl contains 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of 5 membered heteroaryls containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Examples of 5 membered heteroaryls containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Examples of 5-membered heteroaryls containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, thiadiazolyl. Examples of 5 membered heteroaryls containing 4 heteroatoms include, but are not limited to, tetrazolyl. Examples of 6 membered heteroaryls containing 1 heteroatom include, without limitation, pyridinyl. Examples of 6 membered heteroaryls containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Examples of 6 membered heteroaryls containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryls containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxiaziol azothiaziazolazole. Examples of 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Examples of tricyclic heteroaryl include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. Unless otherwise indicated, in each case, the heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted (“substituted heteroaryl”) with 1, 2, 3, 4, or 5 substituents, as described herein. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

“Heteroaralkyl” is a subgroup of “alkyl” and refers to an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein, where the attachment point is on an alkyl group.

As the term is used in this application, the term “partially unsaturated” refers to a ring group that includes at least one double or triple bond. The term "partially unsaturated" covers rings containing several sites of unsaturation, but it does not include the inclusion of aromatic groups (for example, aryl or heteroaryl groups) defined in this application.

Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups defined herein are optionally substituted (eg, “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted "alkynyl," substituted "or" unsubstituted "carbocyclic," substituted "or" unsubstituted "heterocyclic," substituted "or" unsubstituted "aryl or" substituted "or" unsubstituted "heteroaryl group). As a rule, the term “substituted”, regardless of whether the word “optionally” appears before it or not, means that at least one hydrogen atom is present in the group (for example, at the carbon or nitrogen atom, etc.) , is replaced by a possible substituent, for example, a substituent, which upon substitution leads to a stable compound, for example, a compound that is not subject to spontaneous transformation, for example, by rearrangement, cyclization, elimination or other reaction. Unless otherwise indicated, a “substituted” group contains a substituent at one or more substituted positions of that group, and when more than one position in any particular structure is substituted, the substituents are the same or different from each other at each position.

Examples of carbon atom substituents include, but are not limited to, halogen (i.e. fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-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 (= О) N (R ^bb ) ₂ , -OC (= О) N (R ^bb ) ₂ , -NR ^bb C (= О) R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C (= О) N (R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -ОС (= NR ^bb ) R ^aa , -ОС (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -ОС (= 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 ^{a a} ) 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, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups; or two hydrogen atoms attached to the same carbon atom are replaced by = O, = S, = NN (R ^bb ) ₂ , = NNR ^bb C (= О) R ^aa , = NNR ^bb C (= О) OR ^aa , = NNR ^bb S (= O) ₂ R ^aa , = NR ^bb , = NOR ^CC ;

in each case R ^aa is independently selected from 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 a 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

in each case, R ^{bb is} independently selected from 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 _{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 linked to N atom, combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocycle sludge, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

in each case, R ^{cc is} independently selected from 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, C _{6- 14} aryl and 5-14 membered heteroaryl, or two R ^cc groups linked to the N atom, are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

in each case, R ^{dd is} independently selected from 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 (= О) 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 (= О) R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C (= О) N (R ^ff ) ₂ , -C (= NR ^ff ) OR ^ee , -ОС (= NR ^ff ) R ^ee , -OS (= 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 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two R ^dd adjacent substituents may be combined to form = O or = S;

in each case, R ^{ee is} independently selected from 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 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

in each case, R ^{ff is} independently selected from 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, C _{6- 10} aryl and 5-10 membered heteroaryl, or two R ^ff groups linked to the N atom, are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups; and

in each case, R ^gg independently represents 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) N (C _1-6 alkyl) ₂ , -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) 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 adjacent R ^gg substituents can be combined to form = O or = S; where X ^- represents a counterion.

As the term is used herein, a “counterion” is a negatively charged group in association with a positively charged quaternary amine to maintain electronic neutrality. Examples of counterions include halide ions (e.g., F ^- , Cl ^- , Br ^- , I ^- ), NO ₃ ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , sulfonate ions (e.g. methanesulfonate, trifluoromethanesulfonate , p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate and the like) and carboxylate ions (e.g. acetate, ethanoate , propanoate, benzoate, glycerate, lactate, tartrate, glycolate and the like).

Nitrogen atoms may or may not be substituted, as valency permits, and include primary, secondary, tertiary and quaternary nitrogen atoms. Examples of nitrogen 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 5 -14 membered heteroaryl, or two R ^cc groups associated with N atom are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each lkil, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^dd, and wherein R ^aa, R ^bb, R ^cc and R ^dd have the meanings defined above.

In some embodiments, the substituent present on the nitrogen atom is an amino protecting group. Amino protecting groups include, but are not limited to, —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 where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, and where R ^aa , R ^bb , R ^cc and R ^dd have values defined above. Amino-protecting groups are well known from the ternary level and include groups described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

For example, amino protecting groups such as amide groups (e.g., —C (═O) R ^aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -pyridylcarboxamide, derivatives of N-benzoylphenylalanyl, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxycarbonylamino) acetamide, 3- (p-hydroxyphenyl-propanediamide) propane 2-methyl-2- (o-nitrophenoxy) propanamide, 2-methyl-2- (o-phenylazophenoxy) propanamide , 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, a derivative of N-acetylmethionine, o-nitrobenzamide and o- (benzoyloxymethyl) benzamide.

Amino protecting groups such as carbamate groups (e.g., —C (═O) OR ^aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo) fluorenylmethyl carbamate, 9 - (2,7-dibromo) fluorenylmethylcarbamate, 2,7-di-tert-butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methylcarbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1,1-dimethyl -2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromethylcarbamate (DB-tert- BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethyl carbamate (Bpoc), 1- (3,5-di-tert-butylphenyl) - 1-Methyl ethyl carbamate (t-Bumeoc), 2- (2'- and 4'-pyridyl) ethyl carbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc) , vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate, N-hydroxypiperidinyl carbamate, carbamide, benzyl ), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-x lorbenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonyl ethyl carbamate, 2- (p-ethyl-2-tol-ethyl) (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, acyloxybenzylcarbamate, p- (dihydroxyboryl) benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2- (trifluoromethyl) -6-chromonylmethyl rbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzylthiocarbamate, , cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxycarbonylvinylcarbamate, o- (N, N-dimethylcarboxamido) benzylcarbamate, 1,1-dimethyl-3- (N, N-dimethyl-dimethylpropylamide) di (2-pyridyl) methyl carbamate, 2-furanylmethyl carbamate , 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p- (p'-methoxyphenylazo) benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropyl-methyl-1-methyl-1-methyl ethyl carbamate, 1-methyl-1- (p-phenylazophenyl) ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzyl carbamate, 2,4,6 tri-tert-butylphenylcarbamate, 4- (trimethylammonium) benzylcarbamate and 2,4,6-trimethylbenzylcarbamate.

Amine protecting groups such as sulfonamide groups (e.g., -S (= O) ₂ R ^aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6, -trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms) , β-trimethylsilylethanesulfonamide (SES), 9-anthracene ulfonamide, 4- (4 ', 8'-dimethoxynaphthylmethyl) benzene sulfonamide (DNMBS), benzyl sulfonamide, trifluoromethyl sulfonamide and phenacyl sulfonamide.

Other amino protecting groups include, but are not limited to, the phenothiazinyl (10) carbonyl derivative, the N'-p-toluenesulfonylaminocarbonyl derivative, the N'-phenylaminothiocarbonyl derivative, the N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-dienyl -3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, the addition product of N-1,1,4,4-tetramethyldisilylazacyclopentane ( STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-1, 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 salts, N-benzylamine, N-di (4-methoxyphenyl) methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (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-benzylidenamine, N-p-methoxybenzylidenamine, N-diphenylmethyleneamine, N - [(2-pyridyl) mesit il] methyleneamine, N- (N ', N'-dimethylaminomethylene) amine, NN'-isopropylidene diamine, N-p-nitrobenzylideneamine, N-salicylidenamine, N-5-chlorosalicylidenamine, N- (5-chloro-2-hydroxyphenyl) phenylmethyleneamine , N-cyclohexylideneamine, N- (5,5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl (pentacarbonylchromium or tungsten) carbonyl] amine, N - copper chelate compound, N-zinc chelate compound, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Νps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylphenylmeridine

As the term is used in this application, a “leaving group” is a term commonly used in the art that refers to a molecular fragment that is removed with a pair of electrons in the heterolytic cleavage of the bond, where the molecular fragment is an anion or a neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).

These and other examples of substituents are described in more detail in the sections “Detailed Description of the Invention”, “Illustrative Examples” and in the claims. There is no limitation of the present invention to the list of substituents given as an example above.

As the term is used in this application, “its pharmaceutically acceptable form” includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, isomers and / or polymorphs of the compounds of the present invention, as defined below and in this section.

As the term is used in this application, the term "pharmaceutically acceptable salt" refers to those salts which, according to a weighted medical assessment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc. . and correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known from the ternary level. For example, SM Berge et al., Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts formed from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, hematofluorosulfate, heptofluorosulfate, heptofluorosulfate, heptofluorosulfate, heptofluorosulphonate, heptofluorosulfate, heptofluanoate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin, pectin fat, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts formed from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, if appropriate, salts of non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

In some embodiments, the pharmaceutically acceptable form of the compound is an isomer. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, “isomers” include cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures that are encompassed the present invention.

In some embodiments, the pharmaceutically acceptable form of the compound is a tautomer. As used herein, the term “tautomer” includes two or more mutually convertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (for example, a change in a single bond to a double bond, triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., a tautomeric couple reaction) can be catalyzed by acid or base. Examples of tautomerizations include keto → enol tautomerizations; amide → imide; lactam → lactim; enamine → imine; and enamine → (other) enamine.

In some embodiments, the pharmaceutically acceptable form of the compound is a hydrate or solvate. As used herein, the term "hydrate" refers to a compound in non-covalent association with one or more water molecules. Similarly, “solvate” refers to a compound in non-covalent association with one or more molecules of an organic solvent.

In some embodiments, the pharmaceutically acceptable form of the compound is a prodrug. As used herein, the term “prodrug” refers to a derivative of a parent compound that requires conversion in the body to release the parent compound. In some cases, the prodrug has improved physical and / or delivery properties compared to the parent compound. Prodrugs are typically intended to enhance the pharmaceutical and / or pharmacokinetic properties associated with the parent compound. The advantage of the prodrug may be due to its physical properties, such as a higher water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it can increase the stability of the drug during long-term storage.

In some embodiments, the pharmaceutically acceptable form of the compound is a polymorph. As used herein, the term “polymorph” refers to a compound having more than one crystalline structure, for example, as a result of differences in molecular packing and / or molecular conformation of the compound in the solid state.

Sequence Identification Numbers

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

DETAILED DESCRIPTION OF THE INVENTION

I. Compounds

The present invention provides isoxazoline compounds that are FAAH inhibitors having the formula (I):

or a pharmaceutically acceptable form of such compounds wherein:

(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 represents a —LZ group, 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 represents a —LZ group, and Z is selected from a 3-14 membered heterocyclyl and 5-14 membered heteroaryl;

(iii) R ^a and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic fused ring, and R ^b and R ^{c are} independently selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl; or

(iv) R ^c and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic spiro-fused ring, and R ^a and R ^{b are} independently selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl;

L represents a covalent bond or a divalent C _1-6 hydrocarbon group, where one, two or three methylene units in L are optionally and independently replaced by one or more oxygen, sulfur or nitrogen atoms;

G is selected from -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 ^- , where X ^- represents a counterion; and

each R ^{e is} selected from 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 bonded to a nitrogen atom is independently selected from —H, C _1-10 alkyl or an amino protecting group; or R ⁶ and R ^{f are} combined to form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring.

Group G

As defined above, G is selected from —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 ^- , where X ^- represents a counterion;

and wherein R ^{e is} selected from 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 bonded to a nitrogen atom is independently selected from —H, C _1-10 alkyl or an amino protecting group; or R ^e and R ^{f are} combined to form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring.

In some embodiments, G cannot be a leaving group, for example, G is selected from —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 R ^e .

In some embodiments, G is selected from —CN and —NO ₂ . In some embodiments, G is —CN. In some embodiments, G is —NO ₂ .

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

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

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

However, in some embodiments, G is a leaving group, for example, G is selected from —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 ^- , where X ^- is a counterion.

In some embodiments, G is halogen; those. selected from —F, —Cl, —Br, and —I. In some embodiments, G is —F. In some embodiments, G is -Br. In some embodiments, G is -I. In some embodiments, G is —Cl. However, in some embodiments, G is different from halogen. For example, in some embodiments, G is different from -Br. In some embodiments, G is different from -I. In some embodiments, G is other than -F. In some embodiments, G is different from —Cl.

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

In some embodiments, G is selected from —OR ^e and —SR ^e . In some embodiments, G is selected from —OR ^e . In some embodiments, G is —SR ^e .

In some embodiments, G is selected from —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 ^- , where X ^- is a counterion. In some embodiments, G is selected from —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 —NR ^f (C = O) OR ^e . In some embodiments, G is selected from —NR ^f SO ₂ R ^e , —NR ^f R ^e , —NR ^f (C = O) R ^e, and —NR ^f (C = O) OR ^e . In some embodiments, G is —NR ^f SO ₂ R ^e . In some embodiments, G is —NR ^f PO ₂ R ^e . In some embodiments, G is —NR ^f PO ₂ OR ^e . In some embodiments, G is —NR ^f R ^e . In some embodiments, G is —NR ^f (C = O) R ^e . In some embodiments, G is —NR ^f (C = O) OR ^e . In some embodiments, G is —NR ^f (C = NR ^f ) NR ^f R ^e . In some embodiments, G is —NR ^f (C = NR ^f ) OR ^e . In some embodiments, G is - [N (R ^f ) ₂ R ^e ] ⁺ X ^- , where X ^- is a counterion.

Additional embodiments of G included in the description of the groups R ^e and R ^f and further illustrated in the Tables and Examples are presented below and in this section of the application.

R ^e  from Group G

As generally defined above, in some embodiments, where G is selected from —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 , -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 = О) R ^e , -NR ^f (C = О) OR ^e , -О (C = О) 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 ^- where X ^is a counterion, R ^{e is} selected from 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 A 14 membered heteroaryl.

In some embodiments, R ^{e is} selected from 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, where the alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic and heteroaryl groups are substituted with 0, 1, 2, 3, 4 or 5 R ^h groups described below and in this section of the application.

In some embodiments, R ^e is C _1-10 alkyl. In some embodiments, R ^e is C _1-6 alkyl. In some embodiments, R ^e is C _1-6 alkyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e is C _1-5 alkyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e is C _1-4 alkyl substituted with 0, 1, 2, 3, or 4 R ^h groups. In some embodiments, R ^e is C _1-3 alkyl substituted with 0, 1, 2, or 3 R ^h groups. In some 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, where such groups are substituted with 0, 1, 2, 3, 4 or 5 groups R ^h .

In some embodiments, R ^e is C _1-6 perhaloalkyl. In some embodiments, R ^e is C _1-5 perhaloalkyl. In some embodiments, R ^e is C _1-4 perhaloalkyl. In some embodiments, R ^e is C _1-3 perhaloalkyl. In some embodiments, R ^e is C _1-2 perhaloalkyl. Examples of perhaloalkyl groups of R ^e include, but are not limited to, —CF ₃ , —CF ₂ CF ₃ , —CF ₂ CF ₂ CF ₃ , —CCl ₃ , —CFCl _2, and —CF ₂ Cl.

In some embodiments, R ^e is C _2-10 alkenyl. In some embodiments, R ^e is C _2-6 alkenyl. In some embodiments, R ^e is C _2-6 alkenyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e is C _2-5 alkenyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some 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, where such groups are substituted with 0, 1, 2, 3, 4, or 5 groups R ^h .

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

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

In some embodiments, where G is —SR ^e , R ^e cannot be C _1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, aralkyl).

In some embodiments, where G is —NR ^e R ^f and R ^f is —H or C _1-3 alkyl (e.g. methyl, ethyl, aralkyl), in this case, R ^e cannot be C _{1- 6} alkyl.

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

In some embodiments, R ^e is phenyl. In some embodiments, R ^e is phenyl substituted with 0, 1, 2, 3, or 4 R ^h groups. In some embodiments, R ^e is phenyl substituted with 0, 1, 2, or 3 R ^h groups. In some embodiments, R ^e is phenyl substituted with 0, 1 or 2 R ^h groups. In some embodiments, R ^e is phenyl substituted with 0 or 1 R ^h group. In some embodiments, R ^e is disubstituted phenyl (i.e., substituted with 2 R ^h groups). In some embodiments, R ^e is monosubstituted phenyl (i.e., substituted with 1 R ^h group). In some embodiments, R ^e is unsubstituted phenyl (i.e., substituted with 0 R ^h groups).

In some embodiments, R ^e is phenyl substituted with at least one ortho R ^h group. In some embodiments, R ^e is phenyl substituted with at least one meta R ^h group. In some embodiments, R ^e is phenyl substituted with at least one R ^h group.

In some embodiments, R ^e represents a phenyl group of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h has the meaning defined below and in this section of the application. In some embodiments, x is 0, 1, 2, 3, or 4. In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x has a value of 0 or 1. In some embodiments, x has a value of 3. In some embodiments, R ^e is a disubstituted phenyl group (i.e., where x is 2). In some embodiments, R ^e is a monosubstituted phenyl group (i.e., where x is 1). In some embodiments, R ^e represents an unsubstituted phenyl group (i.e., where x is 0).

For example, in some embodiments, R ^e represents a substituted or unsubstituted phenyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is naphthyl. In some embodiments, R ^e represents a naphthyl group of any of the following formulas:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h has the meaning defined below and in this section of the application. In some embodiments, x is 0, 1, 2, 3, or 4. In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x has a value of 0 or 1. In some embodiments, R ^e represents a trisubstituted naphthyl group (i.e., where x is 3). In some embodiments, R ^e represents a disubstituted naphthyl group (i.e., where x is 2). In some embodiments, R ^e is a monosubstituted naphthyl group (i.e., where x is 1). In some embodiments, R ^e represents an unsubstituted naphthyl group (i.e., where x is 0).

For example, in some embodiments, R ^e represents a substituted or unsubstituted 1-naphthyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e represents a substituted or unsubstituted 2-naphthyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

However, in some embodiments, where G is —OR ^e , in this case, R ^e cannot be C ₁₀ aryl (eg, 1-naphthyl, 2-naphthyl).

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

Examples of heteroaryl groups R ^e include, but are not limited to, pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g., 2-pyridinyl 4-pyridinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, indolyl, , indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzo uranyl, benzoizofuranil, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benztiadiazolil, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R ^h groups.

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

For example, in some 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 at least one of Y ^a , Y ^b , Y ^c and Y ^d represents O, S, N or NR ^k , and where R ^h and R ^k have the meaning defined below and in this section of the application.

In some embodiments of the above formula (1-d), Y ^a is O, S, N or NR ^k , and Y ^b , Y ^c and Y ^{d are} independently selected from CH, CR ^h , NR ^k or N. In some embodiments of the above formula (1-d), 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 some embodiments of the above formula (1-d), 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 .

In some embodiments of the above formula (1-d), 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 some embodiments, the embodiments of the above formula (1-d), Y ^b represents O, S or NR ^k , and Y ^a , Y ^c and Y ^{d are} independently selected from CH or CR ^h . In some embodiments of the above formula (1-d), Y ^b is O, S or or NR ^k , Y ^d is N, and Y ^a and Y ^{c are} independently selected from CH or CR ^h .

In some embodiments, R ^e is a substituted or unsubstituted 5-membered heteroaryl of any of the following formulas:

where x has a value of 0, 1 or 2, and R ^h and R ^k have the meaning defined below and in this section of the application. In some embodiments, R ^e is an unsubstituted 5-membered heteroaryl (i.e., where x is 0). In some embodiments, R ^e is a substituted 5-membered heteroaryl (for example, where x is 1 or 2). In some embodiments, R ^e is a monosubstituted 5 membered heteroaryl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted 5-membered heteroaryl (i.e., where x is 2). In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

However, in some embodiments, where G is —OR ^e , R ^e cannot be thiazolyl, for example, of the formula:

where x has a value of 0, 1 or 2, and R ^h and R ^k have the meaning defined below and in this section of the application.

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

For example, in some embodiments, R ^e is a 6 membered heteroaryl group of the formula:

where W ^a , W ^b , W ^c , W ^d and W ^{e are} independently selected from CH, CR ^h or N, provided that at least one of W ^a , W ^b , W ^c , W ^d and W ^e represents N, and where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a pyridinyl group. In some embodiments, R ^e is a pyridinyl group substituted with 0, 1, 2, 3, or 4 R ^h groups. For example, in some embodiments, R ^e is a pyridinyl group of the formula:

where x has the value 0, 1, 2, 3 or 4, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted pyridinyl (i.e., where x is 0). In some embodiments, R ^e is substituted pyridinyl (for example, where x is 1, 2, 3, or 4). In some embodiments, R ^e is monosubstituted pyridinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted pyridinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted pyridinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e represents a 2-pyridinyl group, for example, formulas (ie), where W ^a represents N, and W ^b , W ^c , W ^d and W ^e independently represent CH or CR ^h . In some embodiments, R ^e represents a 3-pyridinyl group, for example, formulas (ie), where W ^b represents N, and W ^a , W ^c , W ^d and W ^e independently represent CH or CR ^h . In some embodiments, R ^e represents a 4-pyridinyl group, for example, formulas (ie), where W ^c represents N, and W ^a , W ^b , W ^d and W ^e independently represent CH or CR ^h .

In some embodiments, R ^e is a substituted or unsubstituted 2-pyridinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e represents a substituted or unsubstituted 3-pyridinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e represents a substituted or unsubstituted 4-pyridinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a pyridazinyl group. In some embodiments, R ^e is a pyridazinyl group substituted with 0, 1, 2, or 3 R ^h groups. For example, in some embodiments, R ^e is a pyridazinyl group of the formula:

where x has a value of 0, 1, 2 or 3, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted pyridazinyl (i.e., where x is 0). In some embodiments, R ^e is substituted pyridazinyl (for example, where x is 1, 2, or 3). In some embodiments, R ^e is monosubstituted pyridazinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted pyridazinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted pyridazinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a 3-pyridazinyl group, for example, formulas (ie), where W ^a and W ^b are N, and W ^c , W ^d and W ^{e are} independently CH or CR ^h . In some embodiments, R ^e is a 4-pyridazinyl group, for example, formulas (ie), where W ^b and W ^c are N, and W ^a , W ^d and W ^e independently are CH or CR ^h .

In some embodiments, R ^e represents a substituted or unsubstituted 3-pyridazinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a substituted or unsubstituted 4-pyridazinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a pyrimidinyl group. In some embodiments, R ^e is a pyrimidinyl group substituted with 0, 1, 2, or 3 R ^h groups. For example, in some embodiments, R ^e is a pyrimidinyl group of the formula:

where x has a value of 0, 1, 2 or 3, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted pyrimidinyl (i.e., where x is 0). In some embodiments, R ^e is substituted pyrimidinyl (for example, where x is 1, 2, or 3). In some embodiments, R ^e is monosubstituted pyrimidinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted pyridazinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted pyrimidinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a 2-pyrimidinyl group, for example, formulas (ie), where W ^a and W ^e are N, and W ^b , W ^c and W ^d independently are CH or CR ^h . In some embodiments, R ^e is a 4-pyrimidinyl group, for example, formulas (ie), where W ^a and W ^c are N and W ^b , W ^d and W ^e independently are CH or CR ^h . In some embodiments, R ^e is a 5-pyrimidinyl group, for example, formulas (ie), where W ^b and W ^d are N, and W ^a , W ^c and W ^e independently are CH or CR ^h .

In some embodiments, R ^e is a substituted or unsubstituted 2-pyrimidinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e represents a substituted or unsubstituted 4-pyrimidinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a substituted or unsubstituted 5-pyrimidinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a pyrazinyl group. In some embodiments, R ^e is a pyrazinyl group substituted with 0, 1, 2, or 3 R ^h groups. For example, in some embodiments, R ^e is a pyrazinyl group of the formula:

where x has a value of 0, 1, 2 or 3, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted pyrazinyl (i.e., where x is 0). In some embodiments, R ^e is substituted pyrazinyl (for example, where x is 1, 2, or 3). In some embodiments, R ^e is monosubstituted pyrazinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted pyrazinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted pyrazinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a substituted or unsubstituted pyrazinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a triazinyl group. In some embodiments, R ^e is a triazinyl group substituted with 0, 1 or 2 R ^h groups. For example, in some embodiments, R ^e is a triazinyl group of the formula:

where x has a value of 0, 1 or 2, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted pyrazinyl (i.e., where x is 0). In some embodiments, R ^e is substituted pyrazinyl (for example, where x is 1 or 2). In some embodiments, R ^e is monosubstituted pyrazinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted pyrazinyl (i.e., where x is 2). In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a substituted or unsubstituted triazinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a tetrazinyl group. In some embodiments, R ^e is a tetrazinyl group substituted with 0 or 1 R ^h groups. In some embodiments, R ^e is a tetrazinyl group of the formula:

where x has a value of 0 or 1, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted pyrazinyl (i.e., where x is 0). In some embodiments, R ^e is substituted pyrazinyl (for example, where x is 1). In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a substituted or unsubstituted tetrazinyl group of any of the following formulas:

where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e is a 9-membered heteroaryl (e.g., 5,6-bicyclic heteroaryl). In some embodiments, R ^e is 5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e is a 5,6-bicyclic heteroaryl selected from indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, indoxylazole, benzoxazolazolazolazole, benzoxazolazolazole, benzoxazolyl azole, benzoxazolyl azole, benzoxazolyl azole where such groups are substituted with 0, 1, 2, 3, 4 or 5 R ^h groups.

For example, in some embodiments, R ^e is a 5,6-bicyclic heteroaryl of the formula:

where Y ^e , Y ^f , Y ^g , Y ⁱ , Y ^j , Y ^k and Y ^m independently represent C, CH, CR ^h , O, S, N or NR ^k , and Y ⁿ represents C or N, when 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} defined below and in this section of the application.

In some embodiments, R ^e is a 5,6-bicyclic heteroaryl group of formula (if), wherein Y ^{e is} selected from O, S or NR ^k , Y ⁿ is C, and Y ^f , Y ^g , Y ⁱ , Y ^j , Y ^k and Y ^m independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

where x has a value of 0, 1, 2, 3, 4 or 5, and R ^h and R ^k have the meanings defined below and in this section of the application. In some embodiments, R ^e is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where x is 0). In some embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted 5,6-bicyclic heteroaryl (i.e., where x is 2). In some embodiments, R ^e is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is 5,6-bicyclic heteroaryl wherein Y ^{e is} selected from O, S, or NR ^k ; Y ^g represents N; Y ⁿ represents C; Y ^f represents C, CH or CR ^h or N, and Y ⁱ , Y ^j , Y ^k and Y ^m independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

where x has a value of 0, 1, 2, 3, 4 or 5, and R ^h and R ^k have the meanings defined below and in this section of the application. In some embodiments, R ^e is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where x is 0). In some embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted 5,6-bicyclic heteroaryl (i.e., where x is 2). In some embodiments, R ^e is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is 5,6-bicyclic heteroaryl, wherein Y ^e is NR ^k , S, or O; Y ^m represents N; Y ⁿ represents C; and Y ^f , Y ^g , Y ⁱ , Y ^j and Y ^k independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

where x has a value of 0, 1, 2, 3, 4 or 5, and R ^h and R ^k have the meanings defined below and in this section of the application. In some embodiments, R ^e is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where x is 0). In some embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted 5,6-bicyclic heteroaryl (i.e., where x is 2). In some embodiments, R ^e is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is 5,6-bicyclic heteroaryl, wherein Y ^g is O, S, or NR ^k ; Y ^m represents N; Y ⁿ represents C; and Y ^e , Y ^f , Y ⁱ , Y ^j and Y ^k independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

where x has a value of 0, 1, 2, 3, 4 or 5, and R ^h and R ^k have the meanings defined below and in this section of the application. In some embodiments, R ^e is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where x is 0). In some embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted 5,6-bicyclic heteroaryl (i.e., where x is 2). In some embodiments, R ^e is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is 5,6-bicyclic heteroaryl wherein Y ^{e is} selected from N; Y ⁿ represents N; and Y ^f , Y ⁱ , Y ^j , Y ^k and Y ^m independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is a 5,6-bicyclic heteroaryl group of the formula:

where x has a value of 0, 1, 2, 3, 4 or 5, and R ^h and R ^k have the meanings defined below and in this section of the application. In some embodiments, R ^e is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where x is 0). In some embodiments, R ^e is a substituted 5,6-bicyclic heteroaryl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted 5,6-bicyclic heteroaryl (i.e., where x is 2). In some embodiments, R ^e is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

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

For example, in some embodiments, R ^e is a 6,6-bicyclic heteroaryl of the formula: (ig)

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 at least one of W ^f , W ^g , W ^h , W ⁱ , W ^j , W ^k , W ^m and W ⁿ is N, and where R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e represents a quinolinyl group; for example, formulas (ig), where W ⁱ represents N, and W ^g , W ^h , W ^f , W ^j , W ^k , W ^m and W ⁿ independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is a quinolinyl group of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted quinolinyl (i.e., where x is 0). In some embodiments, R ^e is substituted quinolinyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted quinolinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted quinolinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted quinolinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e represents an isoquinolinyl group; for example, formulas (ig), where W ^h represents N, and W ^f , W ^g , W ⁱ , W ^j , W ^k , W ^m and W ⁿ independently represent C, CH or CR ^h . For example, in some embodiments, R ^e is an isoquinolinyl group of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted isoquinolinyl (i.e., where x is 0). In some embodiments, R ^e is substituted isoquinolinyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted isoquinolinyl (i.e., where x is 1). In some embodiments, R ^e is a disubstituted isoquinolinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted isoquinolinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e represents a quinoxalinyl group; for example, formulas (ig), where W ^f and W ⁱ are N and W ^g , W ^h , W ^j , W ^k , W ^m and W ⁿ independently are C, CH or CR ^h . For example, in some embodiments, R ^e is a quinoxalinyl group of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h has the meaning defined below and in this section of the application. In some embodiments, R ^e is unsubstituted quinoxalinyl (i.e., where x is 0). In some embodiments, R ^e is substituted quinoxalinyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted quinoxalinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted quinoxalinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted quinoxalinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

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

Examples of heterocyclic groups R ^e include, but are not limited to, aziridinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-diolanyl, 2,5-diolanyl, 2,5-diolanyl, dihydro-diolanyl, 2,5 triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianil, dioxanyl, triazinanil, azepanyl, oxepanyl, thiepanyl, azocanylindolene, oxane, l, dihydrobenzofuranyl, dihydrobenzothienyl, tetragidrobenzotienil, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinoline, oktagidrohromenil, oktagidroizohromenil, dekagidronaftiridinil, decahydro-1,8-naphthyridinyl, pyrrolo [3,2-b] pyrrole, indolinyl, phthalimide, naphthalimide, chromanil, chromenyl, 1H-benzo [e] [l, 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- irrolo [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 and 4,5,6,7-tetrahydrothieno [3,2-b] pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R ^h groups.

In some embodiments, R ^e is a 6 membered heterocyclyl substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e is a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianil, dioxanyl and triazinanil, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R groups ^h .

For example, in some embodiments, R ^e is a 6 membered heterocyclyl of the formula:

where W ⁰ , 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 ¹ represents N, CH, CR ^h , with the proviso that at least one of W ⁰ , W ^p , W ^q , W ^r and W ^{s is} selected from N, NR ^k , O or S, and where R ^h and R ^k are as defined below and in this section of the application.

In some embodiments, R ^e is a piperidinyl group. In some embodiments, R ^e is a piperidinyl group substituted with 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 ⁿ and R ^{k are} defined below and in this section of the application. In some embodiments, R ^e is unsubstituted piperidinyl (i.e., where x is 0). In some embodiments, R ^e is substituted piperidinyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted piperidinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted piperidinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted piperidinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a 1-piperidinyl group, for example, of formula (ih), where W ^t is N and W ⁰ , W ^p , W ^q , W ^r and W ^{s are} independently selected from CH ₂ , CHR ^h , C (R ^h ) ₂ . In some embodiments, R ^e is a 2-piperidinyl group, for example, of formula (ih), where W ⁰ is NR ^k ; W ^p , W ^q , W ^r and W ^s independently represent CHR ^h , C (R ^h ) ₂ or CH ₂ ; and W ^t represents CH or CR ^h . In some embodiments, R ^e is a 3-piperidinyl group, for example, of formula (ih), where W ^p is NR ^k ; W ⁰ , W ^q , W ^r and W ^s independently represent CHR ^h , C (R ^h ) ₂ or CH ₂ ; and W ^t represents CH or CR ^h . In some embodiments, R ^e represents a 4-piperidinyl group, for example, of formula (ih), where W ^q represents NR ^k ; W ⁰ , W ^p , W ^r and W ^s independently represent CHR ^h , C (R ^h ) ₂ or CH ₂ ; and W ^t represents CH or CR ^h .

In some embodiments, R ^e is a piperazinyl group. In some embodiments, R ^e is a piperazinyl group substituted with 0, 1, 2, 3, or 4 R ^h groups, for example, of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h and R ^{k are} defined below and in this section of the application. In some embodiments, R ^e is unsubstituted piperazinyl (i.e., where x is 0). In some embodiments, R ^e is substituted piperazinyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted piperazinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted piperazinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted piperazinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a 1-piperazinyl group, for example, of formula (ih), where W ^t is N, W ^q is NR ^k , and W ⁰ , W ^p , W ^r and W ^{s are} independently selected from CH ₂ , CHR ^h , C (R ^h ) ₂ . In some embodiments, R ^e is a 2-piperazinyl group, for example, of formula (ih), where W ⁰ and W ^r independently are NR ^k , and W ^p , W ^q , W ^r and W ^s independently are CHR ^h , C (R ^h ) ₂ or CH ₂ ; and W ^t represents CH or CR ^h .

In some embodiments, R ^e is a morpholinyl group. In some embodiments, R ^e is a morpholinyl group substituted with 0, 1, 2, 3, or 4 R ^h groups, for example, of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h and R ^{k are} defined below and in this section of the application. In some embodiments, R ^e is unsubstituted morpholinyl (i.e., where x is 0). In some embodiments, R ^e is substituted morpholinyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted morpholinyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted morpholinyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted morpholinyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a morpholinyl group of formula (ih), where W ^t is N, W ^q is O, and W ⁰ , W ^p , W ^r and W ^{s are} independently selected from CH ₂ , CHR ^h , C (R ^h ) ₂ .

In some embodiments, R ^e represents a dioxanyl group. In some embodiments, R ^e is a dioxanyl group substituted with 0, 1, 2, 3, or 4 R ^h groups, for example, of the formula:

where x has the value 0, 1, 2, 3, 4 or 5, and R ^h and R ^{k are} defined below and in this section of the application. In some embodiments, R ^e is unsubstituted dioxanyl (i.e., where x is 0). In some embodiments, R ^e is substituted dioxanyl (for example, where x is 1, 2, 3, 4, or 5). In some embodiments, R ^e is monosubstituted dioxanyl (i.e., where x is 1). In some embodiments, R ^e is disubstituted dioxanyl (i.e., where x is 2). In some embodiments, R ^e is trisubstituted dioxanyl (i.e., where x is 3). In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1.

In some embodiments, R ^e is a dioxanyl group, for example, of formula (ih), where W ⁰ 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 represents CH or CR ^h .

Other 6 membered heterocyclic R ^e groups covered by formula (ih) include monosaccharide sugars, for example, pyranosides selected from ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, iodose, galactose and thalose.

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

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

Rf from Group G

As generally defined above, in some embodiments, where G is selected from —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 ^- , where X ^- is a counterion, each R ^f bonded to a nitrogen atom is independently selected from —H or C _1-10 alkyl or an amino protecting group, or R ^e and R ^{f are} combined with the formation of a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring.

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

In some embodiments, R ^f is H.

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

In some embodiments, R ^f is an amino protecting group. For example, in some embodiments, R ^{f is} selected from —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 , -CC = 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 heterocyclic, C _6-14 aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups, where R ⁱ , R ^k , R ^{m are} defined below and in this section of the application.

However, in some embodiments, G is —NR ^e R ^f and R ^f is —H or C _1-3 alkyl, in which case R ^e cannot be C _1-6 alkyl or thiazolyl.

In addition, in some embodiments, where G is —OC (═O) NR ^f R ^e , R ^e and R ^f cannot both be —CH ₃ .

Alternatively, in some embodiments, R ^e and R ^{f are} combined to form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring; for example, when 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 ^- , where X ^- is a counterion. In some embodiments, where R ^e and R ^{f are} combined to form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring, the heterocyclic ring or heteroaryl ring is substituted with 0, 1, 2, 3, 4, or 5 R ^h groups as defined below and in this section of the application.

In some embodiments, R ^e and R ^{f are} combined to form a 3-14 membered heterocyclic ring. In some embodiments, R ^e and R ^{f are} combined to form a 3-14 membered heterocyclic ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^{f is} combined to form a 5-10 membered heterocyclic ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e and R ^{f are} combined to form a 5-8 membered heterocyclic ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups. In some embodiments, R ^e and R ^{f are} combined to form a 5-6 membered heterocyclic ring substituted with 0, 1, 2, or 3 R ^h groups. In some embodiments, R ^e and R ^{f are} combined to form a 9-10 membered heterocyclic ring substituted with 0, 1, 2, 3, 4, or 5 R ^h groups.

In some embodiments, R ^e and R ^{f are} combined to form a heterocyclic group selected from aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, dihydropyridinyl, thianylazinyl, trianilazinyl, trianilazinyl, , azepanil, oxepanil, tiepanil, azocanil, indolinyl, isoindolinyl, tetrahydrobenzo-thienyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indol limidila where such groups are substituted by 0, 1, 2, 3, 4 or 5 R ^h groups.

For example, in some embodiments, R ^e and R ^{f are} combined to form a 5-membered heterocyclic ring selected from the group:

where x has the value 0, 1, 2 or 3, where R ^h and R ^{k are} defined below and in this section of the application.

In some embodiments, R ^e and R ^{f are} combined to form a 6-membered heterocyclic ring selected from the group:

where x has the value 0, 1, 2 or 3, where R ^h and R ^{k are} defined below and in this section of the application.

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

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

In some embodiments, R ^e and R ^{f are} combined 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 in this section of the application.

However, in some embodiments, where G is —NR ^f R ^e , R ^e and R ^f are not combined to form a 1,2,4-triazolyl ring, for example, of the formula:

where x has a value of 0 or 1, and R ^h has the meaning defined below and in this section of the application.

In some embodiments, R ^e and R ^{f are} combined to form a 9-membered heteroaryl (“5,6-bicyclic heteroaryl”) ring selected from:

where x has a value of 0, 1, 2 or 3, and R ^h and R ^{k are} defined below and in this section of the application.

Group G substituents

Embodiments of R ^h

As the term is used above and in this section of the application, in each case, R ^{h is} independently selected from halogen (fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-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 (= О) 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 , -ОС (= 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 Ri, -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 (Ri) 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) 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 (= О) (NR ^k ) ₂ , -P (R ^j ) ₂ , -P (R ^j ) ₃ , -OP (R ^j ) ₂ , -OP (R ^j ) ₃ , -B (OR ^j ) ₂ , -B 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, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups;

in each case, R ^{i is} independently selected from 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 a 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups;

in each case, R ^{k is} independently selected from 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 _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 associated with the N atom, combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle klyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups;

in each case, R ^{j is} independently selected from 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, C _{6- 14} aryl and 5-14 membered heteroaryl, or two Rj groups bonded to the N atom, are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups;

in each case, R ^{m is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I), -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -ORo, -ON (R ⁿ ) ₂ , -N (Rn) ₂ , -N (Rn) ₃ ⁺ X ^- , -N (ORo) Rn, -SH, -SR ⁰ , -SSR ⁰ , -C (O) R ⁰ , -CO ₂ H, -CO ₂ R ⁰ , -OC (O) R ⁰ , -OCO ₂ R ⁰ , -C (= O) N (R ⁿ ) ₂ , -OC (= O) N (R ⁿ ) ₂ , -NRnC (= О) R ⁰ , -NR ⁿ CO ₂ R ⁰ , -NR ⁿ C (= О) N (R ⁿ ) ₂ , -C (= NR ⁿ ) OR ⁰ , -OC (= NR ⁿ ) R ⁰ , -OC (= NR ⁿ ) OR ⁰ , -C (= NR ⁿ ) N (R ⁿ ) ₂ , -ОС (= NR ⁿ ) N (R ⁿ ) ₂ , -NR ⁿ C (= NR ⁿ ) N (R ⁿ ) ₂ , -NR ⁿ SO ₂ R ⁰ , -SO ₂ N (R ⁿ ) ₂ , -SO ₂ R ⁰ , -SO ₂ OR ⁰ , -OSO ₂ R ⁰ , -S (= O) R ⁰ , -Si (R ⁰ ) ₃ , -OSi (R ⁰ ) ₃ , -C (= S) N (R ⁿ ) ₂ , -C (+ O) SR ⁰ , -C (= S) SR ⁰ , -SC (= S) SR ⁰ , -P (= O) ₂ R ⁰ , -P (= O) (R ⁰ ) ₂ , -OP (= O) (R ⁰ ) ₂ , -OP (= O) (OR ⁰ ) 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- lennogo heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups Rp, or two R ^m adjacent substituents may be combined to form = O or = S ;

in each case, R ^{0 is} independently selected from 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 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^p groups;

in each case, R ^{n is} independently selected from 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, C _{6- 10} aryl and 5-10 membered heteroaryl, or two R ⁿ groups bonded to the N atom, are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^p groups; and

in each case, R ^p independently represents fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-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) N H 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, 5-14 membered heteroaryl; or two adjacent Rp substituents may be combined to form = O or = S;

where X ^- is a counterion.

In some embodiments, R ^{h is} selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-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 Ri, -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 (OR j), C} 1-10 alkyl, -C _1-10 perhalo hernia, C _3-14 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14-membered heteroaryl, wherein each alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^m ; and, where X ^is a counterion.

In some embodiments, R ^{h is} selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-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 (= О) N (R ^k ) ₂ , -ОС (= О) 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, where each alkyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3 or 4 R ^m groups; and, where X ^is a counterion.

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

In some embodiments, R ^h is —SR ⁱ , for example, selected from —SCH ₃ .

In some embodiments, R ^h is —N (R ^k ) ₂ or —N (R ^k ) ₃ ⁺ X ^- , for example, selected from —NH ₂ and —NH ₃ ⁺ X ^- .

In some embodiments, R ^h is —C (═O) R ⁱ , for example, selected from —C (═O) CH _3.

In some embodiments, R ^h is —CO ₂ ⁱ , for example, selected from —CO ₂ CH ₃

In some embodiments, R ^h is —C (= O) N (R ^k ) ₂ , for example, selected from —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 C (= O) OCH ₃ , -C (= O) NHCH ₂ C (= O) OH and - C (= O) NHCH ₂ CH ₂ OH.

In some embodiments, R ^h is —OC (= O) R ⁱ , for example, selected from —OC (= O) CH ₃ .

In some embodiments, R ^h is —OCO ₂ R ⁱ , for example, selected from —OCO ₂ CH ₃ .

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

In some embodiments, R ^h is —NR ^k C (= O) R ⁱ , for example, selected from —NHC (= O) CH ₃ .

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

In some embodiments, R ^h is —NR ^k C (= O) N (R ^k ) ₂ , for example, selected from —NHC (= O) NH ₂ .

In some embodiments, R ^h is —C (= O) NR ^k SO ₂ R ⁱ , for example, selected from —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) NHSO ₂ iBu.

In some embodiments, R ^h is —NR ^k SO ₂ R ⁱ , for example, selected from —NHSO ₂ CH ₃ .

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

In some embodiments, R ^h represents -SO ₂ R ^i, for example, selected from -SO ₂ CH _3, -SO ₂ CH ₂ CH _3, - SO ₂ C ₅ H _9, and -SO ₂ iBu.

In some embodiments, R ^h is C _1-10 alkyl, for example, selected from —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 —CH ₂ CH ₂ CO ₂ NH ₂ .

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

In some embodiments, in each case, R ^{h is} independently selected from fluorine (-F), bromine (-Br), chlorine (-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, C ₆ aryl substituted with 0, 1 or 2 c ppami R ^m, and 5-6-membered heteroaryl substituted with 0, 1 or 2 R ^m groups; and, where X ^is a counterion.

In some embodiments, R ^h is C ₆ aryl (e.g., phenyl) substituted with 0, 1, or 2 R ^m groups. In some embodiments, R ^h is C ₆ aryl (e.g., phenyl) substituted with 1 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 some embodiments, R ^h is a 5-6 membered heteroaryl substituted with 0, 1 or 2 R ^m groups. In some embodiments, R ^h is a 5-membered heteroaryl substituted with 0, 1 or 2 R ^m groups. Examples of 5 membered R ^h heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, where such groups are substituted with 0 or 1 R ^m . In some embodiments, R ^h is a 5-membered heteroaryl group selected from pyrazolyl and oxadiazolyl, where such groups are substituted with 0 or 1 R ^m group.

Embodiments of R ⁱ

In some embodiments, in each case, R ^{i is} independently selected from 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, where each alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is unsubstituted.

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

Embodiments of R ^m

In some embodiments, in each case, R ^{m is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I), -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -OH, -ORo, -ON (R ⁿ ) ₂ , -N (R ⁿ ) ₂ , -N (R ⁿ ) ₃ ⁺ X ^- , -N (ORo) 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 (= О) R ^o , -NR ¹¹ CO ₂ R ^o , -NR ⁿ C (= О) N (R ⁿ ) ₂ , -C (= NR ⁿ ) ORo, -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) ORo, -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 °, -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) (ORo) _2, C _1-6 alkyl, C _1-6 perhaloalkyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14-chlennog heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^p.

In some embodiments, in each case, R ^{m is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I), -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -OH, -ORo, -ON (R ⁿ ) ₂ , -N (R ⁿ ) ₂ , -N (R ⁿ ) ₃ ⁺ X ^- , -N (ORo) 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 , -NRnC (= O) R ^o , -NR ⁿ CO ₂ R ^o , -NR ⁿ C (= O) N (R ⁿ ) ₂ , -C (= NR ⁿ ) ORo, -OC (= NR ⁿ ) R ^o , -OC (= NR ⁿ ) ORo, -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 (= О) R ^o , -C (= S) N (R ⁿ ) ₂ , -C (= О) 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) (ORo) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, 5-14 membered eteroaryl.

In some embodiments, R ^{m is} selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and 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 (= О) CH ₃ , -NHC (= О) OCH ₃ , -NHC (= О) OtBu, -NHC (= О) 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 , - C (= O) NHCH ₂ C (= O) OH and -C (= O) NHCH ₂ CH ₂ OH.

Embodiments of R ^k

As used above and in this section of the application, in each case, R ^{k is} independently selected from -H, -OH, -OR ⁱ , -N (R ^k ) ₂ , -C (= О) R ⁱ , -C (= О ) 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 carbocyclic, 3-14 membered heterocyclic, C _{6- 14} aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups, where R ⁱ , R ^k , R ^m them they have the meaning defined above and in this section of the application.

In some embodiments, in each case, R ^{k is} independently selected from —H, —C (═O) R ⁱ , —C (= O) OR ⁱ , —SO ₂ R ^i, or C _1-6 alkyl. In some embodiments, in each case, R ^{k is} independently selected from —H or C _1-6 alkyl. In some embodiments, in each case, R ^{k is} independently selected from —H and —CH ₃ . In some embodiments, in each case, R ^{k is} independently selected from —H. In some embodiments, in each case, R ^{k is} independently selected from —CH ₃ .

R groups ^a , R ^b  and R ^c

As generally defined above, when R ^d represents a —LZ group, each of R ^a , R ^b and R ^{c are} independently selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl.

In some embodiments, R ^a , R ^b, and R ^{c are} each independently selected from —H, C _1-6 alkyl, and C _1-6 perhaloalkyl. In some 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 some 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 some embodiments, each of R ^a , R ^b, and R ^{c is} independently selected from —H, —CH _3, and —CF _3.

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

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

In some embodiments, each of R ^a , R ^b, and R ^{c is} independently selected from H, —CH _3, and —CF ₃ . In some embodiments, each of R ^a , R ^b, and R ^{c is} independently selected from H or —CH ₃ . In some embodiments, each of R ^a , R ^b, and R ^c is H.

R group ^d

As generally defined above, in some embodiments, R ^d represents a —LZ group, where L is a covalent bond or a divalent C _1-6 hydrocarbon group, wherein one, two, or three methylene units in L are optionally and independently replaced by one or several atoms of oxygen, sulfur or nitrogen, and

Z is selected from C _6-10 aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl.

Group L from R ^d

As generally defined above, L represents a covalent bond or a divalent C _1-6 hydrocarbon group, where one, two or three methylene units in L are optionally and independently replaced by one or more oxygen, sulfur or nitrogen atoms.

In some embodiments, L is a covalent bond.

In some embodiments, L is a divalent C _1-6 hydrocarbon group, wherein one, two, or three methylene units in L are optionally and independently replaced with one or more oxygen (-O-), sulfur (-S-), or nitrogen (eg , -NR ¹ -).

In some embodiments, L is a divalent C _1-6 hydrocarbon group, wherein one, two, or three methylene units in L are optionally and independently replaced with one or more oxygen atoms (—O—).

In some embodiments, L is a divalent C _1-6 hydrocarbon group, wherein one, two, or three methylene units in L are optionally and independently replaced with one or more sulfur atoms (-S-).

In some embodiments, L is a divalent C _1-6 hydrocarbon group, wherein one, two, or three methylene units in L are optionally and independently replaced with one or more nitrogen atoms (—NR ¹ -). However, in some embodiments, when L is a divalent C _1-6 hydrocarbon group comprising one, two or three nitrogen atoms, then L is an unsubstituted divalent C _1-6 hydrocarbon group, and L cannot be a —CH ₂ group NR ¹ -, where R ¹ represents H, C _1-6 alkyl or an amino protecting group.

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

In some embodiments, embodiment L, a divalent C _1-6 hydrocarbon group is an unsubstituted divalent C _1-6 hydrocarbon group. In some embodiments, embodiments of L, a divalent C _1-6 hydrocarbon group contains one oxygen, sulfur or nitrogen atom. In some embodiments, the divalent C _1-6 hydrocarbon group is an unsubstituted divalent C _1-6 hydrocarbon group (for example, an unsubstituted divalent C _1-6 alkyl group).

For example, in some embodiments, L is an unsubstituted divalent C _1-6 alkyl group, wherein one methylene unit in L is replaced by an oxygen, sulfur, or nitrogen atom. In some embodiments, L is an unsubstituted divalent C _1-6 alkyl group, wherein one methylene unit in L is replaced by an oxygen atom. In some embodiments, L is an unsubstituted divalent C _1-6 alkyl wherein one methylene unit in L is replaced by a sulfur atom. In some embodiments, L is an unsubstituted divalent C _1-6 alkyl group, wherein one methylene unit in L is replaced by a nitrogen atom. However, in some embodiments, when L is an unsubstituted divalent C _1-6 alkyl group, then L cannot be a —CH ₂ NR ¹ - group, where R ¹ is H, C _1-6 alkyl or an amino protecting group .

In some embodiments, L is a divalent C ₁ hydrocarbon group, wherein one methylene unit in L is replaced by an oxygen, sulfur, or nitrogen atom, for example, L is selected from oxygen (-O-), sulfur (-S-), or nitrogen (e.g. -NR ¹ -). In some embodiments, L is oxygen (—O—). In some embodiments, L is sulfur (-S-). In some embodiments, L is nitrogen (e.g., —NR ¹ -).

In some embodiments, L is selected from the group consisting of - (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 independently have a value of 0, 1, 2, 3, 4, 5, or 6, and in each case, R ¹⁰ , R ^11, and R ^{12 are} independently selected from H, halogen, or C _1-6 alkyl. In some embodiments, each of R ¹⁰ , R ^11, and R ¹² is —H.

In some embodiments, L is - (C (R ¹⁰ ) ₂ ) _m -. In some embodiments, L is selected from -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 CH ₂ - and - CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

In some embodiments, L is - (C (R ¹¹ ) ₂ ) _m —O— (C (R ¹² ) ₂ ) _n -. In some embodiments, L is selected from —O—, —CH ₂ O—, —OCH ₂ -, —OCH ₂ CH ₂ -, —OCH ₂ CH ₂ - —OCH ₂ CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ O-, -CH ₂ OCH ₂ CH ₂ - and -CH ₂ CH ₂ OCH ₂ -.

In some embodiments, L is - (C (R ¹¹ ) ₂ ) _m —S— (C (R ¹² ) ₂ ) _n -. In some embodiments, L is selected from -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 -.

In some embodiments, L is - (C (R ¹¹ ) ₂ ) _m —NR ¹ - (C (R ¹² ) ₂ ) _n -. In some embodiments, L is selected from -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 group.

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

Embodiments wherein the group Z is from R ^d  is aryl

As defined generally above, in some embodiments, Z is C _6-14 aryl.

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

In some embodiments, Z is phenyl. In some embodiments, Z is phenyl substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups. In some embodiments, Z is phenyl substituted with 0, 1, 2, or 3 R ¹⁵ groups. In some embodiments, Z is phenyl substituted with 0, 1, or 2 R ¹⁵ groups. In some embodiments, Z is phenyl substituted with 0 or 1 R ¹⁵ group. In some embodiments, Z is disubstituted phenyl (i.e., substituted with 2 R ¹⁵ groups). In some embodiments, Z is a monosubstituted phenyl (i.e., substituted with 1 R ¹⁵ group). In some embodiments, Z is unsubstituted phenyl (i.e., substituted with 0 R ¹⁵ groups).

In some embodiments, Z is phenyl substituted with at least one ortho group R ¹⁵ . In some embodiments, Z is phenyl substituted with at least one meta group R ¹⁵ . In some embodiments, Z is phenyl substituted with at least one pair of R ¹⁵ .

In some embodiments, Z is a monosubstituted phenyl substituted with one ortho group R ¹⁵ . In some embodiments, Z is a monosubstituted phenyl substituted with one meta group R ¹⁵ . In some embodiments, Z is a monosubstituted phenyl substituted with one pair of an R ¹⁵ group.

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

In some embodiments, Z is a phenyl group of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z has a value of 0 or 1. In some embodiments, z has a value of 3. In some embodiments, Z is a disubstituted phenyl group (i.e., where z is 2). In some embodiments, Z is a monosubstituted phenyl group (i.e., where z is 1). In some embodiments, Z is an unsubstituted phenyl group (i.e., where z is 0).

For example, in some embodiments, Z is a substituted or unsubstituted phenyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is naphthyl. In some embodiments, Z is a naphthyl group of any of the following formulas:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z has a value of 0 or 1. In some embodiments, Z is a trisubstituted naphthyl group (i.e., where z is 3). In some embodiments, Z is a disubstituted naphthyl group (i.e., where z is 2). In some embodiments, Z is a monosubstituted naphthyl group (i.e., where z is 1). In some embodiments, Z is an unsubstituted naphthyl group (i.e., where z is 0).

For example, in some embodiments, Z is a substituted or unsubstituted 1-naphthyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a substituted or unsubstituted 2-naphthyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

Embodiments wherein Group Z is from R ^d  represents heterocyclyl or heteroaryl

As defined generally above, in some embodiments, Z is selected from 3-14 membered heterocyclyl and 5-14 membered heteroaryl.

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

Examples of heteroaryl Z groups include, but are not limited to, pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, -pyridinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, indolyl, thiolinyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzof wounded, benzoizofuranil, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benztiadiazolil, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups.

In some embodiments, Z is a 5 membered heteroaryl substituted with 0, 1, 2, or 3 R ¹⁵ groups. In some embodiments, Z is a 5-membered heteroaryl selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, where such groups are substituted with 0, 1, 3 groups R ¹⁵ .

For example, in some 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 at least one of Y ¹ , Y ² , Y ^3, and Y ^{4 is} selected from O, S, N or NR ¹⁸ , and where R ¹⁵ and R ¹⁸ are as defined below and in this section of the application.

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

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

In some embodiments, Z is a 5 membered heteroaryl of any of the following formulas:

where R ¹⁵ and R ^{18 are} defined below and in this section of the application, and z has the value 0, 1 or 2,

where z has the value 0, 1 or 2, and R ¹⁵ and R ^{18 are} defined below and in this section of the application. In some embodiments, Z is an unsubstituted 5 membered heteroaryl (i.e., where z is 0). In some embodiments, Z is a substituted 5-membered heteroaryl (for example, where z is 1 or 2). In some embodiments, Z is a monosubstituted 5 membered heteroaryl (i.e., where z is 1). In some embodiments, Z is a disubstituted 5-membered heteroaryl (i.e., where z is 2). In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a 6 membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ^h groups. In some embodiments, Z is a 6-membered heteroaryl selected from the group consisting of pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. , 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazinyl, where such groups are substituted with 0, 1, 2, 3 or 4 R ¹⁵ groups.

For example, in some embodiments, R ^e is a 6 membered heteroaryl group of the formula:

where 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 represents N, and where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a pyridinyl group. In some embodiments, Z is a pyridinyl group substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups. For example, in some embodiments, Z is a pyridinyl group of the formula:

where z has a value of 0, 1, 2, 3 or 4, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted pyridinyl (i.e., where z is 0). In some embodiments, Z is substituted pyridinyl (for example, where z is 1, 2, 3, or 4). In some embodiments, Z is a monosubstituted pyridinyl (i.e., where z is 1). In some embodiments, Z is disubstituted pyridinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted pyridinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a 2-pyridinyl group, for example, 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 some embodiments, Z is a 3-pyridinyl group, for example, formulas (ii-e), where W ² is N and W ¹ , W ³ , W ⁴ and W ^{5 are} independently CH or CR ¹⁵ . In some embodiments, Z is a 4-pyridinyl group, for example, 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 .

In some embodiments, R ^e is a substituted or unsubstituted 2-pyridinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a substituted or unsubstituted 3-pyridinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a substituted or unsubstituted 4-pyridinyl group of the formula:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a pyridazinyl group. In some embodiments, Z is a pyridazinyl group substituted with 0, 1, 2, or 3 R ¹⁵ groups. For example, in some embodiments, Z is a pyridazinyl group of the formula:

where z has a value of 0, 1, 2 or 3, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted pyridazinyl (i.e., where z is 0). In some embodiments, Z is substituted pyridazinyl (for example, where z is 1, 2, or 3). In some embodiments, Z is a monosubstituted pyridazinyl (i.e., where z is 1). In some embodiments, Z is disubstituted pyridazinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted pyridazinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

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

In some embodiments, Z is a substituted or unsubstituted 3-pyridazinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a substituted or unsubstituted 4-pyridazinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a pyrimidinyl group. In some embodiments, Z is a pyrimidinyl group substituted with 0, 1, 2, or 3 R ¹⁵ groups. For example, in some embodiments, Z is a pyrimidinyl group of the formula:

where z has a value of 0, 1, 2 or 3, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted pyrimidinyl (i.e., where z is 0). In some embodiments, Z is substituted pyrimidinyl (for example, where z is 1, 2, or 3). In some embodiments, Z is a monosubstituted pyrimidinyl (i.e., where z is 1). In some embodiments, Z is disubstituted pyridazinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted pyrimidinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a 2-pyrimidinyl group, for example, formulas (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 some embodiments, Z is a 4-pyrimidinyl group, for example, formulas (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 some embodiments, Z is a 5-pyrimidinyl group, for example, formulas (ii-e), where W ² and W ⁴ are N, and W ¹ , W ³ and W ^{5 are} independently CH or CR ¹⁵ .

In some embodiments, Z is a 2-pyrimidinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, R ^e represents a 4-pyrimidinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a 5-pyrimidinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a pyrazinyl group. In some embodiments, Z is a pyrazinyl group substituted with 0, 1, 2, or 3 R ¹⁵ groups. For example, in some embodiments, Z is a pyrazinyl group of the formula:

where z has a value of 0, 1, 2 or 3, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted pyrazinyl (i.e., where z is 0). In some embodiments, Z is substituted pyrazinyl (for example, where z is 1, 2, or 3). In some embodiments, Z is a monosubstituted pyrazinyl (i.e., where z is 1). In some embodiments, Z is disubstituted pyrazinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted pyrazinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a pyrazinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a triazinyl group. In some embodiments, Z is a triazinyl group substituted with 0, 1, or 2 R ¹⁵ groups. For example, in some embodiments, Z is a triazinyl group of the formula:

where z has a value of 0, 1 or 2, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted pyrazinyl (i.e., where z is 0). In some embodiments, Z is substituted pyrazinyl (for example, where z is 1 or 2). In some embodiments, Z is a monosubstituted pyrazinyl (i.e., where z is 1). In some embodiments, Z is disubstituted pyrazinyl (i.e., where z is 2). In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a substituted or unsubstituted triazinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a tetrazinyl group. In some embodiments, Z is a tetrazinyl group substituted with 0 or 1 R ¹⁵ groups. For example, in some embodiments, Z is a tetrazinyl group of the formula:

where z has a value of 0 or 1, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted pyrazinyl (i.e., where z is 0). In some embodiments, Z is substituted pyrazinyl (for example, where z is 1). In some embodiments, z is 0 or 1.

In some embodiments, Z is a tetrazinyl group of any of the following formulas:

where R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is a 9-membered heteroaryl (e.g., 5,6-bicyclic heteroaryl). In some embodiments, Z is a 5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In some embodiments, Z is a 5,6-bicyclic heteroaryl selected from indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl benzyl azothiazothiazole azadiazadi where such groups are substituted with 0, 1, 2, 3, 4 or 5 groups of R ¹⁵ .

For example, in some 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 independently represent C, CH, CR ¹⁵ , O, S, N or NR ¹⁸ , and Y ¹³ represents C or N, when provided that at least one of Y ⁵ , Y ⁶ , Y ^{7 is} selected from O, S, N, or NR ¹⁸ , and where R ¹⁵ and R ^{18 are} defined herein.

In some embodiments, Z is a 5,6-bicyclic heteroaryl group of formula (ii-f), wherein Y ^{5 is} selected from O, S or NR ¹⁸ , Y ¹³ is C, and Y ⁶ , Y ⁷ , Y ⁹ , Y ¹⁰ , Y ¹¹ and Y ¹² independently represent C, CH or CR ¹⁵ . For example, in some embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

where z has the value 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ have the meanings defined below and in this section of the application. In some embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where z is 0). In some embodiments, Z is a substituted 5,6-bicyclic heteroaryl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z is 1). In some embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z is 2). In some embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ^{5 is} selected from O, S, or NR ¹⁸ ; Y ⁷ represents N; Y ¹³ represents C; Y ⁶ represents C, CH or CR ¹⁵ or N, and Y ⁹ , Y ¹⁰ , Y ¹¹ and Y ¹² independently represent C, CH or CR ¹⁵ . For example, in some embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

,

,

where z has the value 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ have the meanings defined below and in this section of the application. In some embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where z is 0). In some embodiments, Z is a substituted 5,6-bicyclic heteroaryl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z is 1). In some embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z is 2). In some embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ⁵ is NR ^k , S, or O; Y ¹² represents N; Y ¹³ represents C; and Y ⁶ , Y ⁷ , Y ⁹ , Y ¹⁰ and Y ¹¹ independently represent C, CH or CR ¹⁵ . For example, in some embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

where z has the value 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ have the meanings defined below and in this section of the application. In some embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where z is 0). In some embodiments, Z is a substituted 5,6-bicyclic heteroaryl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z is 1). In some embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z is 2). In some embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ⁷ is O, S, or NR ^k ; Y ¹² represents N; Y ¹³ represents C; and Y ⁵ , Y ⁶ , Y ⁹ , Y ^10, and Y ¹¹ independently represent C, CH, or CR ¹⁵ . For example, in some embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

where z has the value 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ have the meanings defined below and in this section of the application. In some embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where z is 0). In some embodiments, Z is a substituted 5,6-bicyclic heteroaryl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z is 1). In some embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z is 2). In some embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is 5,6-bicyclic heteroaryl, wherein Y ^{5 is} selected from O, S, or NR ¹⁸ ; Y ¹³ represents N; and Y ⁶ , Y ⁷ , Y ⁸ , Y ⁹ and Y ¹⁰ independently represent C, CH or CR ¹⁵ . For example, in some embodiments, Z is a 5,6-bicyclic heteroaryl group of the formula:

where z has the value 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ¹⁸ have the meanings defined below and in this section of the application. In some embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., where z is 0). In some embodiments, Z is a substituted 5,6-bicyclic heteroaryl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e., where z is 1). In some embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e., where z is 2). In some embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a 10-membered heteroaryl (e.g., 6,6-bicyclic heteroaryl). In some embodiments, Z is 6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In some embodiments, Z is a 6,6-bicyclic heteroaryl selected from naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl, where such groups are substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups .

For example, in some embodiments, Z is a 6,6-bicyclic heteroaryl of the formula:

where 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 at least one of W ⁶ , W ⁷ , W ⁸ , W ⁹ , W ¹⁰ , W ¹¹ , W ^12, and W ¹³ are N, and where R ¹⁵ is as defined below and in this section of the application.

In some embodiments, Z is a quinolinyl group; for example, formulas (ii-g), where W ⁹ is N and W ⁶ , W ⁷ , W ⁸ , W ¹⁰ , W ¹¹ , W ¹² and W ¹³ independently are C, CH or CR ¹⁵ . For example, in some embodiments, Z is a quinolinyl group of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted quinolinyl (i.e., where z is 0). In some embodiments, Z is substituted quinolinyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted quinolinyl (i.e., where z is 1). In some embodiments, Z is a disubstituted quinolinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted quinolinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is an isoquinolinyl group; for example, formulas (ii-g) where W ⁸ is N and W ⁶ , W ⁷ , W ⁹ , W ¹⁰ , W ¹¹ , W ¹² and W ¹³ independently are C, CH or CR ¹⁵ . For example, in some embodiments, Z is an isoquinolinyl group of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted isoquinolinyl (i.e., where z is 0). In some embodiments, Z is substituted isoquinolinyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted isoquinolinyl (i.e., where z is 1). In some embodiments, Z is a disubstituted isoquinolinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted isoquinolinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a quinoxalinyl group; for example, formulas (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 some embodiments, Z is a quinoxalinyl group of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ has the meaning defined below and in this section of the application.

In some embodiments, Z is unsubstituted quinoxalinyl (i.e., where z is 0). In some embodiments, Z is substituted quinoxalinyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted quinoxalinyl (i.e., where z is 1). In some embodiments, Z is a disubstituted quinoxalinyl (i.e., where z is 2). In some embodiments, Z is a trisubstituted quinoxalinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

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

Examples of heterocyclic groups Z include but are not limited to, aziridinyl, oxiranyl, tiorenil, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, digidrotiofenil, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, dioxolanyl, oxathiolanyl, dithiolanyl, triazoline , oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianil, dioxanyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxane, indiolinyl, thiocyanol , Dihydrobenzofuranyl, dihydrobenzothienyl, tetragidrobenzotienil, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinoline, oktagidrohromenil, oktagidroizohromenil, dekagidronaftiridinil, decahydro-1,8-naphthyridinyl, pyrrolo [3,2-b] pyrrole, indolinyl, phthalimide, naphthalimide, 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-p rolo [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 and 4,5,6,7-tetrahydrothieno [3,2-b] pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 groups of R ¹⁵ .

In some embodiments, Z is a 6 membered heterocyclyl. In some embodiments, Z is a 6 membered heterocyclyl substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups. In some embodiments, Z is a 6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianil, dioxanyl and triazinanil, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R ¹⁵ groups .

For example, in some embodiments, Z is a 6 membered heterocyclyl of the formula:

where W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ , W ¹⁸ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ , NR ¹⁸ , O or S, and W ¹⁹ represents N, CH or CR ¹⁵ , with the proviso 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 where R ¹⁵ and R ¹⁸ are as defined below and in this section of the application.

In some embodiments, Z is a piperidinyl group. In some embodiments, Z is a piperidinyl group substituted with 0, 1, 2, 3, 4, or 5 R ¹⁵ groups, for example, of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ^{18 are} defined below and in this section of the application. In some embodiments, Z is unsubstituted piperidinyl (i.e., where z is 0). In some embodiments, Z is substituted piperidinyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted piperidinyl (i.e., where z is 1). In some embodiments, Z is a disubstituted piperidinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted piperidinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a 1-piperidinyl group, for example, formulas (ii-h), where W ¹⁹ is N and W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ and W ^{18 are} independently selected from CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . In some embodiments, Z is a 2-piperidinyl group, for example, formula (ii-h), wherein W ¹⁴ is NR ¹⁸ ; W ¹⁵ , W ¹⁶ , W ¹⁷ and W ¹⁸ independently represent CHR ¹⁵ , C (R ¹⁵ ) ₂ or CH ₂ ; and W ¹⁹ represents CH or CR ¹⁵ . In some embodiments, Z is a 3-piperidinyl group, for example, formula (ii-h), wherein W ¹⁵ is NR ¹⁸ ; W ¹⁴ , W ¹⁶ , W ¹⁷ and W ¹⁸ independently represent CHR ¹⁵ , C (R ¹⁵ ) ₂ or CH ₂ ; and W ¹⁹ represents CH or CR ¹⁵ . In some embodiments, Z is a 4-piperidinyl group, for example, formula (ii-h), wherein W ¹⁶ is NR ¹⁸ ; W ¹⁴ , W ¹⁵ , W ¹⁷ and W ¹⁸ independently represent CHR ¹⁵ , C (R ¹⁵ ) ₂ or CH ₂ ; and W ¹⁹ represents CH or CR ¹⁵ .

In some embodiments, Z is a piperazinyl group. In some embodiments, Z is a piperazinyl group substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups, for example, of the formula:

where x is 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ^{18 are} defined below and in this section of the application. In some embodiments, Z is unsubstituted piperazinyl (i.e., where z is 0). In some embodiments, Z is substituted piperazinyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted piperazinyl (i.e., where z is 1). In some embodiments, Z is disubstituted piperazinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted piperazinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a piperazinyl group, for example, 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 independently represent CHR ¹⁵ , C (R ¹⁵ ) ₂ or CH ₂ . In some embodiments, Z is a piperazinyl group, where W ¹⁹ is CH or CR ¹⁵ , W ¹⁴ and W ¹⁷ independently are NR ¹⁸ , and W ¹⁵ , W ¹⁶ and W ¹⁸ independently are CHR ¹⁵ , C (R ¹⁵ ) ₂ or CH ₂ .

In some embodiments, Z is a morpholinyl group substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups, for example, of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ and R ^{18 are} defined below and in this section of the application. In some embodiments, Z is unsubstituted morpholinyl (i.e., where z is 0). In some embodiments, Z is a substituted morpholinyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted morpholinyl (i.e., where z is 1). In some embodiments, Z is a disubstituted morpholinyl (i.e., where z is 2). In some embodiments, Z is trisubstituted morpholinyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a morpholinyl group; for example, formulas (ii-h), where 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 , C (R ¹⁵ ) ₂ . In some embodiments, Z is a morpholinyl group, where 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 .

In some embodiments, Z is a dioxanyl group. In some embodiments, Z is a dioxanyl group substituted with 0, 1, 2, 3, or 4 R ¹⁵ groups, for example, of the formula:

where z has a value of 0, 1, 2, 3, 4 or 5, and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, Z is unsubstituted dioxanyl (i.e., where z is 0). In some embodiments, Z is substituted dioxanyl (for example, where z is 1, 2, 3, 4, or 5). In some embodiments, Z is a monosubstituted dioxanyl (i.e., where z is 1). In some embodiments, Z is disubstituted dioxanyl (i.e., where z is 2). In some embodiments, Z is trisubstituted dioxanyl (i.e., where z is 3). In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z is 0 or 1.

In some embodiments, Z is a dioxanyl group, for example, of formula (ii-h), where W^fourteen and W¹⁷ represent O and W^fifteen, W¹⁶ and W^eighteen independently represent CHR^fifteen, C (R^fifteen)₂ or CH₂; and W¹⁹ represents CH or CR^fifteen. In some embodiments, Z is a dioxanyl group, where W¹⁹ represents CH or CR^fifteen, W^fourteen and W¹⁶ independently selected from O, and W^fifteen, W¹⁷ and W^eighteen independently represent CHR^fifteen, C (R^fifteen)₂ or CH₂. AT in some embodiments, Z is a dioxanyl group, where W¹⁹ represents CH or CR^fifteen, W^fifteen and W¹⁷ independently selected from O, and W^fourteen, W¹⁶ and W^eighteen independently represent CHR^fifteen, C (R^fifteen)₂ or CH₂.

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

Embodiments wherein R ^a  and R ^d  combined (condensed)

As defined generally above, in some embodiments, R ^a and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic fused ring, and R ^b and R ^{c are} independently selected from —H, C _1-10 alkyl and C _1-10 perhaloalkyl.

In some embodiments, each of R ^b and R ^{c is} independently selected from —H, C _1-6 alkyl, and C _1-6 perhaloalkyl. In some embodiments, each of R ^b and R ^{c is} independently selected from —H, C _1-3 alkyl and C _1-3 perhaloalkyl. In some embodiments, each of R ^b and R ^{c is} independently selected from —H, C ₁ alkyl, and C ₁ perhaloalkyl. In some embodiments, each of R ^b and R ^{c is} independently selected from —H, —CH _3, and —CF ₃ . In some embodiments, each of R ^b and R ^{c is} independently selected from —H and —CH ₃ . In some embodiments, each of R ^b and R ^{c is} independently selected from —H and —CF ₃ . In some embodiments, R ^b and R ^{c are} both —H.

In some embodiments, R ^a and R ^{d are} combined to form a C _5-7 carbocyclic or 5-7 membered heterocyclic fused ring. In some embodiments, R ^a and R ^{d are} combined to form a C _5-7 carbocyclic or 5-7 membered heterocyclic fused ring of the formula:

where W ²⁰ , W ²¹ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application, s has the meaning 0, 1 or 2, and a broken line indicates the merging of the rings.

In some embodiments, R ^a and R ^{d are} combined to form a C _5-7 carbocyclic fused ring. For example, in some 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 carbocyclic groups for the formation of which R ^a and R ^d may be combined include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R groups ¹⁵ .

In some embodiments, R ^a and R ^{d are} combined to form a 5-7 membered heterocyclic fused ring. For example, in some embodiments of formula (ii-j), W ²⁰ is NR ¹⁸ , and W ²¹ , W ^22, and W ²³ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments of formula (ii-j), W ²¹ is NR ¹⁸ , and W ²⁰ , W ^22, and W ²³ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments of formula (ii-j), W ²² is NR ¹⁸ , and W ²⁰ , W ²¹ and W ²³ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . Examples of 5-7 membered heterocyclic groups for which R ^a and R ^d may be combined include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and azepanyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 groups of R ¹⁵ .

In some embodiments, where s is 0, R ^a and R ^{d are} combined to form a C ₅ carbocyclic or 5 membered heterocyclic fused ring of the formula:

where W ²⁰ , W ²¹ and W ²² , independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application, and the broken line indicates the merger rings.

In some embodiments of formula (ii-k), R ^a and R ^{d are} combined to form a C ₅ carbocyclic fused ring (i.e., cyclopentyl), for example, where W ²⁰ , W ²¹ and W ^{22 are} independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ .

In some embodiments of formula (ii-k), R ^a and R ^{d are} combined to form a 5 membered heterocyclic fused ring (e.g., pyrrolidinyl), for example, where W ²¹ is NR ¹⁸ and W ²⁰ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments of formula (ii-k), R ^a and R ^{d are} combined to form a 5-membered heterocyclic fused ring (e.g., pyrrolidinyl), for example, where W ²⁰ is NR ¹⁸ and W ²¹ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ .

In some embodiments, where s is 1, R ^a and R ^{d are} combined to form a C ₆ carbocyclic or 6 membered heterocyclic fused ring of the formula:

where W ²⁰ , W ²¹ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application, and a dashed line indicates merging rings.

In some embodiments of formula (ii-m), R ^a and R ^{d are} combined to form a C ₆ carbocyclic fused ring (i.e., cyclohexyl), for example, where W ²⁰ , W ²¹ , W ^22, and W ^{23 are} independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ .

In some embodiments of formula (ii-m), R ^a and R ^{d are} combined to form a 6 membered heterocyclic fused ring (e.g. piperidinyl), for example, where W ²¹ is NR ¹⁸ and W ²⁰ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments of the formulas (ii-m), R ^a and R ^{d are} combined to form a 6 membered heterocyclic fused ring (e.g. piperidinyl), for example, where W ²⁰ is NR ¹⁸ and W ²¹ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ .

In some embodiments, where s is 2, R ^a and R ^{d are} combined to form a C ₇ carbocyclic or 7 membered heterocyclic ring of the formula:

where W ²⁰ , W ²¹ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application, and a dashed line indicates merging rings.

In some embodiments of formula (ii-n), R ^a and R ^{d are} combined to form a C ₇ carbocyclic ring (i.e., cycloheptyl), for example, where W ²⁰ , W ²¹ , W ^22, and W ^{23 are} independently CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ .

In some embodiments of formula (ii-n), R ^a and R ^{d are} combined to form a 7-membered heterocyclic ring (e.g., azepanil), for example, where W ²¹ is NR ¹⁸ and W ²⁰ , W ²² and W ²³ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments of formula (ii-n), R ^a and R ^{d are} combined to form a 7-membered heterocyclic ring (e.g., azepanil), for example, where W ²² is NR ¹⁸ and W ²⁰ , W ²¹ and W ²³ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) _2.

Embodiments wherein R ^c  and R ^d  combined (spiro-condensed)

As defined generally above, in some embodiments, R ^c and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic spiro-fused ring, and R ^a and R ^{b are} independently selected from —H, C _{1 -10} alkyl and C _1-10 perhaloalkyl.

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

In some embodiments, R ^c and R ^{d are} combined to form a C _5-7 carbocyclic, 5-7 membered heterocyclic, 5,6-bicyclic carbocyclic, 6,6-bicyclic carbocyclic, 5,6-bicyclic heterocyclic or 6,6- a bicyclic heterocyclic spiro-fused ring.

For example, in some embodiments, R ^c and R ^{d are} combined to form a C _5-7 carbocyclic, 5-7 membered heterocyclic, 5,6-bicyclic carbocyclic or 5,6-bicyclic heterocyclic spiro-fused ring of the formula:

where W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently represent 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 a ring or a fused 6-membered heteroaryl ring; t and v are independently 0 or 1; and R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application. In some embodiments, t is 0 and v is 0. In some embodiments, t is 0 and v is 1. In some embodiments, t is 1 and v is 0. In some embodiments, t has a value of 1, and v has a value of 1.

In some embodiments, R ^c and R ^{d are} combined to form a C _5-7 carbocyclic spiro-fused ring. For example, in some 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 . Examples of C _5-7 carbocyclic groups for the formation of which R ^c and R ^d may be combined include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 R groups ¹⁵ .

In some embodiments, R ^c and R ^{d are} combined to form a 5-7 membered heterocyclic spiro-fused ring. For example, in some embodiments of formula (iii-a), W ²⁵ is NR ¹⁸ , and W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . In some embodiments of formula (iii-a), W ²⁶ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁷ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . In some embodiments of formula (iii-a), W ²⁷ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . Examples of 5-7 membered heterocyclic groups for which R ^c and R ^d may be combined include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and azepanyl, where such groups are substituted with 0, 1, 2, 3, 4 or 5 groups of R ¹⁵ .

In some embodiments, where t is 0 and v is 0, R ^c and R ^{d are} combined to form a C ₅ carbocyclic or 5-membered heterocyclic spiro-fused ring of the formula:

where W ²⁵ , W ²⁶ , W ²⁷ and W ²⁸ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , and R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application.

In some embodiments, R ^c and R ^{d are} combined to form a C ₅ carbocyclic spiro-fused ring (eg, cyclopentyl); for example, formulas (iii-b), where W ²⁵ is NR ¹⁸ , and W ²⁶ , W ²⁷ and W ²⁸ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ .

In some embodiments, R ^c and R ^{d are} combined to form a 5-membered heterocyclic spiro-fused ring; for example, formulas (iii-b), where W ²⁶ is NR ¹⁸ and W ²⁵ , W ²⁷ and W ²⁸ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ .

In some embodiments, where t is 0 and v is 1, R ^c and R ^{d are} combined to form a C ₆ carbocyclic or 6 membered heterocyclic spiro-fused ring of the formula:

where W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , and R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application .

In some embodiments, R ^c and R ^{d are} combined to form a C ₆ carbocyclic spiro-fused ring (eg, cyclohexyl); for example, formulas (iii-c), where W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ .

In some embodiments, R ^c and R ^{d are} combined to form a 5-membered heterocyclic spiro-fused ring; for example, formulas (iii-c), where W ²⁶ is NR ¹⁸ , and W ²⁵ , W ²⁷ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, R ^c and R ^{d are} combined to form a 5-membered heterocyclic spiro-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 .

In some embodiments, where t is 1 and v is 1, R ^c and R ^{d are} combined to form a C ₇ carbocyclic or 7-membered heterocyclic spiro-fused ring of the formula:

where W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , and R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application.

In some embodiments, R ^c and R ^{d are} combined to form a C ₇ carbocyclic spiro-fused ring (eg, cycloheptyl); for example, formulas (iii-d), where W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ .

In some embodiments, R ^c and R ^{d are} combined to form a 7-membered heterocyclic spiro-fused ring; for example, formulas (iii-d), where W ²⁵ is NR ¹⁸ and W ²⁴ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments, R ^c and R ^{d are} combined to form a 7-membered heterocyclic spiro-fused ring, where W ²⁶ is NR ¹⁸ and W ²⁴ , W ²⁵ , W ²⁷ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments, R ^c and R ^{d are} combined to form a 7-membered heterocyclic spiro-fused ring, where W ²⁷ is NR ¹⁸ and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ .

In some embodiments, R ^c and R ^{d are} combined to form a 5,6-bicyclic carbocyclic spiro-fused ring or a 5,6-bicyclic heterocyclic spiro-fused ring. For example, in some embodiments of formula (iii-a), t and v are both 0, W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring or a fused 6 membered heteroaryl ring, and W ²⁷ is CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ and NR ¹⁸ , and W ²⁸ represents CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments of formula (iii-a), R ^c and R ^{d are} combined to form a 5,6-bicyclic carbocyclic spiro-fused ring, for example, where t and v are both 0, W ²⁵ and W ²⁶ are substituted with fused C ₆ an aryl ring or a fused 6-membered heteroaryl ring, and W ²⁷ and W ²⁸ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring.

For example, in some embodiments, where t and v are both 0 and W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring, R ^c and R ^{d are} combined to form a 5,6-bicyclic carbocyclic spiro-fused ring of the formula:

where W ²⁷ and W ²⁸ independently represent CH ₂ , CHR ¹⁵ and C (R ¹⁵ ) ₂ , z is 0, 1, 2, 3 or 4; and R ¹⁵ has the meaning defined below and in this section of the application. In some embodiments, W ²⁷ and W ^{28 are} both CH ₂ . In some embodiments, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z has a value of 2. In some embodiments, z has a value of 1. In some embodiments, z has a value of 0.

In some embodiments, R ^c and R ^{d are} combined to form a 6,6-bicyclic carbocyclic spiro-fused ring or a 6,6-bicyclic heterocyclic spiro-fused ring. For example, in some embodiments of formula (iii-a), t is 0 and v is 1, W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring or a fused 6 membered heteroaryl ring, and W ²⁷ and W ²⁸ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ and NR ¹⁸ , and W ²⁹ represents CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ . In some embodiments of formula (iii-a), R ^c and R ^{d are} combined to form a 6,6-bicyclic carbocyclic spiro-fused ring, for example, where t is 0 and v is 1, W ²⁵ and W ²⁶ are substituted a fused C ₆ aryl ring or a fused 6-membered heteroaryl ring, and W ²⁷ , W ²⁸ and W ²⁹ independently represent CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring.

For example, in some embodiments, where t is 0 and v is 1, and W ²⁵ and W ²⁶ are substituted with a fused C ₆ aryl ring, R ^c and R ^{d are} combined to form a 6,6-bicyclic carbocyclic spiro-fused ring of the formula :

where W ²⁷ , W ²⁸ and W ²⁹ independently are 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 in this section applications. In some embodiments, W ²⁷ , W ^28, and W ^{29 are} each CH ₂ . In some embodiments, z is 0, 1, 2, 3, or 4. In some embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0, 1, or 2. In some embodiments, z has a value of 2. In some embodiments, z has a value of 1. In some embodiments, z has a value of 0.

In another aspect, R ^c and R ^{d are} combined to form a bridged carbocyclic or bridged heterocyclic spiro-fused ring of the formula:

where W ³⁰ , W ³¹ , W ³² , W ³³ and W ³⁶ independently represent CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ ; and W ³⁴ and W ³⁵ independently represent CH or CR ¹⁵ , and R ¹⁵ and R ¹⁸ have the meaning defined below and in this section of the application.

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

R ⁷⁵  Groups

As this term is used in this application, in each case, R ^{15 is} independently selected from halogen (i.e. fluorine (-F), bromine (-Br), chlorine (-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, -CO ₂ R ¹⁶ , -ОС (= О ) 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, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups; or two adjacent R ¹⁵ groups are replaced by the group —O (C (R ² ) ₂ ) _1-2 O—, where each R ² independently represents H, C _1-6 alkyl or halogen;

in each case, R ^{16 is} independently selected from 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 independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups;

in each case, R ^{18 is} independently selected from 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 _{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 associated with N atom, combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocycle yl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups;

in each case, R ^{17 is} independently selected from 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, C _{6- 14} aryl and 5-14 membered heteroaryl, or two R ¹⁷ groups bonded to the N atom, are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups;

in each case, R ^{19 is} independently selected from 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 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^22, or two adjacent substituent R ¹⁹ may be combined with education = O or = S;

in each case, R ^{20 is} independently selected from 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 and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ²² groups;

in each case, R ^{21 is} independently selected from 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, C _{6- 10} aryl and 5-10 membered heteroaryl, or two R ²¹ groups linked to the N atom, are combined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ²² groups; and

in each case, R ²² independently represents 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) ₂ 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) S (C _1-6 alkyl), -SC (= S) S (C _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 adjacent substituents may be combined to form = O or = S;

where X ^- is a counterion.

In some embodiments, in each case, R ^{15 is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-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 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ¹⁹ groups.

In some embodiments, R ^{15 is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-1), -OR ¹⁶ and C _1-10 perhaloalkyl. In some embodiments, R ^{15 is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) and -OR ¹⁶ . In some embodiments, R ^{15 is} independently selected from fluorine (-F), bromine (-Br), chlorine (-Cl) and iodine (-I) and C _1-10 perhaloalkyl.

In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

In some embodiments, R ¹⁵ is —OR ¹⁶ . In some embodiments, R ^{16 is} selected 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, where each alkyl, alkenyl , alkynyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ¹⁹ groups.

In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _1-10 alkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ^{16 is} selected from C _1-6 alkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _1-4 alkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _1-2 alkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ¹⁶ is —CH ₃ , —Et, —iPr, —nBu, —n-pentyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is —CH ₃ .

In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _1-10 perhaloalkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _1-6 perhaloalkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ^{16 is} selected from C _1-4 perhaloalkyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ^{16 is} selected from C _1-2 perhaloalkyl. In some 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 some embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is —CF ₃ .

In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _2-10 alkenyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ^{16 is} selected from C _2-6 alkenyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _2-4 alkenyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from —CH ₂ CHCH ₂ (i.e., allyl).

In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from C _2-10 alkynyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ^{16 is} selected from C _2-6 alkynyl. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ^{16 is} selected from C _2-4 alkynyl. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from —CH ₂ CCH (i.e., propargyl).

In some 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. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ¹⁶ is phenyl substituted with 0, 1, or 2 R ¹⁹ groups. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ¹⁶ is phenyl substituted with 1 R ¹⁹ group. In some embodiments, R ¹⁵ is —OR ¹⁶ and R ¹⁶ is phenyl substituted with 0 R ¹⁹ groups (i.e., —C ₆ H ₅ ).

In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from 5-6 membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from a 6 membered heteroaryl substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from pyridinyl (eg, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In some embodiments, R ¹⁵ is —OR ¹⁶ , and R ^{16 is} selected from pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2, or 3 R ¹⁹ groups.

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

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

In some embodiments, R ¹⁵ is C _1-10 perhaloalkyl. In some embodiments, R ¹⁵ is C _1-6 perhaloalkyl. In some embodiments, R ¹⁵ is C _1-4 perhaloalkyl. In some embodiments, R ¹⁵ is C _1-2 perhaloalkyl. In some 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 some embodiments, R ^{15 is} selected from —CF ₃ .

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

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

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

In some embodiments, R ¹⁵ is C _6-14 aryl. In some embodiments, R ^{15 is} selected from C ₆ aryl (eg, phenyl) substituted with 0, 1, 2, 3, or 4 R ¹⁹ groups. In some embodiments, R ¹⁵ is unsubstituted phenyl. In some embodiments, R ¹⁵ is monosubstituted phenyl (i.e., substituted with 1 R ¹⁹ group).

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

R groups ^eighteen

In some embodiments, in each case, R ^{18 is} independently selected from —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 (e.g., aralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclic, 3-14 membered heterocyclic, C _6-14 aryl and 5-14 membered heteroaryl group, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 groups R ¹⁹ where R ^16, R ^17, R ¹⁹ have the values s as defined above in this section of the application.

In some embodiments, in each case, R ^{17 is} independently selected from —H, —C (═O) R ¹⁶ , —C (= O) OR ¹⁶ , —SO ₂ R ^16, or C _1-6 alkyl. In some embodiments, in each case, R ^{17 is} independently selected from —H or C _1-6 alkyl. In some embodiments, in each case, R ^{17 is} independently selected from —H and —CH ₃ . In some embodiments, in each case, R ^{17 is} independently selected from —H. In some embodiments, in each case, R ^{17 is} independently selected from —CH _3.

Additional Embodiments of Compounds of Formula (I)

As defined generally above, the present invention provides compounds of formula (I):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , R ^c and R ^d are as defined herein.

In one aspect, where each R ^a , R ^b , R ^c represents H, and R ^d represents a group Z, the present invention provides compounds of formula (II):

or a pharmaceutically acceptable form of such a compound, wherein G and Z are as defined herein. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

For example, in some embodiments, where L is a covalent bond, each R ^a , R ^b , R ^c is H, and G is an —OR ^e group, the present invention provides compounds of formula (II-a):

or a pharmaceutically acceptable form of such a compound, wherein R ^e and Z are as defined herein.

In some embodiments, where Z is a phenyl ring, the present invention provides compounds of formula (II-b):

or a pharmaceutically acceptable form of such a compound wherein G, L, R ^a , R ^b , R ^c , R ¹⁵ and z are as defined herein. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, z is 2 and R ¹⁵ is in the meta and steam positions. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

For example, in some embodiments, z is 1, and R ¹⁵ is in the vapor position, providing compounds of formula (II-c):

or a pharmaceutically acceptable form of such a compound wherein G, L, R ^a , R ^b , R ^c , R ¹⁵ and z are as defined herein. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

For example, in some embodiments, z is 2, and one R ¹⁵ is in meta and one R ^{15 is} in the pair position, providing compounds of formula (II-c):

or a pharmaceutically acceptable form of such a compound wherein G, L, R ^a , R ^b , R ^c , R ¹⁵ and z are as defined herein. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

For example, in some embodiments, where Z is a phenyl ring and G is —OR ^e , the present invention provides compounds of formula (II-d):

or a pharmaceutically acceptable form of such a compound wherein L, R ^a , R ^b , R ^c , R ¹⁵ , R ^e and z are as defined herein. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, L is a covalent bond. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

In some embodiments, where Z is a phenyl ring, G is a —OR ^e group and R ^e is a phenyl ring, the present invention provides compounds of formula (II-e):

or a pharmaceutically acceptable form of such a compound, wherein L, R ^a , R ^b , R ^c , R ¹⁵ , R ^h , x and z are as defined herein. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, L is a covalent bond. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

In some embodiments, where Z is a phenyl ring, G is an —OR ^e group, and R ^e is a 5-membered heteroaryl ring, the present invention provides compounds of formula (II-f):

or a pharmaceutically acceptable form of such a compound wherein Y ^a , Y ^b , Y ^c , Y ^d , L, R ^a , R ^b , R ^c , R ¹⁵ and z are as defined herein. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, L is a covalent bond. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

In some embodiments, where Z is a phenyl ring, G is an —OR ^e group, and R ^e is a 6 membered heteroaryl ring, the present invention provides compounds of formula (II-g):

or a pharmaceutically acceptable form of such a compound wherein 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 some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In some embodiments, L is a covalent bond. In some embodiments, W ^b is N, and W ^a , W ^c , W ^d and W ^e are selected from CH or CR ^h . In some embodiments, W ^b is N, W ^c is CR ^h , and each W ^a , W ^c , W ^d and W ^e are CH. In some embodiments, W ^b and W ^d are N, and W ^a , W ^c , W ^d and W ^e are selected from CH or CR ^h .

In some embodiments, where Z is a phenyl ring, G is an —OR ^e group, and R ^e is a 9-membered heteroaryl ring, the present invention provides compounds of formula (II-h):

or a pharmaceutically acceptable form of such a compound, where 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 significant, defined in this application. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In some embodiments, L is a covalent bond.

In some embodiments, where Z is a phenyl ring, G is an —OR ^e group, and R ^e is a 10 membered heteroaryl ring, the present invention provides compounds of formula (II-i):

or a pharmaceutically acceptable form of such a compound, 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 significant, defined in this application. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In some embodiments, L is a covalent bond.

In some embodiments, where Z is a phenyl ring and G is a group —NR ^e R ^f , the present invention provides compounds of formula (II-j):

or a pharmaceutically acceptable form of such a compound, wherein L, R ^a , R ^b , R ^c , R ^e , R ^f , R ¹⁵ and z are as defined herein. For example, in some embodiments, z is 1 and R ¹⁵ is in the ortho position. In some embodiments, z is 1 and R ¹⁵ is in the meta position. In some embodiments, z is 1 and R ¹⁵ is in the vapor position. In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl. In some embodiments, L is a covalent bond. In some embodiments, R ^e and R ^{f are} combined to form a 3-10 membered heterocyclic ring. In some embodiments, R ^e and R ^{f are} combined to form a 5-14 membered heteroaryl ring.

In some embodiments of the formula (II), wherein Z is a 5-membered heteroaryl ring, the present invention provides compounds of formula (III-a):

or a pharmaceutically acceptable form of such a compound, wherein Y ¹ , Y ² , Y ³ , Y ⁴ , G, L, R ^a , R ^b, and R ^c are as defined herein. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some 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 defined above and in this section of the application. In some embodiments, Y ⁴ is CH. In some embodiments, the substituent present on Y ² is C ₆ aryl (e.g., phenyl).

In some embodiments, where Z is a 6-membered heteroaryl ring, the present invention provides compounds of formula (III-b):

or a pharmaceutically acceptable form of such a compound wherein W ¹ , W ² , W ³ , W ⁴ , G, L, R ^a , R ^b, and R ^c are as defined herein. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, the 6-membered heteroaryl ring is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) or pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl).

In some embodiments, where Z is a 9-membered heteroaryl ring, the present invention provides compounds of formula (III-c):

or a pharmaceutically acceptable form of such a compound, wherein 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 application. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where Z is a 10 membered heteroaryl ring, the present invention provides compounds of formula (III-e):

or a pharmaceutically acceptable form of such a compound wherein 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 application. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where Z is a 6-membered heterocyclyl, the present invention provides compounds of formula (III-f):

or a pharmaceutically acceptable form of such a compound, wherein W ¹⁴ , W ¹⁵ , W ¹⁶ , W ¹⁷ , W ¹⁸ , W ¹⁹ , G, L, R ^a , R ^b, and R ^c are as defined herein. In some embodiments, L is a covalent bond. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In another aspect, where R ^a and R ^{d are} combined to form C _3-10 carbocyclyl or 3-14 membered heterocyclyl, the present invention provides compounds of formula (IV):

or a pharmaceutically acceptable form of such a compound, wherein 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 as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 0, the present invention provides compounds of formula (IV-a):

or a pharmaceutically acceptable form of such a compound, wherein G, R ^b , R ^c , W ²⁰ , W ²¹ and W ²² are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 0, W ²¹ is NR ¹⁸ , and W ²⁰ , W ²² and W ²³ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (IV -b):

or a pharmaceutically acceptable form of such a compound wherein G, R ^b , R ^c , R ¹⁸ and R ¹⁵ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 1, the present invention provides compounds of formula (IV-c):

or a pharmaceutically acceptable form of such a compound, wherein G, R ^b , R ^c , W ²⁰ , W ²¹ , W ²² and W ²³ have the meaning defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 1, W ²¹ is NR ¹⁸ , and W ²⁰ , W ²² and W ²³ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (IV -d):

or a pharmaceutically acceptable form of such a compound wherein G, R ^b , R ^c , R ¹⁸ and R ¹⁵ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 1, W ²² is NR ¹⁸ , and W ²⁰ , W ²¹ and W ²³ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (IV -e):

or a pharmaceutically acceptable form of such a compound wherein G, R ^b , R ^c , R ¹⁸ and R ¹⁵ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 2, the present invention provides compounds of formula (IV-f):

or a pharmaceutically acceptable form of such a compound, wherein G, R ^b , R ^c , W ²⁰ , W ²¹ , W ²² and W ²³ have the meaning defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where s is 2, W ²² is NR ¹⁸ , and W ²⁰ , W ²¹ and W ²³ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (IV -g):

or a pharmaceutically acceptable form of such a compound wherein G, R ^b , R ^c , R ¹⁸ and R ¹⁵ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In yet another aspect, where R ^c and R ^{d are} combined to form a C _3-10 carbocyclic or 3-14 membered heterocyclic ring, the present invention provides compounds of formula (V):

or a pharmaceutically acceptable form of such a compound wherein W ²⁴ , W ²⁶ , W ²⁷ , W ²⁸ and W ³⁰ independently are CH ₂ , CHR ¹⁵ , C (R ¹⁵ ) ₂ or NR ¹⁸ , optionally where W ²⁵ and W ²⁶ are substituted 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 have the meaning defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, t is 0 and v is 0. In some embodiments, t is 0 and v is 1. In some embodiments, t is 1 and v is 0. In some embodiments, t has a value of 1, and v has a value of 1.

In some embodiments, where t is 0 and v is 0, the present invention provides compounds of formula (V-a):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , W ²⁵ , W ²⁶ , W ²⁷ and W ²⁸ have the meaning defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, W ²⁷ is NR ¹⁸ , and W ²⁵ , W ^26, and W ²⁸ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁵ , W ²⁶ , W ^27, and W ^{28 are} independently CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ .

In some embodiments, where t is 0, v is 0, W ²⁷ is NR ¹⁸ , and W ²⁵ , W ²⁶ and W ²⁸ independently are CH ₂ , CHR ¹⁵ or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (Vb):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , R ¹⁵ and R ¹⁸ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where t is 0 and v is 1, the present invention provides compounds of formula (V-c):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ have the meaning defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, W ²⁶ is NR ¹⁸ , and W ²⁵ , W ²⁷ , W ^28, and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁷ is NR ¹⁸ , and W ²⁵ , W ²⁶ , W ^28, and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁵ , W ²⁶ , W ²⁷ , W ^28, and W ^{29 are} independently CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ .

In some embodiments, where t is 0, v is 1, W ²⁷ is NR ¹⁸ , and W ²⁵ , W ²⁶ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (Vd):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , R ¹⁵ and R ¹⁸ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where t is 1 and v is 1, the present invention provides compounds of formula (V-e):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ²⁸ and W ²⁹ have the meaning defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, W ²⁵ is NR ¹⁸ , and W ²⁴ , W ²⁶ , W ²⁷ , W ^28, and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁶ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁷ , W ^28, and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁷ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁶ , W ^28, and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ . In some embodiments, W ²⁴ , W ²⁵ , W ²⁶ , W ²⁷ , W ^28, and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ .

In some embodiments, where t is 1, v is 1, W ²⁷ is NR ¹⁸ , and W ²⁴ , W ²⁵ , W ²⁶ , W ²⁸ and W ²⁹ independently are CH ₂ , CHR ^15, or C (R ¹⁵ ) ₂ , the present invention provides compounds of formula (Vf):

or a pharmaceutically acceptable form of such a compound wherein G, R ^a , R ^b , R ¹⁵ and R ¹⁸ are as defined above and in this section of the application. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I).

In some embodiments, where 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 substituted with a fused C ₆ aryl ring, R ^c and R ^d combined to form a 5,6-bicyclic carbocyclic spiro-fused ring of formula (Vg):

or its pharmaceutically acceptable form, where G, R ^a , R ^b and R ¹⁵ have the meaning defined above and in this section of the application. In some embodiments, R ^a and R ^b are —H. In some embodiments, z has a value of 1. In some embodiments, G is —OR ^e . In some embodiments, G is -Br. However, in some embodiments, G is different from halogen (e.g., -Br, -Cl, -I). In some embodiments, R ^{15 is} selected from —OR ¹⁶ and C _1-10 perhaloalkyl.

Examples of compounds of the present invention

Examples of compounds of formulas (I) and (II) and subtypes related to this type of compounds are presented in tables 1a-1m below, and are also described in more detail in Examples 1-253 presented in this application. Compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351.

In some embodiments, the compound is any of the compounds shown in Table 1a, or a pharmaceutically acceptable form of such a compound:

Table 1a

In some embodiments, the compound is any of the compounds shown in Table 1b, or a pharmaceutically acceptable form of such a compound:

Table 1b

In some embodiments, the compound is any of the compounds shown in Table 1c, or a pharmaceutically acceptable form of such a compound:

Table 1c

In some embodiments, the compound is any of the compounds shown in Table 1d, or a pharmaceutically acceptable form of such a compound:

Table 1d

In some embodiments, the compound is any of the compounds shown in Table 1e, or a pharmaceutically acceptable form of such a compound:

Table 1e

In some embodiments, the compound is any of the compounds shown in Table 1f, or a pharmaceutically acceptable form of such a compound:

Table 1f

In some embodiments, the compound is any of the compounds shown in Table 1g, or a pharmaceutically acceptable form of such a compound:

Table 1g

In some embodiments, the compound is any of the compounds shown in Table 1h, or a pharmaceutically acceptable form of such a compound:

Table 1h

In some embodiments, the compound is any of the compounds shown in Table 1i, or a pharmaceutically acceptable form of such a compound:

Table 1i

In some embodiments, the compound is any of the compounds shown in Table 1j, or a pharmaceutically acceptable form of such a compound:

Table 1j

In some embodiments, the compound is any of the compounds shown in Table 1k, or a pharmaceutically acceptable form of such a compound:

Table 1k

In some embodiments, the compound is any of the compounds shown in Table 1l, or a pharmaceutically acceptable form of such a compound:

Table 1l

In some embodiments, the compound is any of the compounds shown in Table 1m, or a pharmaceutically acceptable form of such a compound:

Table 1m

Additional examples of compounds of formulas (I), (II), (III) and subtypes related to this type of compounds are presented below in Tables 2a-2e, and are also described in more detail in Examples 254-284 presented in this application. Compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351.

In some embodiments, the compound is any of the compounds shown in Table 2a, or a pharmaceutically acceptable form of such a compound:

Table 2a

In some embodiments, the compound is any of the compounds shown in Table 2b, or a pharmaceutically acceptable form of such a compound:

Table 2b

In some embodiments, the compound is any of the compounds shown in Table 2c, or a pharmaceutically acceptable form of such a compound:

Table 2c

In some embodiments, the compound is any of the compounds shown in Table 2d, or a pharmaceutically acceptable form of such a compound:

Table 2d

In some embodiments, the compound is any of the compounds shown in Table 2e, or a pharmaceutically acceptable form of such a compound:

Table 2e

Additional examples of compounds of formulas (I), (IV) and (V) and subtypes related to this type of compounds are presented below in Tables 3a-3d and are also described in more detail in Examples 285-350 presented in this application. Compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351.

In some embodiments, the compound is any of the compounds shown in Table 3a, or a pharmaceutically acceptable form of such a compound:

Table 3a

In some embodiments, the compound is any of the compounds shown in Table 3b, or a pharmaceutically acceptable form of such a compound:

Table 3b

In some embodiments, the compound is any of the compounds shown in Table 3c, or a pharmaceutically acceptable form of such a compound:

Table 3c

In some embodiments, the compound is any of the compounds shown in Table 3d, or a pharmaceutically acceptable form of such a compound:

Table 3d

However, in some embodiments of the formulas (I) and (II) or subtypes related to this type of compound, any of the following compounds are specifically excluded:

In some embodiments of the formulas (I) (II) and (III) or subtypes related to this type of compounds, where R ¹⁸ has the meaning defined in this application, it is specifically excluded:

In some embodiments of formulas (I), (IV) and (V) or subtypes related to this type of compound, any of the following compounds, wherein R ¹⁸ is as defined herein and R ¹⁵ is —OCH ₃ , —CN, —CO ₂ H, —CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ specifically excluded:

II. Pharmaceutical Compositions

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid carriers, dispersing or suspending agents, surfactants, isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, which are suitable for the particular dosage form desired. General principles for formulating and / or preparing pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 ^st Edition (Lippincott Williams & Wilkins, 2005).

The pharmaceutical compositions described in this application can be obtained by any method known in the field of pharmacology. Typically, such production methods include the steps of bringing the active ingredient into association with a carrier and / or one or more other auxiliary ingredients, and then, if necessary and / or desirable, molding and / or packaging the product in the desired single or multi-dose unit.

Pharmaceutical compositions can be prepared, in packaged form and / or sold unpacked, as a single unit dose and / or as a plurality of individual unit doses. As used herein, the term “unit dose” means a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of active ingredient is usually equal to the dose of the active ingredient to be administered to the subject and / or a convenient portion of such a dose, such as, for example, 1/2 or 1/3 of such a dose.

The relative amounts of the active ingredient, pharmaceutically acceptable carrier and / or any additional ingredients in the pharmaceutical composition of the present invention vary depending on the identity, size and / or condition of the subject being treated, and also depend on the route of administration of the composition. As an example, the composition may include from 0.1% to 100% (w / w) of the active ingredient.

Pharmaceutically acceptable excipients used to prepare the presented pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffering agents, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, perfumes and flavors may also be present in the composition.

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

Examples of granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood processing products, natural calcium silicate, calcium carbonate, natural sponge, calcium carbonate, natural silica , sodium carbonate, crosslinked poly (vinyl pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked sodium salt of carboxymethyl cellulose (croscarmellose), m methylcellulose, pregelatinized starch (Starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds and the like and combinations thereof.

Examples of surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrus, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax and lecithin ), colloidal clays (for example, bentonite [aluminosilicate] and Veegum [magnesium aluminosilicate]), derivatives of long chain amino acids, high molecular weight alcohols (for example, stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, eryl monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxypolymethylene, polyacrylic acid, acrylic acid polymer and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g. sodium carboxymethyl cellulose, hydroxymethyl cellulose, hydrocellulose cellulose, cellulose cellulose, hydrocellulose cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose sorbitan fatty acid esters (eg, polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan itanone mono-oleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan monostearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]) polyoxyethylene esters (eg, polyoxyethylene mono-stearate-oil, , polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (eg Cremophor), polyoxyethylene ethers (eg polyoxyethylene lauryl ether [Brij 30]), poly (vinyl-pi pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, tsetrimoniybromid, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof.

Examples of binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic resins (e.g., Arabian gum, sodium alginate, carrageenan extract, panwar gum, ghatti gum, isapol peel glue, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly (cellulose acetate, poly magnesium aluminosilicate (Veegum) and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof.

Examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives and other preservatives.

Examples of antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butyl hydroxyanisole, butyl hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite.

Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g. sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dicalcium edetate, dipotassium edetate and the like), citric acid and its monohydrates and its hydrates citric acid), 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. Examples of antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

Examples of 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.

Examples of alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate and phenylethyl alcohol.

Examples of acid 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, detoxim mesylate, cetrimide, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), ethylene diamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium bisulfite, sodium sulfite potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, neolon, Kathon and Euxyl. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

Examples of buffering agents include citrate buffers, acetate buffers, phosphate buffers, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glucionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium glycerophosphate, calcium lactate, propanoic acid , calcium levulinate, pentanoic acid, calcium hydrogenorthophosphate, phosphoric acid, tricalcium phosphate, calcium hydroxyphosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, potassium hydrogen phosphate, dihydroor Tokalia phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium hydrogen phosphate, monosodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ring solution ethyl alcohol and the like, and combinations thereof.

Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate and the like, and their combinations.

Examples of oils include almond oil, apricot kernel oil, avocado oil, babassu, bergamot, blackcurrant seeds, pharmacy borage, juniper oil, canola oil, caraway seeds, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn , cotton seeds, emu, eucalyptus, evening primrose, fish oil, flaxseed oil, geraniol, pumpkin, grape seed, hazelnut, pharmacy hyssop, isopropyl myristate, jojoba oil, cucumber, lavender, lavender, lemon, cubeba oil, Australian walnut, mallow, mango seeds, meadow pennic seeds, mink oil, nutmeg oil, olive, orange, orange oil, orange trachikht, palm, stone fruit, palm, peach, peanut, poppy seeds, pumpkin seeds, rapeseed, rice bran rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame oil, shea butter (oil tree), silicone sow, sunflower, tea, artichoke, tsubaki, vetiver, walnut and wheat germ. Examples of oils include, but are not limited to, butyl stearate, caprylic acid triglyceride, capric acid triglyceride, cyclomethicone, diethyl sebacinate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and combinations thereof.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, liquid dosage forms may include inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. cottonseed oil, peanut oil, corn oil, plant seed oil, olive oil, castor oil and sesame oil oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures of these substances. In addition to inert diluents, oral compositions may include adjuvants, such as wetting agents, emulsifiers and suspendresume substances, sweeteners, perfumes and flavorings. In some embodiments for parenteral administration, the conjugates of the present invention are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to methods known in the 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 non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's U.S.P. solution. and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as a solvent or suspension medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used to prepare injectable preparations.

Compositions for injection can be sterilized, for example, by filtration through a bacterial filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile medium for injection before use.

To prolong the action of the drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, which, in turn, may depend on the size of the crystals and crystalline form. Alternatively, delayed absorption of a parenterally administered drug is obtained by dissolving or suspending the drug in an oil vehicle.

Formulations for rectal or vaginal administration are typically suppositories, which can be prepared by mixing the conjugates of the present invention with suitable non-irritant excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at temperature body, and therefore melt in the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking additives, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) humectants, such as glycerin, d) disintegrants such as agar, carbonate alumium, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) retardation agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may include buffering agents.

Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms, such as tablets, dragees, capsules, pills and granules, can be prepared with coatings and coatings, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally include substances that make the composition opaque, and may be such that the release of the active ingredient (s) occurs, only or predominantly, in a certain part of the intestinal tract, not necessarily in a delayed manner. Examples of coating and coating compositions that can be used include polymeric materials and waxes. Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active ingredients may be in micro-encapsulated form with one or more of the excipients mentioned above. Solid forms, such as tablets, dragees, capsules, pills and granules, can be prepared with coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid forms, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such forms may include, as is usually the case, additional substances, in addition to inert diluents, for example, tabletting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may include buffering agents. They may optionally include substances that make the composition opaque, and may be such that the release of the active ingredient (s) occurs, only or predominantly, in a certain part of the intestinal tract, not necessarily in a delayed manner. Examples of coating and coating compositions that can be used include polymeric materials and waxes.

Dosage forms for topical and / or transdermal administration of a compound of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. Typically, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and / or any necessary preservatives and / or buffers that are required. In addition, the present invention provides for the use of transdermal patches, which often have the added benefit of providing controlled delivery of the active ingredient to the body. Such forms can be obtained, for example, by dissolving and / or dispersing the active ingredient in a suitable medium. Alternatively or additionally, the rate can be controlled either 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 the delivery of intradermal pharmaceutical compositions described herein include short-needle devices, such as those described in US Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5141496 and 5417662. Intradermal compositions can be administered using devices that limit the effective penetration length of the needle into the skin, such as those described in PCT Publication WO 99/34850 and their functional equivalents. Injection jet devices that deliver liquid vaccines to the skin through a needleless injection device and / or through a needle that punctures the upper layer of the skin and forms a stream that reaches the dermis layer are suitable. Inkjet injection devices are described, for example, in US Pat. Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5503627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder / particle delivery devices that use compressed gas to accelerate the penetration of the vaccine in powder form through the outer layers of the skin into the dermis are suitable. Alternatively or additionally, traditional syringes can be used in the classical Mantoux method for intradermal administration.

Compositions suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations, such as liniment, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments and / or pastes, and / or solutions and / or suspensions. Compositions for topical administration, for example, may include about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be as high as the solubility limits of the active ingredient in the solvent allow. Compositions for topical administration, in addition, may include one or more additional ingredients described in this application.

The pharmaceutical composition of the present invention can be prepared, packaged and / or delivered for sale in a form suitable for pulmonary administration by mouth. Such a composition may include dry particles that include the active ingredient and which have a diameter in the range of from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are convenient in the form of dry powders for administration using devices including a dry powder reservoir into which a propellant stream can be directed to disperse the powder, and / or using a self-spraying solvent / powder dispersion container, such as a device comprising an active an ingredient dissolved and / or suspended in a low boiling propellant in a hermetically sealed container. Such powders include particles, where at least 98% of the mass. particles have a diameter of more than 0.5 nanometers and at least 95% of the number of particles have a diameter of less than 7 nanometers. Alternatively, at least 95% of the mass. particles have a diameter greater than 1 nanometer, and at least 90% of the number of particles have a diameter less than 6 nanometers. The dry powder compositions may include a solid diluent in the form of a fine powder, such as sugar, and are conveniently provided in unit dosage form.

Low boiling propellants typically include liquid propellants having a boiling point below 65 ⁰ F (18.3 ⁰ C) at atmospheric pressure. Typically, the propellant may comprise from 50 to 99.9% (w / w) of the composition, and the active ingredient may comprise from 0.1 to 20% (w / w) of the composition. The propellant may also include additional ingredients, such as a liquid non-ionic and / or solid anionic surfactant and / or solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

The pharmaceutical compositions of the present invention formulated for pulmonary delivery may provide the active ingredient in the form of drops of a solution and / or suspension. Such compositions may be prepared, packaged, and / or sold as aqueous and / or diluted alcohol solutions and / or suspensions, optionally sterile, including the active ingredient, and conveniently administered using any spray and / or spray device. Such compositions may also include one or more additional ingredients, including, but not limited to, fragrance, such as sodium saccharin, volatile oil, a buffering agent, a surfactant, and / or a preservative, such as methyl hydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range of about 0.1 to about 200 nanometers.

The compositions described herein as useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical composition of the present invention. Another composition suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of from about 0.2 to 500 microns. Such a composition is administered by rapid inhalation through the nasal passage from a container containing a powder held in close proximity to the nostrils.

Compositions suitable for nasal administration, for example, may include from about 0.1% (w / w) to 100% (w / w) of the active ingredient, and may include one or more of the additional ingredients described herein. The pharmaceutical composition of the present invention can be obtained, packaged and / or sold for sale in a form suitable for buccal administration. Such compositions, for example, may be in the form of tablets and / or lozenges prepared using conventional methods, and may contain, for example, from 0.1 to 20% (w / w) of the active ingredient, the remainder being orally soluble and / or a degradable composition and, optionally, one or more additional ingredients described in this application. Alternatively, compositions suitable for buccal administration may include a powder and / or an aerosol and / or sprayable solution and / or suspension comprising the active ingredient. Such powdered, aerosolized and / or sprayable compositions, when dispersed, may have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers and, in addition, may include one or more additional ingredients, described in this application.

The pharmaceutical composition of the present invention can be obtained, packaged and / or sold for sale in a form suitable for ophthalmic administration. Such compositions, for example, may be in the form of eye drops comprising, for example, a 0.1 / 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops, in addition, may include buffering agents, salts and / or one or more other additional ingredients described in this application. Other ophthalmic compositions that are useful include compositions containing the active ingredient in microcrystalline form and / or in the form of a liposome preparation. Ear drops and / or eye drops are contemplated as being within the scope of the present invention.

Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions that are suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to animals of any kind. Modification of pharmaceutical compositions suitable for administration to humans to make such compositions suitable for administration to various animals is well known, and a skilled veterinarian-pharmacologist can develop and / or carry out such a modification by routine experimentation. General considerations regarding the formulation and / or preparation of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 ^st ed., Lippincott Williams & Wilkins, 2005.

Pharmaceutical packaging and / or kits are also covered by the present invention. The pharmaceutical packaging and / or kits provided by the invention may include the composition and container provided by the invention (for example, a vial, ampoule, bottle, syringe, and / or dosage container or other suitable container). In some embodiments, the provided kits may optionally further include a second container comprising a suitable aqueous carrier for diluting or suspending the provided composition for preparing it for administration to a subject. In some embodiments, the contents of the provided container with the composition and the container with the solvent are combined to produce at least one unit dosage form.

In some embodiments, the provided composition of the present invention may be useful in conjunction with devices for subject-controlled administration of opioid analgesia (PCA), where the subject may administer, for example, opioid analgesia as needed to manage pain.

Optionally, a separate container may include one or more compartments for containing the provided composition and / or a suitable aqueous carrier for suspension or dilution. In some embodiments, a separate container may be suitable for modification so that the container can undergo a physical modification that allows combining the compartments and / or components of the individual compartments. For example, a foil or plastic bag may include two or more compartments separated by a perforated partition that can be destroyed so that the contents of two separate compartments can be combined immediately after the signal to destroy the partition. A pharmaceutical package or kit may thus include such multi-compartment containers including the provided composition and a suitable solvent and / or a suitable aqueous suspension vehicle.

Optionally, instructions for use are further provided in such kits of the present invention. Such instructions usually include, for example, dosage and administration instructions. In other embodiments, the instructions may also include further details regarding specific instructions for specific containers and / or administration systems. And besides this, the instructions may include specific instructions for use with and / or in combination with adjunctive therapy. In one non-limiting example, the compositions of the present invention can be used in conjunction with administration of opioid analgesia, which optionally may include the use of a device for subject-controlled administration of opioid analgesia (PCA). Thus, instructions for using the provided compositions may include instructions for use with PCA administration devices.

III. Dosage and administration

The present invention provides methods of treating an FAAH-mediated condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof.

The present invention also provides methods for inhibiting FAAH 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.

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

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

The present invention also provides the use of a compound of formula (I) for the manufacture of a medicament. In some embodiments, the medicament is useful for treating an FAAH-mediated condition.

The “subject”, the introduction of which is intended to include, includes, but is not limited to, a person (ie, a man or woman of any age group, for example, a pediatric subject (eg, infant, child, adolescent) or an adult subject (eg, young, middle years old or older)) and / or other primates (e.g. cynomolgus monkeys, rhesus monkeys); mammals, including mammals of commercial interest, such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds, including birds of commercial interest, such as chickens, ducks, geese and / or turkeys.

As used herein and unless otherwise indicated, the terms “treat” “treating” and “treatment” mean an action that occurs when a subject suffers from a specified disease, disorder or condition that reduces the severity of such a disease, disorder or condition or delays or slows the progression of such a disease, disorder or condition.

As used in this application, unless otherwise indicated, the terms “prevent”, “prophylactic” and “prophylaxis” mean an action that occurs before a subject begins to suffer from a specified disease, disorder or condition that inhibits or reduces the severity of such a disease , disorder or condition.

As used in this application and unless otherwise indicated, the terms “observe and treat further” and “further observation and treatment” cover the prevention of a relapse of the disease, disorder or condition in a subject who has already suffered from the disease, disorder or condition, and / or an extension of the period during which a subject who has suffered from the disease, disorder or condition is in remission. The terms encompass modulation of the threshold, development and / or duration of a disease, disorder or condition, or a change in how a subject responds to that disease, disorder or condition.

As used herein and unless otherwise indicated, a “therapeutically effective amount” of a compound is an amount sufficient to provide therapeutic benefit in treating or further managing a disease, disorder or condition, or to delay or minimize one or more symptoms, associated with a disease, disorder or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or further management of such a disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves general therapy, reduces or eliminates the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As the term is used in this application and unless otherwise indicated, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with another agent, that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" may encompass an amount that improves general prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As the term is used herein, “inhibition”, “inhibitory”, “inhibit” and “inhibitor” and the like, refer to the ability of a compound to reduce, slow down, stop or prevent the activity of a particular biological process (eg, FAAH activity) in a cell, as compared with carrier.

The term “FAAH-mediated condition”, as used herein, refers to a disease, disorder or condition that can be treated by inhibiting FAAH activity. "Disease", "disorder" or "condition" are terms that are used interchangeably in this application. FAAH-mediated conditions include, but are not limited to, painful conditions, inflammatory conditions, immune disorders, central nervous system disorders, metabolic disorders, heart disorders, and glaucoma.

In some embodiments, the FAAH-mediated condition is a painful condition. As used herein, a “painful condition” includes, but is not limited to, neuropathic pain (eg, peripheral neuropathic pain), central pain, differential pain, chronic pain (eg, chronic nociceptive pain and other forms of chronic pain, so as postoperative pain, for example, pain resulting from plastic surgery of the femur, knee, etc.), preoperative pain, irritation of nociceptive receptors (nociceptive pain), acute pain (on example, phantom and transient acute pain), non-inflammatory pain, inflammatory pain, cancer pain, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with premature birth, pain associated with withdrawal symptoms pain, joint pain, arthritic pain (e.g. pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter arthritis), lumbar-joint pain, musculoskeletal pain, headache, migraine muscle pain, lumbar pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like.

One or more painful conditions contemplated herein may include mixtures of the various types of pain described above and in this section of the application (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular type of pain may dominate. In other embodiments, the painful condition includes two or more types of pain, without any dominant. An experienced clinician will be able to determine the dose to obtain a therapeutically effective amount for a particular subject based on the disease state.

In some embodiments, the painful condition is a neuropathic pain. The term "neuropathic pain" refers to pain resulting from nerve damage. Neuropathic pain is different from nociceptive pain, which is pain caused by an acute tissue lesion involving small skin nerves or small nerves in muscle or connective tissue. Neuropathic pain is typically prolonged or chronic and often develops within a few days or months after the initial acute tissue lesion. Neuropathic pain can include persistent, spontaneous pain, as well as allodynia, which is a painful response to an irritant that is usually not painful. Neuropathic pain can also be characterized by hyperalgesia, in which there is an increased response to a painful stimulus, which is usually trivial, such as a pin injection. Neuropathic pain states can develop after nerve damage, and the resulting pain can continue for several months or years, even after the initial damage has been cured. Nerve damage can occur in the peripheral nerves, hind roots, spinal cord, or in some areas of the brain. Conditions of neuropathic pain include, but are not limited to, diabetic neuropathy (eg, peripheral diabetic neuropathy); sciatica; non-specific lumbar pain; pain with multiple sclerosis; carpal tunnel syndrome, fibromyalgia; HIV related neuropathy; neuralgia (for example, post-herpetic neuralgia, trigeminal neuralgia); pain caused by physical trauma (e.g., amputation; surgery, invasive medical procedures, toxins, burns, infections), pain caused by cancer or chemotherapy (e.g. chemotherapy-induced pain, such as chemotherapy-induced peripheral neuropathy), and pain caused by inflammatory a condition (e.g., a chronic inflammatory condition). Neuropathic pain can occur as a result of a disorder of peripheral nerves, such as a neuroma; nerve compression; compression of the nerve, stretching of the nerve or incomplete nerve crossing; mononeuropathy or polyneuropathy. Neuropathic pain can also occur as a result of a disorder, such as compression of the posterior radicular ganglion; spinal cord inflammation; bruising, swelling, or hemisection of the spinal cord; tumors of the brain stem, thalamus or cerebral cortex; or trauma to the brain stem, thalamus, or cerebral cortex.

Symptoms of neuropathic pain are heterogeneous, and they are often called spontaneous shooting and acute pain, or are a long burning pain. In addition, there is pain associated with usually non-painful sensations, for example, pin and pin prick tingling sensations (paresthesia and dysesthesia), increased sensitivity to touch (hyperesthesia), pain after safe stimulation (dynamic, static or thermal allodynia) hypersensitivity to harmful irritants (thermal, low-temperature, mechanical hyperalgesia), prolonged pain after removal of the irritant (hyperpathy) or absence or deficiency of se objective sensory pathways (hypoalgesia).

In some embodiments, the painful condition is non-inflammatory pain. Types of non-inflammatory pain include, but are not limited to, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction of the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), differential pain (e.g., pain caused by loss sensory input into the central nervous system), chronic nociceptive pain (for example, some types of cancer pain), a harmful irritant of nociceptive receptors (for example, pain felt in response to tissue damage or impending tissue damage), phantom pain (for example, pain felt in a part of the body that is no longer there, for example, in an extremity that is amputated), pain felt by psychiatric subjects (for example, pain when there is no physical reason) and wandering pain (for example, pain with constantly changing localization in the body).

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

In some embodiments, the FAAH-mediated condition is an inflammatory condition. The term “inflammatory condition” refers to diseases, disorders or conditions characterized by signs of pain (pain resulting from the formation of harmful substances and stimulation of nerves), heat (fever due to vasodilation), redness of the skin (redness due to vasodilation and blood flow), swelling (swelling due to excessive influx or limited outflow of fluid), and / or loss of function (loss of function, which may be partial or complete, temporary or permanent. Inflammation takes different forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, plastrotic, necrotic, oblast , productive, proliferative, pseudomembrane, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, pyogenic, toxic, traumatic and / or ulcer Noah inflammation.

Examples of inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu arteritis), arthritis (e.g. crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies and whether allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes, type 2 diabetes), skin disease (e.g., psoriasis, eczema , burns, dermatitis, itching (scabies)), endometriosis, Guillain-Barré syndrome, infection, coronary heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, headaches, etc. nervous tension), bowel obstruction (for example, postoperative bowel obstruction and bowel obstruction in sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal upset (for example, selected from peptic ulcers, regional enteritis diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal upset (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux (GORD or its synonym GERD), inflammatory bowel disease (IBD) (for example, Crohn’s disease, ulcerative colitis, collagen colitis, lymphocytic colitis, ischemic colitis, mixed-type colitis, Behet syndrome, colitis indefinite type) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, focal scleroderma, malignant myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g. Parkinson's disease, Huntington's disease and Alzheimer's disease), prostatitis, chronic cranial radiation injury, inflammatory diseases of the pelvic organs, reperfusion injury, regional enteritis, rheumatic rheumatic fever lupus erythematosus, scleroderma, scerodomy, sarcoidosis, spondylarthropathy, Sjogren's syndrome, thyroiditis, graft rejection, tendonitis, trauma or damage (e.g. frostbite, chemical irritants, toxins, scarring, burns, physical trauma), vasculitis, vitiligo and Wegener's granulomatosis. In some embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis, and prostatitis. In some embodiments, the inflammatory condition is an acute inflammatory condition (e.g., inflammation caused by an infection). In some embodiments, the inflammatory condition is a chronic inflammatory condition (eg, a condition caused by asthma, arthritis, and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds may also be useful in treating cancer-related inflammation.

In some embodiments, the FAAH-mediated condition is an immune disorder. Immune disorders, such as autoimmune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthropathy, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated, undifferentiated disease Beheta, hemolytic autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute shoulder pain, psoriatic and juvenile arthritis), asthma, atherosclerosis, osteop rose, bronchitis, tendonitis, bursitis, skin disease (e.g. psoriasis, eczema, burns, dermatitis, itching (scabies)), enuresis, eosinophilic disease, gastrointestinal upset (e.g. selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux (GORD or its synonym GERD,) bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagen colitis, lymphocytic colitis, ischemic colitis, mixed-type colitis, Behet syndrome, indefinite colitis) and inflammatory bowel syndrome (IBS)) and disorders that can be alleviated by a gastroprokinetic agent (e.g., bowel obstruction, postoperative bowel obstruction, and bowel obstruction in sepsis; gastroesophageal reflux (GORD or its synonym GERD); eosinophilic esophagitis, gastroparesis, such as diabetic gastroparesis; food intolerance and food allergies and other functional intestinal disorders such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costal chondritis)).

In some embodiments, the inflammatory disorder and / or immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal upset is selected from a gastrointestinal upset (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal upsets (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, allagenic colitis, lymphocytic colitis, ischemic colitis, mixed-type colitis, Behet syndrome, undetermined type colitis) and inflammatory bowel syndrome (IBS)). In some embodiments, the gastrointestinal upset is an inflammatory bowel disease (IBD).

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

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

In some embodiments, a CNS disorder is neurotoxicity and / or neurotrauma, for example, as a result of acute neuronal damage (e.g., traumatic brain damage (TBI), stroke, epilepsy), or chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson's disease, disease Huntington, amyotrophic lateral sclerosis, Alzheimer's disease). In some embodiments, the compound of the present invention provides a neuroprotective effect, for example, against acute neuronal damage or chronic neurodegenerative disorder.

In some embodiments, a CNS disorder is a stroke (e.g., ischemic stroke).

In some embodiments, the CNS disorder is multiple sclerosis.

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

In some embodiments, the CNS disorder is epilepsy.

In some embodiments, a CNS disorder is a mental disorder, for example, depression, anxiety, or anxiety-related conditions, learning disabilities, or schizophrenia.

In some embodiments, the CNS disorder is depression. "Depression", as the term is used in this application, includes, but is not limited to, depressive disorders or conditions, such as, for example, deep depression (e.g., unipolar depression), dysthymic disorders (e.g., mild chronic depression), bipolar disorders (e.g., manic-depressive disorder), seasonal affective disorder, and / or drug addiction-related depression (e.g. withdrawal syndrome). Depression can be clinical or subclinical depression. Depression may be associated with either premenstrual syndrome and / or premenstrual dysphoric disorder.

In some embodiments, the CNS disorder is anxiety. Anxiety, as the term is used in this application, includes, but is not limited to, anxiety and anxiety-related conditions, such as, for example, clinical anxiety, panic disorder, agarophobia, generalized anxiety, specific phobias, social phobias, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder, adaptability disorders with signs of panic fear, anxiety associated with depression, anxiety caused by general honey Qing condition, and substance-induced anxiety particular, the anxiety associated with drug addiction (e.g., withdrawal syndrome, addiction, reduction), and anxiety associated with nausea and / or vomiting. This treatment may also cause or contribute to drowsiness in a subject (e.g., a subject suffering from anxiety).

In some embodiments, a CNS disorder is a learning disorder (e.g., Attention Deficit Disorder (ADD)).

In some embodiments, the CNS disorder is schizophrenia.

In some embodiments, a CNS disorder is a condition associated with sleep disturbance. "Sleep-related conditions" include, but are not limited to, insomnia, narcolepsy, sleep apnea syndrome, tired leg syndrome (RLS), delayed sleep phase syndrome (DSPS), motor disorder with periodic limb movements (PLMD), syndrome a sharp decrease in the frequency and depth of breathing, behavioral disorder with fast eye movement (RBD), shift-shift sleep disturbance (SWSD), and sleep problems (such as parasomnia) such as nightmares, nightly fears, talking in a dream, noise in the head, snoring and interlocked jaws and / or gnashing of teeth (bruxism).

In some embodiments, a CNS disorder is a motor disorder, for example, disorders associated with the basal nuclei of the brain, such as, for example, Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de la Tourette’s syndrome, tardive dyskinesia and dystonia.

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

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

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

In some embodiments, a CNS disorder is drug addiction (eg, addiction to opiates, nicotine, cocaine, psychostimulants, or alcohol).

In other embodiments, the FAAH-mediated condition is a cardiac disorder, for example, selected from hypertension, circulatory shock, reperfusion myocardial damage, and atherosclerosis.

In some embodiments, the FAAH-mediated condition is a metabolic disorder (for example, a depletion-related condition, an obesity-related condition or its complications).

In some embodiments, the metabolic disorder is a depletion-related condition. An “exhaustion-related condition” as used in this application includes, but is not limited to, anorexia and cachexia of various nature (eg, weight loss associated with cancer, weight loss associated with other general medical conditions, weight loss associated with with failure in business and the like).

In some embodiments, the metabolic disorder is an obesity-related condition or its complications. An “obesity-related condition,” as used in this application, includes, but is not limited to, obesity, an undesirable weight gain (for example, drug-induced weight gain due to smoking cessation), and eating disorders ( for example, uncontrolled overeating, bulimia, an irresistible craving for food or lack of appetite control, each of which, optionally, can lead to an undesirable weight gain or obesity). “Obesity” and “obese”, as these terms are used in this application, refer to class I of obesity, class II of obesity, class III of obesity and prior obesity (for example, the condition of "overweight"), as defined by the World Health Organization .

Reduced fat accumulation is expected to provide various primary and / or secondary beneficial effects in a subject (e.g., a subject who has been diagnosed with complications associated with obesity), such as, for example, increased sensitivity to insulin (e.g., in a subject, diagnosed with type II diabetes mellitus); decrease in high blood pressure; lowering elevated cholesterol levels; and / or a decrease (or a reduced risk or progression) of coronary heart disease, arterial vascular disease, angina pectoris, myocardial infarction, stroke, migraines, congestive heart failure, deep venous thrombosis, pulmonary embolism, gallstones, gastroesophageal reflux, obstructive apnea syndrome in a dream associated with obesity hypoventilation syndrome, asthma, gout, low mobility, back pain, erectile dysfunction, urinary incontinence, liver damage (e.g., liver obesity , Cirrhosis, cirrhosis of alcoholic, endotoxin mediated liver injury) or chronic renal failure. Thus, the method of the present invention is useful for obese subjects, diabetic subjects and alcoholic subjects.

In some embodiments, the treatment of an obesity-related condition or its complications includes weight loss in a subject. In some embodiments, the treatment of an obesity-related condition or its complications includes appetite control in a subject.

In other embodiments, the FAAH-mediated condition is glaucoma.

IV. Introduction

The compounds provided can be administered using any amount and any route of administration effective for treatment. The exact amount that is necessary for different subjects will be different, depending on the type, age and general condition of the subject, the severity of the infection, the specific composition, the method of its administration, the nature of its activity, etc.

The compounds provided herein are typically formulated in unit dosage form for ease of administration and uniform dosage. However, it should be understood that the total daily amount of the compositions of the present invention is determined by the attending physician based on a weighted medical score. The specific therapeutically effective dose level for any particular subject or organism depends on various factors, including the disease, disorder or condition to be treated, and the severity of the disorder; the activity of the particular active ingredient used; specific composition used; age, body weight, general health, gender and diet of the subject; time of administration, route of administration, and rate of excretion of the particular active ingredient used from the body; duration of treatment; medicines used in combination or simultaneously with the specific active ingredient used; and similar factors well known in medicine.

Compounds and compositions presented in this application can be administered by any means, including oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (in the form of ointment powders, and / or drops), through the mucous membrane, nasal, buccal, enteric, sublingual; by intratracheal instillation, bronchial instillation and / or inhalation; and / or as an oral spray, nasal spray and / or aerosol. Specific contemplated routes include systemic intravenous injection, regional administration through the bloodstream and / or lymph, and / or direct administration to the affected area. As a rule, the most suitable route of administration depends on various factors, including the nature of the agent (for example, its stability in the environment of the gastrointestinal tract), the condition of the subject (for example, whether or not the subject is able to tolerate oral administration), etc.

The exact amount of compound required to achieve a therapeutically effective amount will vary for different subjects, depending, for example, on the species, age and general condition of the subject, the severity of side effects or disorder, the type of particular compound (s), route of administration, etc. . The desired dose can be administered three times a day, twice a day, once a day, every other day, once every three days, once a week, once every two weeks, once every three weeks or once every four weeks. In some embodiments, the desired dose may be administered using several separate administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more administrations).

In some embodiments, a therapeutically effective amount of a compound for administration once or several times a day to an adult with a body weight of 70 kg may include about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0, 0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of the compound of the present invention per unit dosage form we. It should be understood that the dose ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. The amount required for administration, for example, to a child or adolescent, is determined by a medical practitioner or specialist in the field, and it may be lower or the same as that administered to adults.

It should also be understood that the compound or composition described herein can be administered in combination with one or more additional therapeutically active agents. The compound or composition may be administered simultaneously with, before or after the administration of one or more additional therapeutically active agents. As a rule, each agent should be administered at a dose and / or in accordance with the schedule of administration defined for this agent. It should also be understood that the additional therapeutically active agent used in such a combination can be administered together in the same composition or administered separately in different compositions. In the particular combination intended for use, the compatibility of the compound of the present invention with an additional therapeutically active agent and / or the desired therapeutic effect to be obtained should be considered. Generally, additional therapeutically active substances used in combination are expected to be used at a level that does not exceed that when they are used alone. In some embodiments, the levels used in combination are less than the levels used separately.

Compounds or compositions can be administered in combination with agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion and / or modify their distribution in the body. It should also be understood that the therapy used can achieve the desired effect for the same disorder (for example, the compound can be administered in combination with an anti-inflammatory agent, an anti-anxiety agent and / or an antidepressant, etc.), and / or can achieve other effects. (e.g. control of adverse side effects).

Examples of active substances include, but are not limited to, anticancer agents, antibiotics, antiviral agents, anesthetics, anticoagulants, enzyme inhibitors, steroid agents, steroid or anti-inflammatory agents, antihistamines, immunosuppressants, antitumor agents, antigens, vaccines, antibodies, decongestants, sedatives, opioids, painkillers, analgesics, antipyretics, hormones, prostaglandins, progestogens, glaucoma, ophthalmic drugs, anti-cholinergic drugs, antidepressants, anti-psychotic drugs, sleeping pills, tranquilizers, anticonvulsants / antiepileptics (e.g. Neurontin, Lyric, valproate (e.g. Depacon) and other neurostabilizing drugs), muscle relaxants, anti-spasmodics , muscle contraction promoters, channel blockers, miotic agents, anti-secretory agents, antithrombotic agents, anticoagulants, anticholinergics, β-adrenergic drugs cataractors, diuretics, cardiovascular active agents, vasoactive agents, vasodilators, antihypertensive agents, angiogenic agents, modulators of cell-extracellular matrix interactions (e.g. cell growth inhibitors and anti-adhesive molecules) or inhibitors / intercalators of DNA, RNA, protein-protein interactions protein, protein-receptor interactions, and the like. Active agents include small organic molecules such as drug compounds (for example, compounds approved by the Food and Drug Administration as provided for in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules associated with proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligo nucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

In some embodiments, the additional therapeutically active agent is a painkiller. Examples of painkillers include, but are not limited to, analgesics such as non-narcotic analgesics [eg, salicylates such as aspirin, ibuprofen (MOTRIN ^® , ADVIL ^® ), ketoprofen (ORUDIS ^® ), naproxen (NAPROSYN ^® ), acetaminophen, indomethine], indomethine or narcotic analgesics [eg, opioid analgesics such as tramadol, fentenyl, sufentanil, morphine, hydromorphone, codeine, oxycodone and buprenorphine]; non-steroidal anti-inflammatory drugs (NSAIDs) [for example, aspirin, acetaminophen, COX-2 inhibitors]; steroids or antirheumatic agents; migraine medications, such as beta adrenergic blockers, ergot derivatives; tricyclic antidepressants (e.g. amitriptyline, desiparamine, imipramine); anti-epilepsy drugs (e.g. clonaxepam, valproic acid, phenobarbital, phenytoin, tiagain, gabapentin, carbamazepine, topiramate, sodium valproate); α ₂ agonists; selective serotonin reuptake inhibitors (SSRIs); selective norepinephrine uptake inhibitors; benzodiazepines; Mexiletine (MEXITIL); flecainide (TAMBOCOR); NMDA receptor antagonists [eg, ketamine, detromethorphan, methadone]; and topical agents [eg, capsaicin (Zostrix), EMLA cream, lidocaine, prilocaine].

In other embodiments, the additional therapeutically active agent is an anti-inflammatory agent. Examples of anti-inflammatory drugs include, but are not limited to, aspirin; ibuprofen; ketoprofen; naproxen; etodolac (LODINE ^® ); COX-2 inhibitors such as celecoxib (CELEBREX ^® ), rofecoxib (VIOXX ^® ), valdecoxib (BEXTRA ^@) , parecoxib, etoricoxib (MK663), deracoxib, 2- (4-ethoxy-phenyl) -3- (4-methanesulfonyl phenyl) pyrazolo [1,5-b] pyridazine, 4- (2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl) benzenesulfonamide, darbufelon, flosulide, 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-methyls ulphonyl) phenyl) cyclo-butenone, 4-amino-N- (4- (2-fluoro-5-trifluoromethyl) -thiazol-2-yl) benzene sulfonamide, 1- (7-tert-butyl-2,3-dihydro -3,3-dimethyl-5-benzo-furanyl) -4-cyclopropylbutan-1-one or their physiologically acceptable salts, esters or solvates; Sulindac (CLINORIL ^® ); diclofenac (VOLTAREN ^® ); piroxicam (FELDENE ^® ); diflunisal (DOLOBID ^® ), nabumetone (RELAFEN ^® ), oxaprozin (DAYPRO ^® ), indomethacin (INDOCIN ^® ); or steroids such as PEDIAPED ^® oral solution of prednisolone sodium phosphate, SOLU-MEDROL ^® methylprednisolone sodium succinate for injection, prednisolone syrup under the brand PRELONE ^® .

Additional examples of anti-inflammatory drugs include naproxen, which is commercially available under the trademark EC-NAPROSYN ^® in the form of sustained release tablets, NAPROSYN ^® , ANAPROX ^® and ANAPROX ^® DS tablets and NAPROSYN ^® suspension from Roche Labs, celecoxib tablets under the CELEBREX ^® brand rofecoxib under the VIOXX ^® trademark, betamethasone under the CELESTONE ^® trademark, penicillamine capsules under the CUPRAMIN ^® trademark, titled penicillamine tablets under the DEPEN ^® trademark, methylprednisolone acetate in the form of a suspension for injection DEPO-MEDROL brand, ARAVA ™ leflunomide tablets, AZULFIDIINE EN-tabs ^® sulfasalazine in the form of delayed-release tablets, FELDENE ^® capsule-shaped capsules, CATAFLAM ^® diclofenac potassium tablets, VOLTAREN ^® slow-release sodium diclofenac in the form of VOLTAREN ^® -XR diclofenac sodium in the form of sustained release tablets or ENBREL ^® etanercept products.

V. Methods for determining biological activity

Methods for determining the activity of the compounds provided herein for various therapeutic applications are known in the art. These methods include, but are not limited to, high throughput screening assays to determine compounds that bind to and / or modulate the activity of isolated FAAH, as well as in vitro and in vivo treatment models.

Assays useful for screening the compounds provided herein can be used to determine the binding of an inhibitor to FAAH or to isolate a reaction product (e.g., a fatty acid amide or ethanolamine) formed by hydrolyzing a substrate such as oleoylethanolamide or ananadamide. The substrate can be labeled to facilitate detection of the reaction products released. US Patent No. 5559410 discloses methods for high throughput screening of proteins, and US Patents Nos. 5576220 and 5541061 disclose high throughput screening methods for determining ligand / antibody binding.

Methods for screening FAAH inhibitors to determine the antinociceptive effect are known in the art. For example, compounds can be tested in mice in a hot plate test and a formalin test in mice, and nociceptive reactions to thermal or chemical damage to tissue were measured (for example, see US Patent No. 6,326,156, a description of screening methods for determining antinociceptive activity; see also Cravatt et al Proc. Natl. Acad. Sci. USA (2001) 98: 9371-9376).

Two animal models of anxiety generally recognized in pharmacology are the cascade zero maze method and the method of isolation-induced ultrasonic emission. The zero labyrinth consists of a cascading circular platform with two open and two closed sectors and is based on the conflict between the animal’s instinct to study its environment and its fear of open spaces (see, for example, Bickerdike, MJ et al., Eur. J. Pharmacol, ( 994) 271, 403-411; Shepherd, JK et al., Psychopharmacology, (1994) 116, 56-64). Clinically used anxiolytic drugs, such as benzodiazepines, increase the time spent in open wards and the number of visits to open wards.

A second test for determining an anti-anxiety compound is an ultrasonic voice signal emitting model that is designed to measure the amount of stress-induced voice signals emitted by rat pups that are removed from their nests (see, for example, Insel, TR et al ., Pharmacol. Biochem. Behav., 24, 1263-1267 (1986); Miczek, KA et al., Psychopharmacology, 121, 38-56 (1995); Winslow, JT et al., Biol. Psychiatry, 15, 745 757 (1991).

The effect of the compounds provided herein in the treatment of depression can be determined in a model of constant mild stress-induced anhedonia in rats. This model is based on the observation that constant mild stress causes a gradual decrease in sensitivity to rewards, for example, absorption of sucrose, and that this decrease in a dose-dependent manner prevents and ensures the reverse development of this process by prolonged treatment with antidepressants. See, for example, Willner, Paul, Psychopharmacology, 1997, 134, 319-329.

Another test to determine the activity of a compound as an antidepressant is a forced swimming test (Nature 266, 730-732, 1977). In this test, the animals are injected with the agent 30 or 60 minutes before being placed in a container of water, and the time during which they remain stationary is recorded. A decrease in the immobility time of mice is an indicator of antidepressant activity.

A similar test to determine the activity of a compound as an antidepressant is a method of hanging the mouse by the tail (Psychopharmacology, 85, 367-370, 1985). In this test, the animals are injected with the agent 30 or 60 minutes before they are hung by the tail, and the time during which they remain motionless is recorded. A decrease in the immobility time of mice is an indicator of antidepressant activity.

Animal models are available for evaluating the anticonvulsant activity of the tested compounds (see, for example, US Patent Nos. 6309406 and 6326156).

Inhibition of FAAH has been reported to induce sleep in test animals (see, for example, US Patent No. 6096784). Research methods for sleep-inducing compounds are known in the art (see, for example, US Patent Nos. 6,096,784 and 6,271,015). Compounds can be administered to a test animal (eg, rat or mouse) or human, and subsequent sleep time (eg, falling asleep, duration of sleep) can be monitored (eg, eyes closed, immobility). See also WO 98/24396.

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

Methods for evaluating appetite behavior are known in the art (see, for example, US Patent No. 6344474). One way of assessing the effect on appetizing behavior involves administering a rat FAAH inhibitor and evaluating the effect on the absorption of sucrose solution (see, for example, W. C. Lynch et al., Physiol. Behav., 1993, 54, 877-880).

The two animal models of neuropathic pain recognized in pharmacology are the rat spinal nerve ligation model (Chang model) and the chemotherapeutic-induced neuropathic pain model. After the establishment of neuropathy in these models, as an indicator of mechanical allodynia, the paw withdrawal reaction thresholds were measured by stimulation using von Frey fibers (see, for example, Kim SH and Chung JM, Pain (1992) 50, 355-63; Nozaki-Taguchi N, et al, Pain (2001) 93, 69-76). Clinically used medications for neuropathic pain, such as Gabapentin (Neurontin), increase the threshold for paw withdrawal caused by von Frey fiber stimulation.

Two animal models of inflammatory and mechanical pain that are generally recognized in pharmacology are the model of compression of joints in rats treated with adjuvant or substances that cause joint degeneration. Treatment with clinically used anti-inflammatory drugs, such as naproxen, raises the threshold for a behavioral response to joint compression (see, for example, Wilson AW, et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius SA, et al. , Pain (2007) 128, 272-282).

The animal model of cancer pain generally recognized in pharmacology is a mouse model where implantation of fibrosarcoma cells in the calcaneus causes hyperalgesia of the limb. Treatment with clinically used analgesics, such as morphine, raises the threshold for a behavioral response to mechanical algesia (see, for example, Khasabova, et al., J. Neurscience (2008) 28, 11141-52).

Illustrative examples

The invention will now be described in general terms and more readily with reference to the examples below, which are included solely to illustrate certain aspects and embodiments of the present invention and are not intended to limit the invention.

General synthesis methods

Method 1

General conditions for the preparation of 3-bromo-isoxazolines: Alkene (1.2 equiv.) And potassium hydrogen carbonate (2.5 equiv.) Were suspended in ethyl acetate (0.40 M, calculated on alkene). N, N-dibromoformaldoxime (1.0 equiv.) Was added and the reaction mixture was allowed to stir at 23 ° C. for 14-28 hours. Immediately after completion of the reaction, as determined by thin layer chromatography, the reaction mixture was partitioned between water and tert-butyl methyl ether, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired 3-bromo-isoxazoline.

Method 2

General conditions for the preparation of 3-bromo-isoxazolines: glyoxylic acid monohydrate (1.0 eq.) And hydroxylamine hydrochloride (1.1 eq.) Were charged into the flask. The mixture was dissolved in water (2.0 M, based on 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 obtain the desired crude oxime, which was used directly in the subsequent cycloaddition reaction. The obtained oxime (1.1 equiv.) From the first stage was suspended in a 3: 1 mixture of dimethoxyethane: water (v / v) (0.15 M per oxime) and cooled to 0 ° C. N-bromosuccinimide was added. (NBS) (2.0 equiv.) And the reaction mixture was allowed to stir 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 per alkene) and the reaction mixture was left to stir for 20 hours at 23 ° C. . Immediately after completion of the reaction, as determined by thin layer chromatography, the reaction mixture was partitioned between water and tert-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired 3-bromo-isoxazoline.

Method 3

General conditions for the preparation of 3-aryloxy-isoxazolines or 3-heteroaryloxy-isoxazolines: the resulting 3-bromo-isoxazoline (1.0 eq.) And alcohol (for example, phenol or hydroxypyridine) (3.0 eq.) Were loaded into the microwave reaction vessel and dissolved in N-methylpyrrolidine (0.50 M, calculated on isoxazoline). Ground sodium hydroxide (2.0 eq.) Was added and the mixture was sealed and heated in a microwave reaction vessel at 150 ° C. for 30 minutes. The reaction mixture was then partitioned between water and tert-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired isoxazoline.

Method 4

General conditions for the preparation of 3-aryloxy-isoxazolines or 3-heteroaryloxy-isoxazolines: the resulting 3-bromo-isoxazoline (1.0 eq.) And alcohol (e.g. phenol or hydroxypyridine) (2.0 eq.) Were charged into a flask and dissolved in N, N-dimethylformamide (0.4 M, calculated on isoxazoline). Sodium hydride (2.0 equiv.) Was added and the reaction mixture was allowed to stir for 10 minutes until gas evolution ceased. The reaction mixture was then heated to 150 ° C for 1-5 hours. After completion of the reaction, as determined by thin layer chromatography, the reaction mixture was then partitioned between water and ethyl acetate and the organic layer was washed with 1 N NaOH solution and brine and then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired isoxazoline.

Method 5

General conditions for the preparation of 3-aryloxy-isoxazolines: the obtained 3-bromo-isoxazoline (1.0 eq.) And alcohol (e.g. phenol or hydroxypyridine) (2.0 eq.) Were charged into a flask and dissolved in N, N-dimethylformamide or N-methylpyrrolidinone (0.15 M calculated as isoxazole). Cesium carbonate (1.2-3 equiv.) Was added and the reaction mixture was heated to 120 ° C in an oil bath for 1 hour. The reaction mixture was then partitioned between water and tert-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (methanol / methylene chloride) to give the desired isoxazoline.

Method 6

General conditions for the production of alkenes: in a nitrogen atmosphere, 0.25 M methyltriphenylphosphonium bromide (1.1 eq.) Dissolved in tetrahydrofuran was cooled to 0 ° C, then the mixture was treated dropwise with sodium hexamethyldisilazane (NaHMDS) in tetrahydrofuran (1.0 M, 1.2 equiv.). After stirring for an additional 30 minutes at 0 ° C, the resulting aldehyde or ketone was added and the reaction mixture was allowed to slowly warm to 23 ° C overnight. The mixture was quenched with a saturated solution of ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired alkene.

Method 7

General conditions for the production of alkenes: in a nitrogen atmosphere, 0.15 M methyltriphenylphosphonium bromide (1.5 eq.) Dissolved in tetrahydrofuran was cooled to -78 ° C, then the mixture was treated dropwise with a solution of n-butyllithium in hexane (2.5 M , 1.5 equiv.). After stirring for another 1 hour at -78 ° C, the resulting aldehyde or ketone was added and the reaction mixture was allowed to slowly warm to 23 ° C overnight. The mixture was quenched with a saturated solution of ammonium chloride and concentrated to remove tetrahydrofuran. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired alkene.

Method 8

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

Method 9

General conditions for the preparation of styrenes: aryl bromide (1.0 eq.), Potassium vinyl trifluoroborate (1.2 eq.), The product of addition of 1,1-bis (diphenylphosphino) -ferrocene dichloropalladium (II) and methylene chloride were charged into a dried flask under argon atmosphere (0.02 equiv.) And triethylamine (1.0 equiv.) And the mixture were suspended in isopropanol (0.25 M calculated as aryl bromide) and heated at 80 ° C. for 2-24 hours. The mixture was then diluted with water and extracted diethyl ether.The organic layer was washed with brine and then dried over magnesium sulfate and concentrated under vacuum The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired styrene.

Method 10

General conditions for the preparation of styrenes: aryl bromide (1.0 eq.), Tributylvinyltin (1.1 eq.) And dissolved in toluene (0.3 M per bromide) were charged into a dried flask under nitrogen atmosphere. The resulting mixture was again purged with nitrogen for 10 minutes, then tetrakis (triphenylphosphine) palladium (0.1 eq.) Was added and the reaction mixture was refluxed for 1.5 hours. After completion of the reaction, as determined by TLC, the mixture was allowed to cool and loaded directly onto a silica gel column, where it was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired styrene.

Method 11

General conditions for the hydrolysis of pyridyl and pyrimidinyl boronic acids to their corresponding phenols: the resulting boronic acid or its ester (1.0 eq.) Was charged into a flask and dissolved in tetrahydrofuran (1.1 M, 10 volumes). Sodium perborate (1.0 eq.) Was dissolved in water (1.1 M calculated as boronic acid, 10 volumes) and sonicated for 10 minutes. A suspension of perborate was then added to the THF solution using tetrahydrofuran (1.6 volumes) to wash the remaining solid perborate in the reaction mixture. The reaction mixture was allowed to stir at room temperature (the reaction is slightly exothermic), then ammonium chloride was added in three portions (10 equiv.) And the reaction mixture was again cooled to room temperature. After 40 minutes, the reaction mixture was concentrated in vacuo until tetrahydrofuran was completely 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 obtain the desired phenol in 80% yield.

Chiral HPLC Method

Enantiomeric or diastereomeric mixtures of compounds can be separated using known methods, including chiral high performance liquid chromatography (HPLC) and chiral supercritical liquid chromatography (SFC). Examples of chiral columns that can be used to separate such mixtures of the compounds of the present invention include, but are not limited to, ChiralPak® AD-H, ChiralPak® OD-H, ChiralPak® AY, RegisPack ™ and S, S Whelkθ-1 columns and LUX ™ Cellulose2. One or more of these columns was used to separate the enantiomeric mixtures of the compounds of the present invention to obtain substantially enantiomerically pure compounds.

SYNTHESIS OF ILLUSTRATIVE COMPOUNDS OF FORMULA I

The synthesis of illustrative compounds is presented below. The compounds were tested as inhibitors of human FAAH using the method described in detail in Example 351. The activity designated as “A” refers to compounds having a K _i value less than or equal to 100 nM, “B” refers to compounds having a K value _i ranging from 100 nM to 1 μM, and “C” refers to compounds having a K _i value greater than or equal to 1 μM.

Example 1

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

Example 2

3-bromo-4,5-dihydroisoxazole I-2a and I-2b were prepared in 1 step starting from 4-fluorostyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. Activity: B

Example 3

3-bromo-4,5-dihydroisoxazole I-3a and I-3b were prepared in 1 step starting from 4-chlorostyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 259.0 m / z. Activity: A

Example 4

3-bromo-4,5-dihydroisoxazole I-4a and I-4b were prepared in 1 step starting from 3-chlorostyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 258.9 m / z. Activity: B

Example 5

3-bromo-4,5-dihydroisoxazole I-5a and I-5b were prepared in 1 step starting from 2-chlorostyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 258.9 m / z. Activity: B

Example 6

3-bromo-4,5-dihydroisoxazole I-6a and I-6b were prepared in 1 step starting from 4-methoxystyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 255.0 m / z. Activity: A

Example 7

3-bromo-4,5-dihydroisoxazole I-7a and I-7b were prepared in 1 step starting from 3-methoxystyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 255.0. Activity: B

Example 8

3-bromo-4,5-dihydroisoxazole I-8a and I-8b were prepared in 1 step starting from 2-methoxystyrene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 255.0 m / z. Activity: C

Example 9

3-bromo-4,5-dihydroisoxazole I-9a and I-9b were prepared in 1 step starting from 4-vinyl biphenyl using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 301.6 m / z. Activity: A

Example 10

3-bromo-4,5-dihydroisoxazole I-10a and I-10b were obtained in 1 step starting from 4-phenoxystyrene using Method 2. These compounds were separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 317.0 m / z. Activity: A

Example 11

3-bromo-4,5-dihydroisoxazole I-11a and I-11b were obtained in 2 stages, starting from the formation of an alkene from 3-phenoxybenzaldehyde using Method 8, followed by cycloaddition using Method 2. These compounds can be separated using chiral methods HPLC known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 317.0 m / z. Activity: A

Example 12

3-bromo-4,5-dihydroisoxazole I-12a and I-12b were obtained in 2 stages, starting from the formation of an alkene from 4- (pyridin-3-yloxy) benzaldehyde using Method 8, followed by cycloaddition using Method 2. These the compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 318.0 m / z. Activity: A

Example 13

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

Example 14

3-bromo-4,5-dihydroisoxazole I-14a and I-14b were prepared in 2 stages, starting from the formation of an alkene from 4-trifluoromethoxybenzaldehyde using Method 8, followed by cycloaddition using Method 1. These compounds can be separated using chiral methods HPLC known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 309.6 m / z. Activity: A

Example 15

3-bromo-4,5-dihydroisoxazole I-15a and I-15b were obtained in 2 stages, starting from the formation of an alkene from 4-isopropoxybenzaldehyde using Method 8, followed by cycloaddition using Method 2. These compounds can be separated using chiral methods HPLC known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 238.0 m / z. Activity: A

Example 16

3-bromo-4,5-dihydroisoxazole I-16a and I-16b were obtained in 2 stages, starting from the formation of alkene from piperonal using Method 7, followed by cycloaddition using Method 2. These compounds can be separated using chiral HPLC methods, known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 269.0 m / z. Activity: A

Example 17

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

Example 18

(I-18)

3-bromo-4,5-dihydroisoxazole I-18a and I-18b were obtained in 2 stages, starting from the formation of an alkene from 3- (4-bromophenoxy) -6-methylpyridazine using Method 9, followed by cycloaddition using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 333.0 m / z. Activity: B

Example 19

3-bromo-4,5-dihydroisoxazole I-19a and I-19b were obtained in 2 stages, starting from the formation of an alkene from 2- (4-bromophenyl) -5-phenyl-1,3,4-oxadiazole using Method 9 s subsequent cycloaddition using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 369.0 m / z. Activity: A

Example 20

3-bromo-4,5-dihydroisoxazole I-20a and I-20b were obtained in 2 stages, starting from the formation of an alkene from 4-butoxybenzaldehyde using Method 8, followed by cycloaddition using Method 1. These compounds can be separated using chiral methods HPLC known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 297.0 m / z. Activity: A

Example 21

3-bromo-4,5-dihydroisoxazole I-21a and I-21b were obtained in 2 stages, starting with the coupling reaction between 4-vinylbenzoic acid and benzyl alcohol as follows: 4-vinylbenzoic acid (1.0 eq.) Was dissolved in N , N-dimethylformamide (0.20 M based on acid). Benzyl alcohol (2.0 eq.) Was added, followed by EDC (1.05 eq.) And a catalytic amount of DMAP (0.05 eq.). The reaction mixture was allowed to stir at 23 ° C for 14 hours, after which the reaction mixture was partitioned between water and tert-butyl methyl ether and the organic layer was washed with a 0.5 M citric acid solution (2 ×) and saturated sodium bicarbonate solution (1 ×) , dried over magnesium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired ester. This compound was then converted to the desired 3-bromo-4,5-dihydroisoxazole using Method 1. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 359.8 m / z. Activity: A

Example 22

3-bromo-4,5-dihydroisoxazole I-22a and I-22b were obtained using a procedure similar to that of Example 21, except that benzylamine was used instead of benzyl alcohol. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 358.9 m / z. Activity: B

Example 23

3-phenoxy-4,5-dihydroisoxazole I-23a and I-23b were prepared in 1 step starting from compound I-10 and phenol using Method 3. These compounds can be separated using chiral HPLC methods known in the art. . For example, see the chiral HPLC method disclosed herein. [MH] ^- = 331.1 m / z. Activity: C

Example 24

3-phenoxy-4,5-dihydroisoxazole I-24a and I-24b were prepared in step 1 starting from compound I-10 and 4-fluorophenol using Method 4. These compounds can be separated using chiral HPLC methods known in the art. areas of technology. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 350.3 m / z. Activity: C

Example 25

3-phenoxy-4,5-dihydroisoxazole I-25a and I-25b were obtained in 1 step starting from compound I-10 and 3-fluorophenol using Method 4. These compounds can be separated using chiral HPLC methods known in this areas of technology. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 349.3 m / z. Activity: B

Example 26

3-phenoxy-4,5-dihydroisoxazole I-26a and I-26b were prepared in step 1 starting from compounds I-10 and 3-trifluoromethylphenol using Method 4. These compounds can be separated using chiral HPLC methods known in the art. areas of technology. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 400.3 m / z. Activity: C

Example 27

3-phenoxy-4,5-dihydroisoxazole I-27a and I-27b were prepared in step 1 starting from compound I-10 and 4-cyanophenol using Method 3. These compounds can be separated using chiral HPLC methods known in the art. areas of technology. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 356.1 m / z. Activity: A

Example 28

3-phenoxy-4,5-dihydroisoxazole I-28a and I-28b were obtained in 1 step starting from compound I-10 and 2-cyanophenol using Method 4. These compounds can be separated using chiral HPLC methods known in the art. areas of technology. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 357.3 m / z. Activity: C

Example 29

3-phenoxy-4,5-dihydroisoxazole I-29a and I-29b were prepared in 1 step starting from compound I-10 and 4-nitrophenol using Method 4. These compounds can be separated using chiral HPLC methods known in the art. areas of technology. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 376.8 m / z. Activity: B

Example 30

3-phenoxy-4,5-dihydroisoxazole I-30a and I-30b were obtained in 1 step starting from compound I-10 and 4-methylsulfonylphenol using Method 4. These compounds can be separated using chiral HPLC methods known in this areas of technology. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 409.0 m / z. Activity: A

Example 31

3-phenoxy-4,5-dihydroisoxazole I-31a and I-31b were obtained in 1 step starting from compound I-10 and 4-methyl-3-fluorophenol using Method 4. These compounds can be separated using chiral HPLC methods. known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 364.4 m / z. Activity: C

Example 32

Racemic compound I-10 (1.0 equiv.) And aniline (4.0 equiv.) Were loaded into the microwave reaction vessel. The mixture was sealed and heated in a microwave reactor at 150 ° C for 2 hours. The reaction mixture was then partitioned between water and tert-butyl methyl ether, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired 3-amino-4,5-dihydroisoxazole I-32a and I-32b. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 330.1 m / z. Activity: C.

Example 33

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

Example 34

(I-34)

The racemic compound I-10 (1.0 eq.) And the sodium salt of 1,2,4-triazole (2.0 eq.) Were loaded into the microwave reaction vessel. The reagents were dissolved in N-methylpyrrolidine (0.18 M, based on compound I-10). The mixture was sealed and heated in a microwave reactor at 100 ° C for 30 minutes. Excess water was added and a brown solid precipitated, which was isolated using vacuum filtration and dried to give the desired 3- (1H-1,2,4-triazol-1-yl) -4,5-dihydroisoxazole I-34a and I-34b. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 306.1 m / z. Activity: C.

Example 35

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

Example 36

3- (pyridin-4-yloxy) -4,5-dihydroisoxazole I-36a and I-36b were prepared in step 1 starting from compound I-10 and 4-hydroxypyridine using Method 3. These compounds can be separated using methods chiral HPLC known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 332.1 m / z. Activity: C

Example 37

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-37a and I-37b were prepared in step 1 starting from racemic compound 1-10 and 3-hydroxypyridine using Method 3 or Method 5. These compounds can be split using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 332.1 m / z. Activity: A

Example 38

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-38a and I-38b were prepared in step 1 starting from racemic compound 1-6 and 3-hydroxypyridine using Method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 270.1 m / z. Activity: B

Example 39

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-39a and I-39b were prepared in step 1 starting from racemic compound 1-10 and methyl 5-hydroxynicotinate using Method 3 or Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 392.2 m / z. Activity: A

Example 40

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-40a and I-40b were prepared in step 1 starting from racemic compound 1-10 and 5-hydroxy-2-methylpyridine using Method 4. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 346.1 m / z. Activity: A

Example 41

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-41a and I-41b were prepared in step 1 starting from racemic compound 1-10 and 5-hydroxypyrimidine using Method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 333.1 m / z. Activity: A

Example 42

3- (Quinolin-3-yloxy) -4,5-dihydroisoxazole I-42a and I-42b were prepared in step 1 starting from racemic compound 1-10 and 3-hydroxyquinoline using Method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 382.1 m / z. Activity: A

Example 43

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-43a and I-43b were prepared in step 1 starting from racemic compound 1-10 and 5-fluoro-3-hydroxypyridine using Method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 350.1 m / z. Activity: A

Example 44

3- (1-methyl-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4,5-dihydroisoxazole I-44a and I-44b were obtained in stage 1, starting from racemic compound 1-10 and 1 -methyl-1H-pyrrolo [2,3-b] pyridin-5-ol using Method 3. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 385.1 m / z. Activity: B

Example 45

The racemic compound I-10 (1.0 equiv.) Was loaded into the vessel and dissolved in methanol (0.05 M based on isoxazole). Potassium carbonate (5.0 eq.) Was added and the reaction mixture was sealed and heated to 50 ° C. for 24 hours. The reaction mixture was then partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired 3-methoxy-4,5-dihydroisoxazole I-45a and I-45b. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 269.1 m / z. Activity: C.

Example 46

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-46a and I-46b were prepared in step 1 starting from racemic compound 1-14 and methyl 5-hydroxynicotinate using Method 5. These compounds can be separated with using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 384.0 m / z. Activity: B

Example 47

The racemic compound I-39 was dissolved in ammonia in methanol (7.0 M in methanol, 0.02 M based on isoxazole). The reaction mixture was sealed and allowed to stir at 23 ° C. for 24 hours, after which the solvent and excess ammonia were removed under a stream of nitrogen to give a light brown solid, which was triturated with hexane to give the desired amide I-47a and I-47b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 374.0 m / z. Activity: B

Example 48

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

Example 49

3-bromo-4,5-dihydroisoxazole I-49a and I-49b were obtained in 1 step starting from 4-phenyl-1-butene using Method 2. These compounds can be separated using chiral HPLC methods known in the art. technicians. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 253.0 m / z. Activity: In

Example 50

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

Example 51

Phenol (1.2 equiv.) Was dissolved in N, N-dimethylformamide (0.4 M calculated as phenol) and cesium carbonate (1.3 equiv.) Was added, followed by 5-bromo-1-pentene (1.0 equiv.) and tetrabutylammonium iodide (0.10 equiv.). The mixture was heated to 50 ° C for 16 hours. The reaction mixture 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. The crude alkene was directly converted to the desired 3-bromo-4,5-dihydroisoxazole I-51a and I-51b in 1 step using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 283.0 m / z. Activity: A

Example 52

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

Example 53

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

Example 54

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

Example 55

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-55a and I-55b were prepared in step 1 starting from racemic compound I-46 and methyl 5-hydroxynicotinate using Method 5 and isolated as a by-product reactions during flash chromatography on silica gel. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 367.0 m / z. Activity: C

Example 56

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-56a and I-56b were prepared in step 1 starting from racemic compound I-10 and 5-hydroxy-2-trifluoromethylpyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 401.5 m / z. Activity: A

Example 57

3- (1H-pyrrolo [3,2-b] pyridin-6-yloxy) -4,5-dihydroisoxazole I-57a and I-57b were obtained in 1 step starting from racemic compound I-10 and 1H-pyrrolo [3 , 2-b] pyridin-6-ol, using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 370.0 m / z. Activity: A

Example 58

3-phenoxy-4,5-dihydroisoxazole I-58a and I-58b were obtained in 1 step starting from racemic compound I-10 and 3-cyanophenol using Method 4. These compounds can be separated using chiral HPLC methods known in the art. this technical field. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 356.8 m / z. Activity: B

Example 59

3-phenoxy-4,5-dihydroisoxazole I-59a and I-59b were obtained in 1 step starting from the racemic compound I-10 and 2-fluorophenol using Method 4. These compounds can be separated using chiral HPLC methods known in the art. this technical field. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 350.3 m / z. Activity: B

Example 60

3-phenoxy-4,5-dihydroisoxazole I-60a and I-60b were prepared in step 1 starting from racemic compound I-10 and 4-fluoro-3- (trifluoromethyl) phenol using Method 4. These compounds can be separated with using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. Activity: C

Example 61

3-phenoxy-4,5-dihydroisoxazole I-61a and I-61b were obtained in 1 step starting from racemic compound I-10 and methyl 3-hydroxybenzoate using Method 4. These compounds can be separated using chiral HPLC methods known in the art. in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 390.5 m / z. Activity: A

Example 62

3-phenoxy-4,5-dihydroisoxazole I-62a and I-62b were obtained in 1 step starting from racemic compound I-10 and methyl 4-hydroxybenzoate using Method 4. These compounds can be separated using chiral HPLC methods known in the art. in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 389.7 m / z. Activity: A

Example 63

3-phenoxy-4,5-dihydroisoxazole I-63a and I-63b were prepared in step 1 starting from racemic compound I-10 and 3- (methylsulfonyl) phenol using Method 4. These compounds can be separated using chiral HPLC methods. known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 409.0 m / z. Activity: C

Example 64

3-phenoxy-4,5-dihydroisoxazole I-64a and I-64b were obtained in 1 step starting from racemic compound I-10 and 3-hydroxybenzenesulfonamide using Method 4. These compounds can be separated using chiral HPLC methods known in the art. this technical field. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 409.0 m / z. Activity: C

Example 65

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-65a and I-65b were obtained in step 1 based on the racemic compound I-10 and 5-methoxypyridin-3-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 363.2 m / z. Activity: A

Example 66

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-66a and I-66b were prepared in step 1 starting from racemic compound I-10 and 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 364.6 m / z. Activity: A

Example 67

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67a and I-67b were prepared in step 1 starting from racemic compound I-10 and methyl 5-hydroxypicolinate using Method 3. These compounds can be separated with using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 392.1 m / z. Activity: A

Example 68

3- (1H-pyrrolo [2,3-6] pyridin-5-yloxy) -4,5-dihydroisoxazole I-68a and I-68b were obtained in stage 1 starting from racemic compound I-10 and 1H-pyrrolo [2 , 3-b] pyridin-5-ol, using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 370.0 m / z. Activity: A

Example 69

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

Example 70

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-70a and I-70b were prepared in step 1 based on the racemic compound I-14 and 3-hydroxypyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 324.1 m / z. Activity: A

Example 71

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-71a and I-71b were prepared in step 1 based on the racemic compound I-14 and 5-bromo-3-hydroxypyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 402.5 m / z. Activity: A

Example 72

The racemic compound I-71 (1.0 eq.), Phenylboronic acid (1.1 eq.), Potassium acetate (1.0 eq.), Cesium carbonate (3.0 eq.) And the dichloro addition product [1.1 'bis (diphenylphosphino) ferrocene] palladium (II) and dichloromethane (14 mol%) were suspended in 1 ml of DMSO and purged with Ar. The resulting mixture was sealed and heated to 80 ° C for 1 hour. The crude mixture was transferred to a separatory funnel with excess water and extracted with methyl tert-butyl ether (2 ×). The organic layers were combined, dried over Na ₂ SO ₄ and purified using flash chromatography on silica gel (gradient 2-10% MeOH) to give the desired 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-72a and I -72b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 402.3 m / z. Activity: B

Example 73

The racemic compound I-71 (1.0 eq.), 3-carbamoylphenylboronic acid (1.1 eq.), Potassium acetate (1.0 eq.), Cesium carbonate (3.0 eq.) And the dichloro addition product [1 , 1'-bis (diphenylphosphino) ferrocene] palladium (II) and dichloromethane (14 mol%) were suspended in 1 ml of DMSO and purged with Ar. The resulting mixture was sealed and heated to 80 ° C for 1 hour. The crude mixture was transferred to a separatory funnel with excess water and extracted with methyl tert-butyl ether (2 ×). The organic layers were combined, dried over Na ₂ SO ₄ and purified using flash chromatography on silica gel (gradient 2-10% MeOH) to give the desired 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-73a and I -73b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 442.0 m / z. Activity: A

Example 74

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

Example 75

3-bromo-4,5-dihydroisoxazole I-75a and I-75b were obtained in 2 stages, starting from the formation of an alkene from 4 '(trifluoromethoxy) acetophenone using Method 6, followed by cycloaddition using Method 1. These compounds can be separated with using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 323.0 m / z. Activity: A

Example 76

3-bromo-4,5-dihydroisoxazole I-76a and I-76b were obtained in 2 stages, starting from the formation of an alkene from 4'-phenoxyacetophenone using Method 6, followed by cycloaddition using Method 2. These compounds can be separated using methods chiral HPLC known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 331.0 m / z. Activity: A

Example 77

3-bromo-4,5-dihydroisoxazole I-77a and I-77b were obtained in 1 step starting from trans-anethole using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 269.0 m / z. Activity: C

Example 78

3-bromo-4,5-dihydroisoxazole I-78a and I-78b were obtained in 2 stages, starting from the formation of an alkene from 4-phenoxybenzaldehyde using Method 6 (except that ethyl triphenylphosphonium bromide was used instead of methyl triphenylphosphonium bromide) followed by cycloaddition using the Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 331.0 m / z. Activity: A

Example 79

3-bromo-4,5-dihydroisoxazole I-82a and I-82b were obtained in 3 stages, starting from 4-phenoxybenzaldehyde, as follows: 4-phenoxybenzaldehyde (1.0 equiv.) Was dissolved in tetrahydrofuran (0.20 M calculated on tetrahydrofuran) and cooled to 0 ° C. Ethyl magnesium bromide (1.0 M in THF, 1.2 eq.) Was added dropwise, then the reaction mixture was allowed to stir at 23 ° C. for 2 hours. The mixture was quenched with a saturated solution of 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, and then dried over sodium sulfate and concentrated in vacuo. The concentrated reaction mixture was purified by flash chromatography on silica gel (ethyl acetate / hexane) to give the desired alcohol I-80.

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

Alken I-81 was then converted to the desired 3-bromo-4,5-dihydroisoxazole I-82a and I-82b using Method 2. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 331.0 m / z. Activity: B.

Example 80

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-83a and I-83b were obtained in 1 step starting from racemic compound I-14 and methyl 3- (5-hydroxypyridin-2-yl) benzoate, s using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 460.1 m / z. Activity: B

Example 81

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-84a and I-84b were obtained in 1 step starting from racemic compound I-14 and ethyl 3- (5-hydroxypyridin-2-yl) benzoate, s using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 474.1 m / z. Activity: B

Example 82

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

Example 83

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-86a and I-86b were prepared in step 1 based on the racemic compound I-14 and 6-phenylpyridin-3-ol using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 402.2 m / z. Activity: B

Example 84

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-87a and I-87b were prepared in step 1 based on the racemic compound I-12 and 3-hydroxypyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 333.5 m / z. Activity: A

Example 85

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-88a and I-88b were prepared in stage 1 starting from racemic compound I-75 and 3-hydroxypyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 340.2 m / z. Activity: B

Example 86

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-89a and I-89b were prepared in step 1 based on the racemic compound I-76 and 3-hydroxypyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 348.4 m / z. Activity: A

Example 87

3-phenoxy-4,5-dihydroisoxazole I-90a and I-90b were obtained in 1 step starting from racemic compound I-10 and 4-hydroxybenzenesulfonamide using Method 4. These compounds can be separated using chiral HPLC methods known in the art. this technical field. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 410.8 m / z. Activity: A

Example 88

Trans 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-91a and I-91b were obtained in step 1 based on the racemic compound I-78 or 1-82 and 3-hydroxypyridine using Method 5. These the compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 346.2 m / z. Activity: C

Example 89

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-92a and I-92b were obtained in 2 stages starting from the racemic compound I-10 and tert-butyl ether (5-hydroxy-pyridin-2-yl) -carbamic acid using Method 5 after the formation of (5-hydroxy-pyridin-2-yl) -carbamic acid tert-butyl ester from tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) pyridin-2-ylcarbamate using Method 11. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 447.9 m / z. Activity: C

Example 90

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-92 was dissolved in trifluoroacetic acid (0.20 M based on isoxazole) and stirred at room temperature for 1 hour. The solvent was then removed under vacuum and the crude residue was subjected to azeotropic distillation with toluene (2 ×) to give I-93a and I-93b as the TFA salt (white solid). These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 347.1 m / z. Activity: A

Example 91

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-93 was dissolved in methylene chloride (0.03 M based on isoxazole), then triethylamine (4.0 equiv.) And acetic anhydride (3.0 equiv.). The reaction mixture was allowed to stir for 16 hours, then was diluted with ethyl acetate and washed with saturated NaHCO ₃ solution (2 ×) and brine (1 ×). The organic layer was then dried over sodium sulfate and concentrated in vacuo to give acetate I-94a and I-94b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 388.1 m / z. Activity: A

Example 92

3-bromo-4,5-dihydroisoxazole I-95a and I-95b were obtained in 2 stages, starting from the formation of alkene from 1- (4-phenoxyphenyl) propan-1-one using Method 8, followed by cycloaddition using Method 1 These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 347.7 m / z. Activity: A

Example 93

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-96a and I-96b were obtained in stage 1, starting from racemic compound I-14 and 5-hydroxypicolinic acid methyl ester, in accordance with the following procedure: 3- bromo-5- (4- (trifluoromethoxy) phenyl) -4,5-dihydroisoxazole (1.0 equiv.), 5-hydroxypicolinic acid methyl ester (1.2 equiv.) and cesium bicarbonate (1.50 equiv.) in N, N-dimethylformamide (0.32 M calculated as dihydroisoxazole). The mixture was then degassed using argon, then heated to 130 ° C for 4 hours, after which only the desired product and the corresponding acid were observed by LC / MS. The reaction mixture was allowed to cool to room temperature and quenched by pouring the mixture into a solution of ammonium chloride in water (30% wt., 0.08 M based on dihydroisoxazole). The aqueous phase was extracted with ethyl acetate (2 ×), dried over sodium sulfate, filtered and concentrated to give the product as a brown solid, which could be recrystallized from absolute ethanol to give racemic 3- (pyridin-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. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 383.8 m / z. Activity: A

Example 94

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-96 (1.0 equiv.) Was dissolved in a 1: 1 mixture of tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv. .). The reaction mixture was allowed to stir at room temperature for 1 hour, after which tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH <2 1 N. HCl solution to give the desired acid enantiomers I-97a and I-97b as a white solid, which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 369.3 m / z. Activity: A

Example 95

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-98a and I-98b were obtained in 1 step starting from racemic compound I-10 and 3- (5-hydroxypyridin-2-yl) propanoic acid methyl ester using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 418.1 m / z. Activity: A

Example 96

The racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-98 (1.0 equiv.) Was dissolved in a 1: 1 tetrahydrofuran / water mixture (0.06 M) and lithium hydroxide (8.0 equiv. .). The reaction mixture was allowed to stir at room temperature for 1 hour, after which tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH <2 1 N. HCl solution to give the desired acid I-99a and I-99b as a white solid, which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 402.8 m / z. Activity: A

Example 97

The racemic compound I-98 was dissolved in a solution of ammonia in methanol (7.0 M in methanol, 0.02 M based on isoxazole). The reaction mixture was sealed and allowed to stir at 23 ° C for 72 hours, after which the solvent and excess ammonia were removed under a stream of nitrogen to give a light brown solid, which was triturated with hexane to give the desired amide I-100a and I-100b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 404.5 m / z. Activity: A

Example 98

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-101a and I-101b were prepared in step 1 based on the racemic compound I-9 and 3-hydroxypyridine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 316.8 m / z. Activity: A

Example 99

3-bromo-4,5-dihydroisoxazole I-102a and I-102b were prepared in 2 stages, starting from the formation of an alkene from 1- (biphenyl-4-yl) ethanone using Method 8, followed by cycloaddition using Method 1. These the compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 315.7 m / z. Activity: A

Example 100

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-103a and I-103b were prepared in step 1 starting from racemic compound I-9 and 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 318.7 m / z. Activity: A

Example 101

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-104a and I-104b were prepared in step 1 based on the racemic compound I-102 and 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 332.6 m / z. Activity: A

Example 102

The racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-97 (1.0 equiv.) Was dissolved in methylene chloride (0.03 M based on isoxazole). Thionyl chloride (2.0 equiv.) Was added and the reaction mixture was stirred for 1 hour at room temperature, then the mixture was concentrated in vacuo to give a beige solid, which was subjected to azeotropic distillation with toluene (2 ×). The resulting solid was again dissolved in tetrahydrofuran (0.03 M based on isoxazole), then glycine methyl ester (1.5 equivalents) was added, followed by triethylamine (3.0 equivalents). The reaction mixture was stirred for 1 hour at room temperature, then the mixture was transferred to a separatory funnel with excess water and ethyl acetate. The organic layer was then washed with saturated NaHCO ₃ solution and brine, dried over magnesium sulfate and concentrated in vacuo to give a crude material, which was purified using flash chromatography on silica gel (ethyl acetate / hexane) to give amide I-105a and I -105b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 437.5 m / z. Activity: A

Example 103

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-105 (1.0 equiv.) Was dissolved in a 1: 1 mixture of tetrahydrofuran / water (0.06 M) and lithium hydroxide (8.0 equiv. .). The reaction mixture was allowed to stir at room temperature for 1 hour, after which tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH <2 1 N. HCl solution to give the desired acid I-106a and I-106b as a white solid, which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 423.7 m / z. Activity: A

Example 104

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-107a and I-107b were obtained using a procedure similar to that of Example 102, except that methylamine was used instead of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 382.5 m / z. Activity: A

Example 105

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-108a and I-108b were obtained using a procedure similar to that of Example 102, except that dimethylamine was used instead of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 396.6 m / z. Activity: B

Example 106

3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-109a and I-109b were obtained using a procedure similar to that of Example 102, except that ethanolamine was used instead of glycine methyl ester. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [MH] ^- = 409.9 m / z. Activity: A

Example 107

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67 (1.0 equiv.) Was dissolved in a 1: 1 tetrahydrofuran / water mixture (0.06 M) and lithium hydroxide (8.0 equiv. .). The reaction mixture was allowed to stir at room temperature for 1 hour, after which tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH <2 1 N. HCl solution to give the desired acid I-110a and I-110b as a white solid, which was isolated by vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 376.5 m / z. Activity: A

Example 108

Racemic 3- (pyridin-3-yloxy) -4,5-dihydroisoxazole I-67 was dissolved in a solution of dimethylamine in methanol (2.0 M in tetrahydrofuran, 0.02 M based on isoxazole). The reaction mixture was sealed and allowed to stir at 23 ° C for 72 hours, after which the solvent and excess dimethylamine were removed under a stream of nitrogen to give a light brown solid, which was triturated with hexane to give the desired amide I-111a and I-111b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. [M + H] ⁺ = 405.1 m / z. Activity: A

Example 109

3- (pyrimidin-5-yloxy) -4,5-dihydroisoxazole I-112a and I-112b were prepared in step 1 based on the racemic compound I-14 and 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see the chiral HPLC method disclosed herein. Activity: A

Example 110

Claims (32)

1. The compound of formula (I):

or its pharmaceutically acceptable form, where:
each of R ^a , R ^b and R ^c independently represents —H, C _1-10 alkyl or C _1-10 perhaloalkyl, R ^d represents a —LZ group and Z represents C _6-14 aryl, which may be substituted ( R ¹⁵ ) z, where z is 0, 1, 2, 3, 4 or 5, or unsubstituted, and R ¹⁵ is fluoro, bromo, chloro and iodo, fluorophenyl, C _1-10 perhaloalkyl, SO ₂ N (R ¹⁸ ) ₂ , -OR ¹⁶ , -C (= O) N (R ¹⁸ ) ₂ , C _1-10 alkyl, C _6-14 aryl, R ¹⁶ independently is C _6-14 aryl, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkynyl, 5-14 membered heteroaryl containing 1-4 heteroatoms in the ring present in the aromatic ring the core system, where each heteroatom is independently selected sludge of nitrogen, oxygen and sulfur;
or two adjacent R ¹⁵ groups are replaced by the group —O (C (R ² ) ₂ ) _1-2 O—, where each R ^{2 is} independently halogen;
R ¹⁸ independently represents hydrogen, C _1-10 alkyl, —CH ₂ Ph;
L is a covalent bond;
G represents —OR ^e ; and
R ^e is C _6-14 aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected nitrogen, oxygen and sulfur, and which may be substituted (R ^h ) _x , where x is 0, 1, 2, 3 or 4, and each R ^h independently represents fluorine, bromine, chlorine, iodine, —CN, —NO ₂ , —OR ⁱ , —N (R ^k ) ₂ , -SR ⁱ , -CO ₂ H, -CO ₂ R ⁱ , -OC (= O) R ⁱ , -C (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -C (= O) NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , SO ₂ R ⁱ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _{6 -14} aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms in the ring, present in an aromatic ring system where each heteroatom is independently selected from nitrogen, oxygen and sulfur, where each alkyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups;
in each case, R ⁱ independently represents C _1-10 alkyl, C _3-10 carbocyclyl;
in each case, R ^k independently represents hydrogen, —OH, C _1-10 alkyl, which is independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups;
in each case, R ^m independently represents fluorine, bromine, chlorine, iodine, —OH, —CO ₂ H, —CO ₂ R ^o , —C (= O) N (R ⁿ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl or two adjacent R ^m substituents may be combined to form = O;
in each case, R ^o independently represents C _1-6 alkyl;
in each case, R ⁿ independently represents hydrogen. 2. The compound according to claim 1, where R ^a and R ^b represent —H and R ^c represents —CH ₃ or —CF ₃ . 3. The compound according to claim 1, where each of R ^a , R ^b and R ^c represents —H. 4. The compound according to claim 1, where z has a value of 1. 5. The compound according to claim 4, where the compound is a compound of the formula:

or its pharmaceutically acceptable form. 6. The compound according to claim 5, where the compound is a compound of the formula:

or its pharmaceutically acceptable form,
where R ¹⁶ independently represents C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkynyl or 5-14 membered heteroaryl containing 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur;
or two adjacent R ¹⁵ groups are replaced by the group —O (C (R ² ) ₂ ) _1-2 O—, where each R ^{2 is} independently halogen. 7. The compound according to claim 6, where the compound is a compound of the formula:

or its pharmaceutically acceptable form. 8. The compound according to claim 1, where R ^e represents a 5-14 membered heteroaryl. 9. The compound of claim 8, wherein R ^e is a pyridinyl group of the formula:

x is 0, 1, 2, 3 or 4, and
each R ^h independently represents fluorine, bromine, chlorine, iodine, —CN, —NO ₂ , —OR ⁱ , —N (R ^k ) ₂ , —SR ⁱ , —CO ₂ H, —CO ₂ R ⁱ , —OC (= O) R ⁱ , -C (= O) N (R ^k ) ₂ , -NR ^k C (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -С (= O) NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ¹ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _6-14 aryl or 5-14 membered heteroaryl containing 1-4 heteroatoms in the ring present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, where each alkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^m groups;
in each case, R ⁱ independently represents C _1-10 alkyl, C _3-10 carbocyclyl;
in each case, R ^k independently represents hydrogen, —OH, C _1-10 alkyl, which is independently substituted with 0, 1, 2, 3, 4 or 5 R ^m groups;
in each case, R ^m independently represents fluorine, bromine, chlorine, iodine, —OH, —CO ₂ H, —CO ₂ R ^o , —C (= O) N (R ⁿ ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl or two adjacent R ^m substituents may be combined to form = O;
in each case, R ^o independently represents C ^1-6 alkyl;
in each case, R ⁿ independently represents hydrogen. 10. The compound according to claim 9, where R ^h represents fluorine, bromine, chlorine, iodine, —CN, —NO ₂ , —OR ⁱ , —N (R ^k ) ₂ , SR ⁱ , —CO ₂ H, —CO ₂ R ⁱ , -OC (= O) R ⁱ , -C (= O) N (R ^k ) ₂ , -NR ^k С (= O) R ⁱ , -NR ^k CO ₂ R ⁱ , -C (= O ) NR ^k SO ₂ R ⁱ , -SO ₂ N (R ^k ) ₂ , -SO ₂ R ⁱ , C _1-10 alkyl, C ₆ aryl or 5-6 membered heteroaryl containing 1-4 heteroatoms in the ring, present in an aromatic ring system where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, where each alkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, or 4 R ^m groups. 11. The compound of claim 10, wherein R ^h is —C (═O) R ⁱ , —CO ₂ H, —SO ₂ R ^i, or 5 membered heteroaryl independently substituted with 0 or 1 R ^m group. 12. The compound of claim 11, wherein the 5-membered heteroaryl is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl. 13. The compound according to claim 9, where the pyridinyl group is a 3-pyridinyl group of the formula:

14. The compound of claim 8, where G is —OR ^{e of the} formula:

15. The compound of claim 14, wherein G is:

16. The compound of claims 1-15, wherein the compound is substantially enantiomerically pure. 17. The compound according to claim 1, where the compound is:

Compound G R ^a R ^c I-23

-H -H I-24

-H -H I-25

-H -H I-26

-H -H I-27

-H -H I-28

-H -H I-29

-H -H I-30

-H -H I-31

-H -H I-36

-H -H I-37

-H -H I-39

-H -H I-40

-H -H I-41

-H -H I-42

-H -H
I-43

-H -H I-44

-H -H I-47

-H -H I-56

-H -H I-57

-H -H I-58

-H -H I-59

-H -H I-60

-H -H I-61

-H -H I-62

-H -H I-63

-H -H I-64

-H -H I-65

-H -H I-66

-H -H
I-67

-H -H I-68

-H -H I-69

-H -H I-90

-H -H I-92

-H -H I-93

-H -H I-94

-H -H I-98

-H -H I-99

-H -H I-100

-H -H I-110

-H -H I-111

-H -H I-146

-H -H I-147

-H -H I-155

-H -H
I-159

-H -H I-160

-H -H I-197

-H -H I-257

-H -H I-91 (trans)

-CH ₃ -H I-89

-H -CH ₃ I-131

-H -CF ₃ Compound

R ^a R ^c I-46

-H -H I-53

-H -H I-54

-H -H I-55

-H -H I-70

-H -H
I-71

-H -H I-72

-H -H I-73

-H -H I-83

-H -H I-84

-H -H I-85

-H -H I-86

-H -H I-96

-H -H I-97

-H -H I-105

-H -H I-106

-H -H I-107

-H -H I-108

-H -H
I-109

-H -H I-112

-H -H I-118

-H -H I-128

-H -H I-132

-H -H I-133

-H -H I-134

-H -H I-135

-H -H I-136

-H -H I-151

-H -H I-152

-H -H I-157

-H -H I-161

-H -H I-162

-H -H I-163

-H -H
I-165

-H -H I-173

-H -H I-174

-H -H I-175

-H -H I-176

-H -H I-177

-H -H I-178

-H -H I-182

-H -H I-183

-H -H I-184

-H -H I-186

-H -H I-187

-H -H I-188

-H -H
I-189

-H -H I-190

-H -H I-191

-H -H I-192

-H -H I-193

-H -H I-194

-H -H I-195

-H -H I-199

-H -H I-200

-H -H I-201

-H -H I-218

-H -H I-220

-H -H
I-221

-H -H I-223

-H -H I-224

-H -H I-225

-H -H I-226

-H -H I-230

-H -H I-236

-H -H I-258

-H -H I-88

-H -CH ₃ I-113

-H -CH ₃
I-114

-H -CH ₃ I-115

-H -CH ₃ I-116

-H -CH ₃ I-117

-H -CH ₃ I-129

-H -CH ₃ I-154

-H -CH ₃ I-156

-H -CH ₃ I-158

-H -CH ₃ I-164

-H -CH ₃ I-167

-H -CH ₃ I-172

-H -CH ₃ I-185

-H -CH ₃ I-196

-H -CH ₃
I-198

-H -CH ₃ I-222

-H -CH ₃ I-227

-H -CH ₃ I-228

-H -CH ₃ I-229

-H -CH ₃ I-231

-H -CH ₃ I-232

-H -CH ₃ I-233

-H -CH ₃ I-234

-H -CH ₃
I-235

-H -CH ₃ I-240

-H -CH ₃ I-241

-H -CH ₃ I-242

-H -CH ₃ I-261

-H -CH ₃

Compound G R ^a R ^c I-168

-H -H I-169

-H -H I-170

-H -H I-216

-H -H I-217

-H -H I-219

-H -H
I-238

-H -H I-259

-H -H

Compound G R ^a R ^c R ¹⁵ = halogen I-121

-H -H -F I-122

-H -H -F I-123

-H -H -F I-125

-H -H -Cl

Compound G R ^a R ^c R ¹⁶ = unsubstituted alkyl, alkynyl I-143

-H -H

I-144

-H -H

I-145

-H -H

I-140

-H -H

I-141

-H -H

I-137

-H -H n-butyl I-138

-H -H n-butyl I-139

-H -H n-butyl I-38

-H -H -CH ₃

Compound G R ^a R ^c R ¹⁵ = alkyl, aryl I-180

-H -H n-butyl I-181

-H -H n-butyl I-104

-H -CH ₃ -C ₆ N ₅ I-101

-H -H -C ₆ N ₅ I-103

-H -H -C ₆ N ₅

Compound G R ¹⁵ = halogen I-153

-Cl I-149

-Br
I-150

-Br I-237

-Br

Compound G R ^a R ^c I-87

-H -H

Compound G R ^a R ^c I-166

-H -H

Compound G R ^a R ^c R ² = H, halogen I-127

-H -H -F, -F

Compound G R ^a R ^c R ¹⁸ I-214

-H -H H, -CH ₂ Ph
I-215

-H -H H, -CH ₂ Ph I-212

-H -H -CH ₃ , -CH ₃

Compound G R ³ R ⁰ R ¹⁸ I-213

-H -H -CH ₃ , -CH ₃

or its pharmaceutically acceptable form. 18. The compound according to claim 1, where the compound is:

or its pharmaceutically acceptable form. 19. The compound according to claim 1, where the compound is:

or a pharmaceutically acceptable salt thereof. 20. The compound according to claim 19, where the compound is an (R) enantiomer. 21. The compound according to claim 1, where the compound is a

or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 1, where the compound is a

or a pharmaceutically acceptable salt thereof. 23. The compound according to claim 1, where the compound is a

or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 1, where the compound is a

or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition that inhibits fatty acid amide hydrolase (FAAH), comprising an effective amount of a compound according to claims 1-24 or a pharmaceutically acceptable form thereof and a pharmaceutically acceptable excipient. 26. The pharmaceutical composition according A.25, where the compound is a

or a pharmaceutically acceptable salt thereof. 27. A method of treating an FAAH-mediated condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claims 1-24 or a pharmaceutically acceptable form thereof, wherein the FAAH-mediated condition is selected from a painful condition, inflammatory condition, immune disorders, disorders of the central nervous system, metabolic disorder, heart disorder and glaucoma. 28. The method according to clause 27, where the painful condition is selected from neuropathic pain, central pain, differential pain, chronic pain, postoperative pain, preoperative pain, nociceptive pain, acute pain, non-inflammatory pain, inflammatory pain, cancer-related pain, wound pain, burn pain, pain associated with medical procedures, pain resulting from itching, painful bladder syndrome, pain associated with premenstrual dysphoric disorder, pain associated with premenstrual system droma, pain associated with chronic fatigue syndrome, pain associated with preterm delivery, pain associated with withdrawal symptoms from drug dependence, joint pain, arthritic pain, lumbosacral pain, musculoskeletal pain, headache, migraine, muscle pain, lumbar pain, neck pain, dental pain of dental / maxillofacial pain and visceral pain. 29. The method of claim 27, wherein the inflammatory condition or immune disorder is a gastrointestinal disorder or skin disease. 30. The method of claim 27, wherein the FAAH-mediated condition is a central nervous system disorder selected from neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord lesions, epilepsy, a mental disorder, a condition associated with sleep disturbance, motor disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction. 31. The method of claim 27, wherein the FAAH-mediated condition is a metabolic disorder selected from a depletion-related condition or an obesity-related condition or its complications. 32. The method of claim 27, wherein the FAAH-mediated condition is a heart disorder selected from hypertension, circulatory shock, reperfusion myocardial damage, and atherosclerosis.