AMINOTRIAZOLES FOR THE TREATMENT OF DEMYELINATING DISEASES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/430,813, filed December 6, 2016, the entire contents of which are hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system, characterized by myelin loss and degeneration of axons (see, Blakemore, et al., J. ofNeuroimmunology, 98, 69-76, 1999). Activation and CNS infiltration of the peripheral immune system is typical in early stages of the disease, but can become less prevalent as disease progresses.

[0003] A hallmark of MS is loss of myelin, accompanied by the death of associated oligodendrocytes (see, Merrill, J.E. et al., Neuropathology and Applied Neurobiology, 25, 435-458, 1999). Myelin, which is produced by oligodendrocytes, ensheathes axons and dramatically increases conduction velocity of neural impulses while providing trophic support to the neuron. Myelin is thought to regenerate early in disease, as oligodendroycte progenitor cells (OPCs) proliferate and generate new myelinating oligodendrocytes in response to demyelination events. As the disease progresses the regenerative capacity of the OPCs becomes less robust, and axons remain chronically demyelinated. Chronic demyelination is thought to underlie axon loss, as loss of trophic support combined with the metabolic stress of transmitting impulses along a demyelinated membrane can lead to a breakdown of axonal integrity and permanent damage to the demyelinated circuit. In addition, exposure of a demyelinated axon to an inflammatory milieu, including infiltrating immune cells and activated microglial cells, is also thought to produce permanent damage and axonal loss. Axon loss as a result of demyelination is thought to underlie long term disease progression and disability in MS patients (see, Compston, et a\.,The Lancet, Vol. 359, 1221-1231, 2002 and D. Kremer et al, Trends in Neurosciences, Vol. 39, No. 4, 246- 263, 2016).

[0004] The loss of remyelinating capacity in MS is not well understood, but is thought to involve a block in the differentiation capacity of OPCs, or the absence of a necessary signal present in the cell environment of the demyelinating lesion or in the demyelinated axons (see, R. Franklin et al., Nature Review s/Neuroscience, Vol. 9, 839-855, 2008). The OPC cell population is prevalent in MS patients, but fails to generate new myelin in response to demyelination. Thus, a compound that can promote differentiation and myelination of OPCs should function to restore this regenerative capacity and blunt or reverse the degenerative effects of MS (see, Stangel, M. et al., Progress in Neurobiology, 68, 361-376, 2002, Nairn, F. J. et al., Nature (Letter), published online 20 April 2015, doi: 10.1038/naturel4335). Such an agent could both increase the function of neurons and provide trophic support to enhance their survival (see, Mei, F. et al. Nature Medicine, Vol. 20, No. 8, 954-961, 2014).

[0005] Leukodystrophies are degenerative white matter diseases characterized by dysmyelination or demyelination. Multiple genetic or metabolic disorders can lead to progressive white matter damage in pediatric or adult populations resulting in severe motor or cognitive deficits, mental retardation or death. A compound that can delay myelin damage or promote repair of demyelinated axons could significantly alter the course of leukodystrophies and improve their outcome. Such a compound could be also useful in combination with other therapies that can correct the disease-specific defect, metabolic, genetic or other, responsible for initiating or maintaining the disease in order to accelerate repair, restore function or prevent further damage.

[0006] Hypoxic-ischemic insults leading to reduced oxygenation and blood supply into the brain can cause severe damage to OPCs, and demyelination. Periventricular leukomalacia is a condition characterized by toxic death of OPCs in the

periventricular region and leading to severe dysmyelination and demyelination. This pathology has been proposed as the root cause of cerebral palsy, a life-long debilitating CNS disorder characterized by various motor and/or cognitive deficits of variable intensity. A compound promoting differentiation of surviving OPCs and remyelination of damaged areas could be used for the treatment or prevention of cerebral palsy in vulnerable infant populations.

[0007] Current therapies for MS are immunomodulatory in nature and do not directly promote repair. In addition, some of these immunomodulatory agents can leave patients vulnerable to opportunistic infection or neoplasia. Thus, there remains a need for compounds, such as those of the present invention, that can promote differentiation and myelination of OPCs and lead to the repair of demyelinated axons. Such a compound could also be useful in combination with existing or experimental immunmodulating and other relevant therapies to treat MS and other neurological and demyelinating diseases.

SUMMARY OF THE INVENTION

[0008] The present invention provides compounds or a pharmaceutically acceptable salt thereof and the methods, compositions and kits disclosed herein for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy. These compounds have the general formula (Γ):

(Γ)

[0009] wherein:

[0010] A is selected from the group consisting of (i), (ii), (iii), (iv), (v), and (vi)

(ϋ) iii)

[0011] X ¹ is N or CR ¹ ;

[0012] X ² is N or CR ² ;

[0013] X ³ is N or CR ³ ;

[0014] X ⁴ is N or CR ⁴ ; 0015] X ⁵ is N or CR ⁵ ;

[0017] A ¹ is N or CH;

[0018] A ² is -CH2-, -0-, or -N(R ¹¹⁰ )-;

[0019] Y ¹ is -CH2-, -0-, or -N(R ¹²⁰ )-;

[0020] Y ² is -CH2-, -0-, or -N(R ¹¹⁰ )-;

[0021] R ¹⁰⁰ is hydrogen, Ci-4alkyl, -Ci-6alkylene-OCi-4alkyl, or -Ci-6alkylene- OH;

[0022] R ¹¹⁰ is hydrogen, Ci- ₄ alkyl, or C(0)Ci- ₄ alkyl;

[0023] R ¹²⁰ is R ⁶ , hydrogen, Ci- ₄ alkyl, C(0)Ci- ₄ alkyl, -Ci-6alkylene-OCi-4alkyl, or -Ci- ₆ alkylene-OH;

[0024] R ¹ and R ⁵ are each independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl;

[0025] R ² is selected from the group consisting of -L ¹ -^, hydrogen, Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -OC3- ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), -NR ²⁰ C(O)OCi-4alkyl, - C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci-4haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- 6haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi-4alkyl)-Ci-3alkylene-R ²¹ , -L ² -C2- 4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2-4alkylene- R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi-4alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi-4alkyl;

[0026] R ³ is selected from the group consisting of -L ³ -G ^B , hydrogen, Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi-4alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; [0027] R ⁴ is selected from the group consisting of hydrogen, Ci-4alkyl, Ci- 4haloalkyl, halogen, -OCi-4alkyl, -OCi-4haloalkyl, and G ^c ;

[0028] L ¹ is a bond, -0-, - R ¹⁰ -, -NR ¹⁰ -Ci-4alkylene- -0-Ci- ₄ alkylene-, -Ci- ₄ alkylene-, -C(0) R ¹⁰ -, -NR ¹⁰ C(O)-, or -C(O)-;

[0029] L ² is a bond, -0-, - H-, -N(Ci-4alkyl)-, - HC(O)-, or -N(Ci- ₄ alkyl)C(0)-;

[0030] L ³ is a bond, -0-, -NR ³⁰ -, -NR ³⁰ -Ci-4alkylene- -0-Ci- ₄ alkylene-, -Ci- ₄ alkylene-, -C(0)NR ³⁰ -, -NR ³⁰ C(O), or -C(O)-;

[0031] R ¹⁰ , at each occurrence, is independently selected from the group consisting of hydrogen, Ci-4alkyl, C(0)Ci-4alkyl, oxetanyl, cyclopropyl, and cyclobutyl;

[0032] R ³⁰ , at each occurrence, is independently selected from the group consisting of hydrogen, Ci-4alkyl, C(0)Ci-4alkyl, oxetanyl, cyclopropyl, and cyclobutyl;

[0033] R ²⁰ and R ⁴⁰ , at each occurrence, are each independently hydrogen or Ci- 4alkyl;

[0034] R ²¹ is -OCi- ₄ alkyl, OH, CN, -NH ₂ , -NH(Ci- ₄ alkyl), -N(Ci-4alkyl)(Ci- ₄ alkyl), -C(0)NH ₂ , -C(0)NH(Ci- ₄ alkyl), -C(0)N(Ci-4alkyl)(Ci-4alkyl), - NHC(0)OCi- ₄ alkyl, -N(Ci-4alkyl)C(0)OCi-4alkyl, -NHC(0)Ci- ₄ alkyl, -N(Ci- ₄ alkyl)C(0)Ci-4alkyl, -NHS(0) ₂ Ci- ₄ alkyl, -N(Ci-4alkyl)S(0) ₂ Ci-4alkyl, or -C(0)Ci- 4alkyl;

[0035] G ^A is selected from the group consisting of -G^R ⁷ , G ^2A , G ^3A , G ^4A , G ^5A , G ^6A , G ^7A , and G ^8A ;

[0036] G ⁶ is selected from the group consisting of -G^R ⁷ , G ²¹³ , G ^3B , G ^4B , G ^5B , G ^6B , and G ^7B ;

[0037] G ^c is selected from the group consisting of G ^6C and G ^8C ;

[0038] G ¹ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms, G ¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-

4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, and oxo; [0039] R ⁶ is (a) a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being attached at a ring carbon ring atom of R ⁶ and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, -CH2S(0)2phenyl, halogen, hydroxyl, oxo, -OCi-4alkyl, -Ci- ₆ alkylene- OCi-4alkyl, and -Ci- ₆ alkylene-OH; or (b) a C3-scycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, -C(0)OCi- ₄ alkyl, -C(0)OH, oxo, -OCi- ₄ alkyl, -Ci- 6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH;

[0040] R ⁷ is (a) a 4- to 12-membered heterocycle containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the heterocycle being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, -CH2S(0)2phenyl, halogen, hydroxyl, oxo, - OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH; (b) a C3-scycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -C(0)OCi-4alkyl, -C(0)OH, oxo, -OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH; (c) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -C(0)OCi-4alkyl, -C(0)OH, -OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH; or (d) a 5- or 6- membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH;

[0041] G ^2A and G ^2B are each independently a 4- to 8-membered monocyclic heterocycle containing 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur, G ^2A and G ²³ optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms, wherein G ^2A and G ^2B are attached to L ¹ or L ³ , respectively, through a ring nitrogen of G ^2A or G ^2B , and are independently optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, oxo, cyano, -OCi-4alkyl, -C(0)Ci-4alkyl, -C(0)OCi- ₄ alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH;

[0042] G ^3A and G ^3B are each independently a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G ^3A and G ^3B optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, wherein G ^3A and G ^3B are attached to L ¹ or L ³ , respectively, at a ring carbon ring atom of G ^3A or G ^3B , and are independently optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, oxo, cyano, -OCi- ₄ alkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH;

[0043] G ^4A and G ^4B are each independently a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8- membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L ^l or L ³ , respectively, the second ring being a C3-scycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle;

[0044] G ^5A and G ^5B are each independently a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; wherein G ^4A , G ^4B , G ^5A and G ^5B are independently optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, and oxo;

[0045] G ^6A , G ^6B , and G ^6C are each independently a C3-scycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, oxo, - HC(0)(Ci- ₄ alkyl), -N(Ci- 4alkyl)C(0)(Ci- ₄ alkyl), -C(0)OCi- ₄ alkyl, -C(0)OH, -OCi- ₄ alkyl, -Ci-ealkylene- OCi-4alkyl, and -Ci- ₆ alkylene-OH;

[0046] G ^7A and G ^7B are each independently a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, G ^7A and G ^7B being optionally substituted with 1-3 substituents

independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, and cyano; [0047] G and G are each independently phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, and cyano;

[0048] R ⁸ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R ⁸ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, -S(0)2Ci-4alkyl, -S(0)Ci-4alkyl, -SCi- 4alkyl, Ci-4alkyl, Ci-4haloalkyl, -C ₃ - ₆ alkenyl, -OCi-4alkyl, -OCi-4haloalkyl, -Ci- 4alkylene-OCi- ₄ alkyl, -Ci-4alkylene-N(Ci-4alkyl)(Ci-4alkyl), - H(Ci-4alkylene-OCi- ₄ alkyl), - H(Ci- ₄ alkylene-OH), -N(Ci-4alkyl)(Ci-4alkylene-OCi-4alkyl), -N(Ci- ₄ alkyl)(Ci-4alkylene-OH), - H ₂ , - H(Ci- ₄ alkyl), -N(Ci-4alkyl)(Ci-4alkyl), - C(0) H ₂ , -C(0) H(Ci- ₄ alkyl), -C(0)N(Ci-4alkyl)(Ci-4alkyl), -L ⁴ -G ¹⁰ , C ₃ - 6cycloalkyl, C5-6cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, and optionally an oxygen or sulfur atom, the monocyclic heterocycle optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, the C ₃ -6cycloalkyl, the C5-6cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, hydroxyl, -OCi-4alkyl, Ci-4alkyl, Ci-4haloalkyl, -Ci-4alkylene-OCi-4alkyl, and -Ci-4alkylene-OH;

[0049] L ⁴ is -0-, - R ⁹ -, - R ⁹ -Ci- ₄ alkylene-, or -0-Ci- ₄ alkylene-;

[0050] R ⁹ , at each occurrence, is independently hydrogen or Ci-4alkyl; and

[0051] G ¹⁰ is phenyl or a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, G ¹⁰ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, and cyano;

[0052] wherein

(a) no more than one of X ¹ , X ² , X ³ , X ⁴ , or X ⁵ is N;

(b) at least one of X ² and X ³ is other than N or CH;

(c) no more than three of X ¹ , X ² , X ³ , X ⁴ , or X ⁵ are other than N or CH;

(d) R ² and R ³ are not simultaneously -I^-G^R ⁷ ;

(e) R ³ is -L ³ -G ¹ -R ⁷ , -L ³ -G ^3B , -L ³ -G ^4B , or-L ³ -G ^5B , when X ¹ , X ² , X ⁴ , and X ⁵ are N or CH; (f) R ² is not -OCi-4alkyl, morpholino or -NH-Ci-4alkylene-morpholino when X ³ is N or CH, X ¹ , X ⁴ and X ⁵ are CH, and R ⁸ is phenyl or 4-cyanophenyl;

(g) R ² , R ³ , and R ⁴ are not simultaneously -OCi-4alkyl when R ⁸ is phenyl or 4- cyanophenyl; and

(h) R ² is not cyano when R ³ is an imidazolyl optionally substituted with one or two Ci-4alkyl.

[0053] In another aspect, the present invention provides compounds of formula (Γ)·

[0054] Another aspect of the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of a compound of formula (Γ), or a pharmaceutically acceptable salt thereof.

[0055] In another aspect, the invention provides compounds of formula (Γ), or a pharmaceutically acceptable salt thereof, which promote remyelination of

demyelinated axons.

[0056] In another aspect, the invention provides compounds of formula (Γ), or a pharmaceutically acceptable salt thereof, which differentiate endogenous

oligodendrocyte precursor cells.

[0057] In another aspect, the invention provides methods of treating multiple sclerosis by administering to a patient in need thereof a therapeutically effective amount of a compound or composition of formula (Γ), or a pharmaceutically acceptable salt thereof.

[0058] In another aspect, the present invention provides a method of treating, preventing or ameliorating one or more symptoms of a subject with multiple sclerosis or another neurological disease.

[0059] In another aspect, the invention provides the use of a compound of formula (Γ), or a pharmaceutically acceptable salt thereof, for the manufacture of a

medicament for the treatment of multiple sclerosis, the promotion of remyelination of demyelinated axons, or the differentiation of endogenous oligodendrocyte precursor cells.

[0060] In another aspect, the invention provides compounds of formula (Γ), or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis, promoting remyelination of demyelinated axons, or differentiating endogenous oligodendrocyte precursor cells.

[0061] In another aspect, the invention provides compounds of formula (Γ), or a pharmaceutically acceptable salt thereof for treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a

1 eukody strophy in .

[0062] In another aspect, the invention provides compounds of formula (Γ), or a pharmaceutically acceptable salt thereof

[0063] In another aspect, the invention provides compounds of formula (Γ), or a pharmaceutically acceptable salt thereof can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.

[0064] The present invention also features kits comprising compounds of formula

(Γ)·

DETAILED DESCRIPTION OF THE INVENTION

[0065] 1. Definitions

[0066] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of

Chemistry and Physics, 75 ^th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 ^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0067] As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables in formula I encompass specific groups, such as, for example, alkyl and cycloalkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0068] The phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted ." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0069] The compounds of the invention are defined according to the terms in the claims and the embodiments. The following definitions are provided as a general guide to understanding the claims and embodiments and are applicable where specific definitions are absent. [0070] The term "alkyl" as used herein, means a straight or branched chain saturated hydrocarbon. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. [0071] The term "alkylene," as used herein, means a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH ₂ CH(CH ₃ )CH ₂ -, and -CH ₂ CH(CH ₃ )CH(CH ₃ )CH ₂ -.

[0072] The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0073] The term "aryl," as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl. The phenyl and bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl or bicyclic aryl.

[0074] The term "halogen" means a chlorine, bromine, iodine, or fluorine atom.

[0075] The term "haloalkyl," as used herein, means an alkyl, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen. For example, representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoro-l,l-dimethylethyl, and the like.

[0076] The term "haloalkoxy," as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. Representative examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2- fluoroethoxy, and pentafluoroethoxy.

[0077] The term "heteroaryl," as used herein, means an aromatic heterocycle, i.e., an aromatic ring that contains at least one heteroatom. A heteroaryl may contain from 5 to 12 ring atoms. A heteroaryl may be a 5- to 6-membered monocyclic heteroaryl or an 8- to 12-membered bicyclic heteroaryl. A 5-membered monocyclic heteroaryl ring contains two double bonds, and one, two, three, or four heteroatoms as ring atoms. Representative examples of 5-membered monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl. A 6- membered heteroaryl ring contains three double bonds, and one, two, three or four heteroatoms as ring atoms. Representative examples of 6-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic heteroaryl is an 8- to 12-membered ring system having a monocyclic heteroaryl fused to an aromatic, saturated, or partially saturated carbocyclic ring, or fused to a second monocyclic heteroaryl ring. Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzothienyl, indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H-cyclopenta[b]pyridinyl. The heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups.

[0078] The term "cycloalkyl" as used herein, means a monocyclic all-carbon ring containing zero heteroatoms as ring atoms, and zero double bonds. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.

[0079] The term "cycloalkenyl" as used herein, means a monocyclic non-aromatic all-carbon 5- to 6-membered ring containing zero heteroatoms as ring atoms and one double bond. Examples of cycloalkenyl include cyclopentenyl and cyclohexenyl. The cycloalkenyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.

[0080] The terms "heterocycle" or "heterocyclic" refer generally to ring systems containing at least one heteroatom as a ring atom where the heteroatom is selected from oxygen, nitrogen, and sulfur. In some embodiments, a nitrogen or sulfur atom of the heterocycle is optionally substituted with oxo. Heterocycles may be a monocyclic heterocycle, a fused bicyclic heterocycle, or a spiro heterocycle. The monocyclic heterocycle is generally a 4, 5, 6, 7, or 8-membered non-aromatic ring containing at least one heteroatom selected from O, N, or S. The 4-membered ring contains one heteroatom and optionally one double bond. The 5-membered ring contains zero or one double bond and one, two or three heteroatoms. The 6, 7, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms.

Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl , 4,5- dihydroisoxazol-5-yl, 3,4-dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl,

thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1, 1- dioxidothiomorpholinyl, thiopyranyl, and trithianyl. The fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle fused to a phenyl, to a saturated or partially saturated carbocyclic ring, or to another monocyclic heterocyclic ring, or to a monocyclic heteroaryl ring. Representative examples of fused bicyclic heterocycle include, but are not limited to, l,3-benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro-lH-furo[3,4-c]pyrrolyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 2,3-dihydro- lH-indolyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, and 1,2,3,4- tetrahydroquinolinyl. Spiro heterocycle means a 4, 5-, 6-, 7-, or 8-membered monocyclic heterocycle ring wherein two of the substituents on the same carbon atom form a second ring having 3, 4, 5, 6, 7, or 8- members. Examples of a spiro heterocycle include, but are not limited to, l,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 8-azaspiro[4.5]decane. The monocyclic heterocycle groups of the present invention may contain an alkylene bridge of 1, 2, or 3 carbon atoms, linking two non-adjacent atoms of the group.

Examples of such a bridged heterocycle include, but are not limited to, 2,5- diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, and oxabicyclo[2.2.1]heptanyl. The monocyclic, fused bicyclic, and spiro heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group.

[0081] The term "oxo" as used herein refers to an oxygen atom bonded to the parent molecular moiety. An oxo may be attached to a carbon atom or a sulfur atom by a double bond. Alternatively, an oxo may be attached to a nitrogen atom by a single bond, i.e., an N-oxide.

[0082] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "Ci-4alkyl," "C3-6cycloalkyl," "Ci-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the

representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "C3alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "Ci-4, " the members of the group that follows may have any number of carbon atoms falling within the recited range. A "Ci-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0083] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula I. The structures also include zwitterioinc forms of the compounds or salts of formula I where appropriate.

[0084] 2. Compounds

[0085] In one aspect of the invention are rovided compounds of formula (I)

[0086] or a pharmaceutically acceptable salt thereof, wherein R ⁸ , X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are as defined herein. [0087] In another aspect of the invention are provided compounds of formula (X),

(X)

[0088] or a pharmaceutically acceptable salt thereof, wherein R ⁸ , R ² , and are as defined herein.

[0089] In another aspect of the invention are provided compounds of formula

(xi),

[0090] or a pharmaceutically acceptable salt thereof, wherein R is as defined herein.

[0091] In another aspect of the invention are provided compounds of formula (XII),

[0092] or a pharmaceutically acceptable salt thereof, wherein R ⁸ , A ¹ , and R ¹⁰⁰ are as defined herein.

[0093] In another aspect of the invention are provided compounds of formula (XIII),

[0094] or a pharmaceutically acceptable salt thereof, wherein R ⁸ , A ² , and Y ¹ are as defined herein.

[0095] In another aspect of the invention are provided compounds of formula (XIV),

(XIV)

[0096] or a pharmaceutically acceptable salt thereof, wherein R ⁸ and Y ² are as defined herein.

[0097] In some embodiments, compounds of formula (I) may be represented by formula (II), wherein X ² is CR ² , R ² is -L ^l -G ^A , G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A , and X ³ is as defined in formula (I), or X ³ is CR ³ , R ³ is -L ³ -G ^B , G ⁶ is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B , and X ² is as defined in formula (I); provided that G ^A and G ^B are not

simultaneously -G^R ⁷ ; and wherein R ⁸ , X ¹ , X ⁴ , X ⁵ , L ¹ and L ³ are as defined in formula (I).

(II)

[0098] In some embodiments, the compounds of formula (II) may have formula (IIA) or (IIB), wherein X^X ⁵ , L ¹ , L ³ , G ^A , G ^B , and R ⁸ are as defined in formula (II). In some embodiments of formulas (I), (II), (IIA), or (IIB), one of G ⁴ and G ⁶ is -G ¹ - R ⁷ .

(IIA) (IIB)

[0099] In some embodiments of formula (IIA), G ^A is -G^R ⁷ ; X ³ is N or CR ³ ; and R ³ is L ³ -G ^2B . In some embodiments of formula (IIA), G ^A is -G^R ⁷ ; X ³ is N or CR ³ ; and R ³ is L ³ -G ^3B . In some embodiments of formula (IIA), G ^A is -G^R ⁷ ; X ³ is N or CR ³ ; and R ³ is L ³ -G ^4B . In some embodiments of formula (IIA), G ^A is -G^R ⁷ ; X ³ is N or CR ³ ; and R ³ is L ³ -G ^5B . In some embodiments of formula (IIA), G ^A is -G^R ⁷ ; X ³ is N or CR ³ ; and R ³ is L ³ -G ^6B . In some embodiments of formula (IIA), G ⁴ is -G ¹ - R ⁷ ; X ³ is N or CR ³ ; and R ³ is L ³ -G ^7B . In some embodiments of formula (IIA), G ^A is - G^R ⁷ ; X ³ is N or CR ³ ; and R ³ is selected from the group consisting of hydrogen, Ci- 4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, - C(0)Ci-4alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ .

[00100] In some embodiments of formula (IIB), G ^B is -G^R ⁷ ; X ² is N or CR ² ; and R ² is L ¹ ^. In some embodiments of formula (IIB), G ^B is -G^R ⁷ ; X ² is N or CR ² ; and R ² is L ¹ -G ^3A . In some embodiments of formula (IIB), G ^B is -G^R ⁷ ; X ² is N or CR ² ; and R ² is L ¹ -G ^4A . In some embodiments of formula (IIB), G ⁶ is -G^R ⁷ ; X ² is N or CR ² ; and R ² is V-G ^5A . In some embodiments of formula (IIB), G ^B is -G^R ⁷ ; X ² is N or CR ² ; and R ² is I^-G^. In some embodiments of formula (IIB), G ^B is -G ¹ - R ⁷ ; X ² is N or CR ² ; and R ² is V-G ^7A . In some embodiments of formula (IIB), G ^B is - G^R ⁷ ; X ² is N or CR ² ; and R ² is L ¹ -G ^8A . In some embodiments of formula (IIB), G ⁸ is -G^R ⁷ ; X ² is N or CR ² ; and R ² is selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci-4haloalkyl), -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi-4alkyl)-Ci-3alkylene- R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2- 4alkylene-R ²¹ , -C ₃ -8alkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi-4alkyl, -C ₃ - 8alkynylene-OH, and -C ₃ -8alkynylene-OCi-4alkyl. [00101] In some embodiments of formulas (I), (II), (IIA), or (IIB), G ^A is selected from the group consisting of G ^3A , G ^4A , and G ^5A ; and/or G ^B is selected from the group consisting of G ^3B , G ^4B , and G ^5B . For example, in some embodiments of formula (IIA), G ^A is selected from the group consisting of G ^3A , G ^4A , and G ^5A ; X ³ is N or CR ³ ; and R ³ is selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ . In some embodiments of formula (IIB), G ⁶ is selected from the group consisting of G ^3B , G ^4B , and G ^5B ; X ² is N or CR ² ; and R ² is selected from the group consisting of hydrogen, Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OC ₃ -6alkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, -NR ²⁰ R ²⁰ , - R ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene- C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -8alkenylene-OH, - C ₃ -8alkenylene-OCi- ₄ alkyl, -C ₃ -8alkynylene-OH, and -C ₃ -8alkynylene-OCi- ₄ alkyl.

[00102] In other embodiments, are compounds of formula (IIA) wherein X ⁴ is CH or N when X ³ is CH or N and R ² is -L ¹ -^.

[00103] In some embodiments of formula (IIA) are compounds wherein X ¹ , X ³ , X ⁴ , and X ⁵ are each independently N or CH; and G ⁴ is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In one embodiment, G ^A is -G^R ⁷ . In another embodiment, G ^A is G ^3A . In another embodiment, G ^A is G ^4A . In another embodiment, G ^A is G ^5A . In each of the foregoing embodiments are further embodiments wherein X ³ and X ⁵ are independently N or CH, and X ¹ and X ⁴ are each CH. In each of the foregoing embodiments are further embodiments wherein X ⁵ is N and X ¹ , X ³ , and X ⁴ are each CH. In other embodiments, X ³ is N and X ¹ , X ⁴ , and X ⁵ are each CH. In yet other embodiments, X ¹ , X ³ , X ⁴ , and X ⁵ are each CH.

[00104] In some embodiments of formula (IIB) are compounds wherein X ¹ , X ² , X ⁴ , and X ⁵ are each independently N or CH; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In one group of compounds, G ^B is -G^R ⁷ . In another group of compounds, G ^B is G ^3B . In another group of compounds, G ^B is G ^4B . In another group of compounds, G ⁶ is G ^5B . In each of the foregoing embodiments are further embodiments wherein X ¹ , X ³ , X ⁴ , and X ⁵ are each CH. [00105] In some embodiments of formula (IIA) are compounds wherein X ¹ and X ⁵ are each independently N or CH; X ³ is CR ³ ; R ³ is selected from the group consisting of -I^-G ⁶ , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A .

[00106] In some embodiments of compounds of formula (IIA), X ¹ , X ⁴ , and X ⁵ are each independently N or CH; X ³ is CR ³ ; R ³ is selected from the group consisting of - L ³ -G ^B , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In either of the foregoing embodiments are further embodiments wherein R ³ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, - OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ . In further embodiments, R ³ is G ^3B , Ci-4alkyl, halogen, or -OCi-4alkyl. In further embodiments, L ¹ is a bond, G ⁴ is G ^3A , and R ³ is G ^3B . In further embodiments according to the foregoing, X ¹ is N or CH, and X ⁴ and X ⁵ are each CH. In some embodiments, X ¹ , X ⁴ , and X ⁵ are each CH. In other embodiments, X ¹ is N, and X ⁴ and X ⁵ are each CH.

[00107] In other embodiments of formula (IIA), X ¹ and X ⁵ are each independently N or CH; X ³ is CR ³ ; R ³ is selected from the group consisting of -I^-G ⁶ , Ci-4alkyl, Ci- 4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -C(0)Ci-4alkyl, - C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O)NR ⁴⁰ R ⁴⁰ ; X ⁴ is CR ⁴ ; R ⁴ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi- 4haloalkyl; and G ⁴ is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In further embodiments according to the foregoing, R ³ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, - OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ . In further embodiments, R ³ is Ci-4alkyl or -OCi-4alkyl; and R ⁴ is Ci-4alkyl. In still further embodiments, one of X ¹ and X ⁵ is N and the other CH. In yet other embodiments, X ¹ and X ⁵ are each CH.

[00108] In other embodiments, are compounds of formula (IIB), wherein X ¹ and X ⁵ are each independently N or CH; X ² is CR ² ; R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci- ₄ haloalkyl), -NR ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi- ₄ alkyl)-Ci-3alkylene- R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi- ₄ alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi- ₄ alkyl; and G ⁶ is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B .

[00109] In some embodiments of compounds of formula (IIB), X ¹ , X ⁴ , and X ⁵ are each independently N or CH; X ² is CR ² ; R ² is selected from the group consisting of - I^-G ⁴ , Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OC ₃ - ₆ alkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene-C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene- R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ - ₈ alkenylene-OH, -C ₃ - ₈ alkenylene-OCi- ₄ alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi- ₄ alkyl; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In further embodiments, R ² is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, nitro, hydroxyl, - OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OC ₃ - ₆ alkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci- ₄ haloalkyl), -L ² - Ci-6alkylene-R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene-C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2-

₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ - ₈ alkenylene-OH, -C ₃ - ₈ alkenylene- OCi- ₄ alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi- ₄ alkyl. In further embodiments, R ² is selected from the group consisting of Ci- ₄ alkyl, halogen, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, or -OC ₃ - ₆ alkenyl and/or G ^B is -G^R ⁷ or G ^3B . In further embodiments, X ¹ is N or CH, and X ⁴ and X ⁵ are each CH. In some embodiments, X ¹ , X ⁴ , and X ⁵ are each CH. In other embodiments, X ¹ is N, and X ⁴ and X ⁵ are each CH.

[00110] In other embodiments of formula (IIB), X ¹ and X ⁵ are each independently N or CH; X ² is CR ² ; R ² is selected from the group consisting of -L ^l -G ^A , Ci- ₄ alkyl, Ci- 4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -OC3- ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), -NR ²⁰ C(O)OCi- ₄ alkyl, - C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ehaloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi- ₄ alkyl)-Ci-3alkylene-R ²¹ , -L ² -C ₂ - ₄ alkylene-0-C ₂ - ₄ alkylene-R ²¹ , -L ² -C ₂ - ₄ alkylene-0-C ₂ - ₄ alkylene-0-C ₂ - ₄ alkylene- R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi- ₄ alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi- ₄ alkyl; X ⁴ is CR ⁴ ; R ⁴ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In further embodiments, R ² is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OC ₃ - ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), -NR ²⁰ C(O)OCi- ₄ alkyl, - C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci-

6haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene-C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C ₂ - ₄ alkylene-0-C ₂ - ₄ alkylene-R ²¹ , -L ² -C ₂ - ₄ alkylene-0-C ₂ - ₄ alkylene-0-C ₂ - ₄ alkylene- R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ - ₈ alkenylene-OH, -C ₃ - ₈ alkenylene-OCi- ₄ alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi- ₄ alkyl. In further embodiments, R ² is halogen, R ⁴ is halogen, L ³ is a bond, and G ⁶ is G ^3B . In further embodiments of formula (IIB), one of X ¹ and X ⁵ is N and the other CH. In yet other embodiments of formula (IIB), X ¹ and X ⁵ are each CH.

[00111] In other embodiments of formula (IIA) are compounds wherein X ³ and X ⁴ are each independently N or CH; X ¹ is CR ¹ ; R ¹ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A .

[00112] In some embodiments of formula (IIA), X ³ , X ⁴ , and X ⁵ are each independently N or CH; X ¹ is CR ¹ ; R ¹ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In further embodiments, R ¹ is Ci- ₄ alkyl and/or G ^A is G^R ⁷ or G ^3A . In further embodiments, X ³ , X ⁴ , and X ⁵ are each CH. [00113] In other embodiments of formula (IIA) are compounds wherein X ³ and X ⁴ are each independently N or CH; X ¹ is CR ¹ ; R ¹ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In further embodiments, R ¹ is Ci- ₄ alkyl, R ⁵ is Ci- ₄ alkyl, and/or G ^A is G^R ⁷ . In further embodiments, X ³ and X ⁴ are each CH.

[00114] In other embodiments are compounds of formula (II), wherein X ¹ is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; and R ⁵ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl.

[00115] In other embodiments are compounds of formula (IIA), wherein X ¹ is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A .

[00116] In other embodiments are compounds of formula (IIA), wherein X ¹ is N or CH; X ³ is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ^A is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In further embodiments, R ⁵ is Ci- ₄ alkyl. In other embodiments, X ¹ is CH; X ³ is N or CH; and X ⁴ is N or CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is N. In other embodiments, X ¹ is CH; X ³ is N; and X ⁴ is CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is CH.

[00117] In other embodiments are compounds of formula (IIA), wherein X ¹ is N or CH; X ⁴ is N or CH; X ³ is CR ³ ; R ³ is selected from the group consisting of -I^-G ⁶ , Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, - C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and G ⁴ is selected from the group consisting of -G^R ⁷ , G ^3A , G ^4A , and G ^5A . In further embodiments, R ³ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, - C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl. In further embodiments, R ³ is halogen, R ⁵ is halogen, L ¹ is a bond, and/or G ^A is G ^3A . In other embodiments according to the foregoing

embodiments of formula (IIA), X ¹ is CH; and X ⁴ is CH.

[00118] In other embodiments are compounds of formula (IIB), wherein X ¹ is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In other embodiments are compounds of formula (IIB), wherein X ¹ is N or CH; X ² is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In further embodiments, R ⁵ is Ci-4alkyl or halogen, and/or G ^B is -G ¹ - R ⁷ . In other embodiments, X ¹ is CH; X ² is CH; and X ⁴ is CH.

[00119] In other embodiments are compounds of formula (IIB), wherein X ¹ is N or CH; X ⁴ is N or CH; X ² is CR ² ; R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci-4haloalkyl), -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi-4alkyl)-Ci-3alkylene- R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2- 4alkylene-R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi-4alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi-4alkyl; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi- 4haloalkyl; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In other embodiments are compounds of formula (IIB), wherein X ¹ is N or CH; X ⁴ is N or CH; X ² is CR ² ; R ² is selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -OC ₃ - ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), -NR ²⁰ C(O)OCi-4alkyl, - C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci-4haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ehaloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene-C(H)(OCi-4alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C ₂ - 4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2-4alkylene- R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ - ₈ alkenylene-OH, -C ₃ - ₈ alkenylene-OCi-4alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi-4alkyl; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi- 4haloalkyl; and G ^B is selected from the group consisting of -G^R ⁷ , G ^3B , G ^4B , and G ^5B . In other embodiments according to the foregoing description of formula (IIB), X ¹ is CH; and X ⁴ is CH.

[00120] In some embodiments, compounds of formula (I) may be represented by formula (III), wherein X ¹ , X ³ , X ⁴ , and X ⁵ are each independently N or CH; R ² is selected from the group consisting of -I^-G ⁴ , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -OC ₃ - ₆ alkenyl, -C(0)Ci-4alkyl, COOH, -C(0)OCi- ₄ alkyl, -NR ²⁰ R ²⁰ , - R ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene- C(H)(OCi-4alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2- 4alkylene-0-C2-4alkylene-0-C2-4alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -salkenylene-OH, - C ₃ -8alkenylene-OCi-4alkyl, -C ₃ -salkynylene-OH, and -C ₃ -8alkynylene-OCi-4alkyl; and G ⁴ is selected from the group consisting of G? ^A , G ^6A , G ^7A , and G ^8A ; provided that R ² is not morpholino or - H-Ci-4alkylene-morpholino when X ³ is N, X ¹ , X ⁴ and X ⁵ are CH, and R ⁸ is phenyl or 4-c anophenyl.

(III)

In some embodiments of formula (III), as defined above, R ² is selected from the group consisting of -I^-G ⁴ , Ci-4alkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi-

₄ haloalkyl, COOH, - R ²⁰ R ²⁰ , - R ²⁰ C(O)(Ci-4alkyl), -C(O) R ²⁰ R ²⁰ , and -L ² -Ci- ealkylene-R ²¹ ; L ¹ is a bond, -0-, - R ¹⁰ -Ci- ₄ alkylene-, -0-Ci- ₄ alkylene-, - C(0) R ¹⁰ -, -NR ¹⁰ C(O)-, or -C(O)-; L ² is a bond or -0-; and R ²¹ is -OCi- ₄ alkyl or OH. In each of the foregoing embodiments are further groups of compounds wherein X ⁵ is N and X ¹ , X ³ , and X ⁴ are each CH. In other groups of compounds, X ³ is N and X ¹ , X ⁴ , and X ⁵ are each CH. In yet other groups of compounds, X ¹ , X ³ , X ⁴ , and X ⁵ are each CH.

[00121] In some embodiments of formula (III), as defined above, G ⁴ is not piperidinyl, piperazinyl, or morpholino, when L ¹ is a bond or -NH-Ci-4alkylene-, X ³ is N, and X ¹ , X ⁴ and X ⁵ are CH. In some embodiments of formula (III), as defined above, G ^A is not a 6-membered saturated heterocycle containing at least one nitrogen atom when L ¹ is a bond or - H-Ci- ₄ alkylene- X ³ is N, and X ¹ , X ⁴ , and X ⁵ are CH. In some embodiments of formula (III), as defined above, G ^A is not piperidinyl, piperazinyl, or morpholino, when X ³ is N, and X ¹ , X ⁴ and X ⁵ are CH. In some embodiments of formula (III), as defined above, G ^A is not a 6-membered saturated heterocycle containing at least one nitrogen atom, when X ³ is N, and X ¹ , X ⁴ and X ⁵ are CH. In some embodiments of formula (III), as defined above, R ² is not -L ¹ -G ^2A , when X ³ is N, and X ¹ , X ⁴ and X ⁵ are CH.

[00122] In some embodiments, compounds of formula (I) may be represented by formula (IV), wherein X ¹ and X ⁵ are each independently N or CH; R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, - C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene- C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2- ₄ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -salkenylene-OH, - C ₃ -8alkenylene-OCi- ₄ alkyl, -C ₃ -salkynylene-OH, and -C ₃ -8alkynylene-OCi- ₄ alkyl; R ³ is selected from the group consisting of -I^-G ⁶ , Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; G ^A is selected from the group consisting of G ^2A , G ^6A , G ^7A , and G ^8A ; G ^B is selected from the group consisting of G ^2B , G ^6B , and G ^7B ; and R ⁸ and X ⁴ are as defined herein.

In some embodiments of formula (IV), as defined above, X ⁴ is N or CH. In further embodiments, X ¹ is N or CH, and X ⁴ and X ⁵ are each CH. In some embodiments, X ¹ , X ⁴ , and X ⁵ are each CH. In other embodiments, X ¹ is N, and X ⁴ and X ⁵ are each CH. [00123] In some embodiments of formula (IV), as defined above, X ⁴ is CR ⁴ ; and R ⁴ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi- 4alkyl, -OCi-4haloalkyl, and G ^c . In further embodiments of formula (IV), one of X ¹ and X ⁵ is N and the other CH. In yet other embodiments of formula (IV), X ¹ and X ⁵ are each CH. In some groups of compounds of formula (IV), as defined in any embodiment herein, R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, halogen, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -C(O) R ²⁰ R ²⁰ , and -C(O) R ²⁰ (Ci-4haloalkyl); R ³ is selected from the group consisting of -L ³ -G ^B , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -C(0)OCi- ₄ alkyl, and -C(O) R ⁴⁰ R ⁴⁰ ; L ¹ is a bond -0-Ci-4alkylene- or - C(0) R ¹⁰ -; and L ³ is a bond, -0-, - R ³⁰ -Ci-4alkylene- -0-Ci- ₄ alkylene-, or - C(O)-. In some embodiments of formula (IV), as defined above, R ² is selected from the group consisting of -L ¹ -G ^A and halogen; R ³ is selected from the group consisting of halogen and -OCi-4alkyl; R ⁴ is selected from the group consisting of Ci-4alkyl, halogen, and -OCi-4alkyl; and L ¹ is a bond.

[00124] In some embodiments, compounds of formula (I) may be represented by formula (V), wherein X ³ and X ⁴ are each independently N or CH; X ⁵ is N or CR ⁵ ; R ¹ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -OC3- ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), -NR ²⁰ C(O)OCi-4alkyl, - C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci-4haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- 6haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi-4alkyl)-Ci-3alkylene-R ²¹ , -L ² -C2- 4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2-4alkylene- R ²¹ , -C ₃ - ₈ alkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi-4alkyl, -C ₃ - ₈ alkynylene-OH, and -C ₃ - ₈ alkynylene-OCi-4alkyl; and G ^A is selected from the group consisting of G ^2A , G ^6A , G ^7A and G ^8A .

In some embodiments of formula (V), as defined above, X ⁵ is N or CH. In some embodiments, X ³ , X ⁴ , and X ⁵ are each CH. In some embodiments of formula (V), as defined above, X ⁵ is CR ⁵ ; and R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl. In some embodiments, X ³ and X ⁴ are each CH. In some groups of compounds of formula (V), as defined in any embodiment herein, R ¹ is selected from the group consisting of Ci-4alkyl and -OCi- 4alkyl; R ² is selected from the group consisting of -I^-G ⁴ , Ci-4alkyl, halogen, -OCi- 4alkyl, -C(0)Ci-4alkyl, and -L ² -Ci-6alkylene-R ²¹ ; L ¹ is a bond; L ² is a bond or - H-; R ²¹ is -OCi- ₄ alkyl or OH; and G ^A is G ^2A .

[00125] In some embodiments, compounds of formula (I) may be represented by formula (VI), wherein X ¹ and X ⁴ are each independently N or CH; X ² is N or CR ² ; X ³ is N or CR ³ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; R ² and R ³ are defined according to formula (I), G ^A is selected from the group consisting of G ^2A , G ^6A , G ^7A , and G ^8A ; and G ⁶ is selected from the group consisting of G ^2B , G ^6B , and G ^7B ; provided that at least one of X ² or X ³ is other than N or CH.

(VI)

In some embodiments according to formula (VI), as defined herein, R ² is selected from the group consisting of -L ^l -G ^A , hydrogen, Ci-4alkyl, halogen, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ C(O)(Ci-4alkyl), -

C(O) R ²⁰ R ²⁰ , -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -Cs-salkenyl, and - C3-8alkenylene-OCi-4alkyl; R ³ is selected from the group consisting of hydrogen, Ci- 4alkyl, halogen, -OCi-4alkyl, and - R ⁴⁰ R ⁴⁰ ; R ⁵ is selected from the group consisting of Ci-4alkyl, halogen, and -OCi-4alkyl; L ¹ is a bond, - R ¹⁰ -Ci-4alkylene-, or -O-Ci- ₄ alkylene-; L ² is a bond, -O- or - H-; R ²¹ is -OCi-4alkyl or OH; and G ^A is selected from the group consisting of G ^2A , G ^7A , and G ^8A .

[00126] In some embodiments, the compounds of formula (VI) may have formula (VIA), wherein X ¹ , X ⁴ , R ⁵ , and R ⁸ are as defined in formula (VI); R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, - C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene- C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -L ² -C ₂ - ₄ alkylene-0-C ₂ -4alkylene-0-C ₂ -4alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -salkenylene-OH, - C ₃ -8alkenylene-OCi- ₄ alkyl, -C ₃ -salkynylene-OH, and -C ₃ -8alkynylene-OCi- ₄ alkyl; and R ³ is selected from the group consisting of -L ³ -G ^B , Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O R ⁴⁰ R ⁴⁰ .

(VIA)

In some groups of compounds of formula (VIA), R ² is selected from the group consisting of Ci- ₄ alkyl, halogen, - R ²⁰ R ²⁰ , and -C(O)NR ²⁰ R ²⁰ ; R ³ is selected from the group consisting of Ci- ₄ alkyl, halogen, -OCi- ₄ alkyl, and - R ⁴⁰ R ⁴⁰ ; and R ⁵ is selected from the group consisting of Ci- ₄ alkyl, halogen, and -OCi- ₄ alkyl. In other embodiments according to the foregoing embodiments of formula (VIA), X ¹ is CH; and X ⁴ is CH.

[00127] In some embodiments, the compounds of formula (VI) may have formula (VIB), wherein X ¹ , X ⁴ , R ⁵ , and R ⁸ are as defined in formula (VI); X ³ is N or CH; and R ² is selected from the group consisting of -L ¹ -^, Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OC ₃ - ₆ alkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, -NR ²⁰ R ²⁰ , - R ²⁰ (Ci- ₄ haloalkyl), - R ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene- C(H)(OCi- ₄ alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C ₂ -4alkylene-0-C ₂ -4alkylene-R ²¹ , -L ² -C ₂ - ₄ alkylene-0-C ₂ -4alkylene-0-C ₂ -4alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -salkenylene-OH, - C ₃ -8alkenylene-OCi- ₄ alkyl, -C ₃ -salkynylene-OH, and -C ₃ -8alkynylene-OCi- ₄ alkyl.

(VIB)

In some groups of compounds of formula (VIB), R ² is selected from the group consisting of -I^-G ⁴ , Ci-4alkyl, halogen, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, - C(0)Ci- ₄ alkyl, -NR ²⁰ R ²⁰ , - R ²⁰ C(O)(Ci-4alkyl), -C(O) R ²⁰ R ²⁰ , -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -C ₃ -salkenyl, and -C ₃ -8alkenylene-OCi-4alkyl; R ⁵ is selected from the group consisting of Ci-4alkyl, halogen, and -OCi-4alkyl; L ¹ is a bond, - R ¹⁰ -Ci-4alkylene- or -0-Ci- ₄ alkylene-; L ² is a bond, -0-, or - H-; R ²¹ is -OCi-4alkyl or OH; and G ^A is selected from the group consisting of G ^2A , G ^7A , and G ^8A . In other embodiments, X ¹ is CH; X ³ is N or CH; and X ⁴ is N or CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is N. In other embodiments, X ¹ is CH; X ³ is N; and X ⁴ is CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is CH.

[00128] In some embodiments, the compounds of formula (VI) may have formula (VIC), wherein X ¹ , X ⁴ , R ⁵ , and R ⁸ are as defined in formula (VI); X ² is N or CH; and R ³ is selected from the group consisting of -L ³ -G ^B , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ .

(VIC)

In some groups of compounds of formula (VIC), R ³ is halogen; and R ⁵ is Ci-4alkyl. In other embodiments of formula (VIC), X ¹ is CH; X ² is CH; and X ⁴ is CH.

[00129] In some embodiments, compounds of formula (I) may be represented by formula (VII), wherein X ³ is N or CH; X ¹ , X ⁵ , and R ⁸ are as defined herein; R ² is selected from the group consisting of -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, -OC ₃ - ₆ alkenyl, -C(0)Ci-4alkyl, COOH, -C(0)OCi- ₄ alkyl, -NR ²⁰ R ²⁰ , - R ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -C(O) R ²⁰ R ²⁰ , -C(O) R ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene- C(H)(OCi-4alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2- 4alkylene-0-C2-4alkylene-0-C2-4alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -salkenylene-OH, - C ₃ -8alkenylene-OCi-4alkyl, -C ₃ -salkynylene-OH, and -C ₃ -8alkynylene-OCi-4alkyl; R ⁴ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, -OCi-4haloalkyl, and G ^c ; G ^A is selected from the group consisting of G ^2A , G ^6A , G ^7A , and G ^8A ; and G ^c is selected from the group consisting of G ^6C and G ^8C In some embodiments, G ^A is G ^2A (e.g., pyrrolidin-l-yl) and G ^c is G ^8C (e.g., phenyl). In other embodiments, G ^A is G ^2A (e.g., mo holin-4-yl) and G ^c is G ^6C (e.g., cyclopropyl). In other embodiments, G ^A is G ^6A e.g., cyclopropyl) and G ^c is G ^6C (e.g., cyclopropyl).

(VII)

In some embodiments according to formula (VII), R ² is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi-4alkyl, - OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci-4haloalkyl), -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene-C(H)(OCi-4alkyl)-Ci- ₃ alkylene- R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2- 4alkylene-R ²¹ , -C ₃ -salkenyl, -C ₃ -8alkenylene-OH, -C ₃ -8alkenylene-OCi-4alkyl, -C ₃ - 8alkynylene-OH, and -C ₃ -8alkynylene-OCi-4alkyl. In further embodiments of formula (VII), R ² is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, -OCi-4alkyl, -OCi-4haloalkyl, -C(0)Ci-4alkyl, COOH, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci-4haloalkyl), -NR ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci-4haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -L ² -Ci- ₆ alkylene-R ²¹ , -L ² -Ci- ₆ haloalkylene-R ²¹ , -L ² -Ci- ₃ alkylene-C(H)(OCi-4alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene- R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-0-C2-4alkylene-R ²¹ , and -C ₃ -8alkynylene- OH. In some groups of compounds according to the embodiments of formula (VII), L ² is a bond, -0-, - H-, -N(Ci-4alkyl)-, or - HC(O)-; and R ²¹ is -OCi- ₄ alkyl, OH, CN, -NH2, -N(Ci-4alkyl)(Ci-4alkyl), -C(0)N(Ci-4alkyl)(Ci-4alkyl), -N(Ci- 4alkyl)C(0)OCi- ₄ alkyl, - HC(0)Ci- ₄ alkyl, -NHS(0) ₂ Ci-4alkyl, or -C(0)Ci- ₄ alkyl.

[00130] In some embodiments of the compounds of formula (VII), as defined herein, X ¹ , X ³ , and X ⁵ are each independently N or CH. In further embodiments of formula (VII), X ¹ is CH; X ³ is CH; and X ⁵ is CH. In other embodiments of formula (VII), X ¹ is CH; X ³ is N; and X ⁵ is CH. In other embodiments of formula (VII), X ¹ is CH; X ³ is CH; and X ⁵ is N. In other embodiments of formula (VII), X ¹ is N; X ³ is CH; and X ⁵ is CH.

[00131] In some embodiments, the compounds of formula (VII) may have formula (VIIA), wherein X ¹ , X ³ , R ² , R ⁴ , and R ⁸ are as defined in the embodiments of formula (VII); and R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalk l.

(VIIA)

[00132] In some embodiments, the compounds of formula (VII) may have formula (VIIB), wherein X ³ , X ⁵ , R ² , R ⁴ , and R ⁸ are as defined in the embodiments of formula (VII); and R ¹ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalk l.

[00133] In some embodiments are compounds of the foregoing formulas with combinations of L ¹ and G ^A . For example, in some embodiments, R ² is G ^A ,

G ^A , -0-G ^A , -NR ¹⁰ -Ci-4alkylene-G ^A , -0-Ci-4alkylene-G ^A , -Ci-4alkylene- C(O) R ¹⁰ -G ^A , - R ¹⁰ C(O)-G ^A , or -C(0)-G ^A . [00134] In some embodiments, formula (X) may be represented by formulas (X-1) to X-11), where R ² , R ⁸ , R ¹¹⁰ , and R ¹²⁰ are as defined herein.

(X-1) (X-2) (X-3)

(X-10) (X-l l) [00135] In some embodiments of formulas (X-1) - (X-11), R ² is hydrogen.

[00136] In some embodiments of formula (X-6), R ² is -C(O)NR ²⁰ R ²⁰ . In further embodiments R ² is -C(0) H(Ci- ₄ alkyl).

[00137] In some embodiments of formula (X-7), R ¹¹⁰ is hydrogen. In other embodiments, R ¹¹⁰ is Ci-4alkyl. In other embodiments, R ¹¹⁰ is C(0)Ci-4alkyl. In further embodiments in combination with the foregoing R ¹¹⁰ description, R ² may be hydrogen. [00138] In some embodiments of formula (X-8), R ² is -L ^l -G ^A , where L ¹ and G ^A are as described herein. In some embodiments, -L ^l -G ^A is -G^R ⁷ (i.e., L ¹ is a bond), where G ¹ and R ⁷ are as described herein.

[00139] In some embodiments of formulas (X-9) - (X-l 1), R ¹²⁰ is hydrogen. In other embodiments, R ¹²⁰ is Ci-4alkyl (e.g., methyl, ethyl, isopropyl). In yet other embodiments, R ¹²⁰ is C(0)Ci-4alkyl (e.g., C(0)CH ₃ ). In some embodiments, R ¹²⁰ is R ⁶ , where R ⁶ is as defined herein.

[00140] In some embodiments, formula (XII) may be represented by formulas (XII-1) or (XII-2), where R ¹⁰⁰ is as defined herein. In further embodiments, R ² is hydrogen in combination with an option of R ¹⁰⁰ .

(XII-1) (XII-2)

[00141] In some embodiments, formula (XIII) may be represented by formulas XIII-1) - (XIII-3).

[00142] In some embodiments of formulas (XIII), (XIII-1), and (XIII-2), R ¹¹⁰ is hydrogen. In other embodiments, R ¹¹⁰ is Ci-4alkyl. In other embodiments, R ¹¹⁰ is C(0)Ci-4alkyl. In further embodiments of formulas (XIII), (XIII-1), and (XIII-3) and/or in combination with the foregoing description of R ¹¹⁰ , R ¹²⁰ is hydrogen. In other embodiments, R ¹²⁰ is Ci-4alkyl (e.g., methyl, ethyl, isopropyl). In yet other embodiments, R ¹²⁰ is C(0)Ci-4alkyl (e.g., C(0)CH ₃ ). In some embodiments of formulas (XIII), (XIII-1), and (XIII-3), R ¹²⁰ is R ⁶ , where R ⁶ is as defined herein.

[00143] In some embodiments, formula (XIV) may be represented by formula (XIV-1). In some embodiments of formulas (XIV) and (XIV-1), R ¹²⁰ is R ⁶ , where R ⁶ is as defined herein. In other embodiments of formulas (XIV) and (XIV-1), R ¹²⁰ is hydrogen. In other embodiments, R is Ci-4alkyl (e.g., methyl, ethyl, isopropyl). In yet other embodiments, R ¹²⁰ is C(0)Ci- ₄ alkyl (e.g., C(0)CH ₃ ).

XIV- 1

[00144] In the embodiments were R ¹²⁰ is R ⁶ , the 4- to 12-membered heterocycle at R ⁶ may be an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom and connected to the parent molecular moiety through a ring carbon atom of R ⁶ and optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms. In other embodiments, R ⁶ is an optionally substituted 4- to 6-membered monocyclic heterocycle containing containing one nitrogen or oxygen atom and connected to the parent molecular moiety through a ring carbon atom of R ⁶ . For example, R ⁶ may be piperidin-3-yl, piperidin- 4-yl, l-methylpiperidin-3-yl, l-(methoxycarbonyl)piperidin-3-yl, 1- (methoxycarbonyl)piperidin-4-yl, 1 -(3 -methoxypropyl)piperidin-4-yl, 1 - acetylpiperidin-4-yl, 3-hydroxypiperidin-4-yl, 3-fluoro-l-methylpyrrolidin-3-yl, 3- hydroxy- l-methylpyrrolidin-3-yl, l-acetylpyrrolidin-3-yl, l-(2,2- difluoroethyl)pyrrolidin-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,6- dihydro-2H-pyran-4-yl, 2,5-dihydrofuran-3-yl, tetrahydrofuran-3-yl, 2- methyltetrahydrofuran-2-yl, oxetan-3-yl, 3-hydroxyoxetan-3-yl, 3-methyloxetan-3-yl, or azetidin-3-yl.

[00145] In other embodiments, R ⁶ may be a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, -C(0)OCi- ₄ alkyl, -C(0)OH, and oxo. In other embodiments, R ⁶ is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, -C(0)OCi- ₄ alkyl, -C(0)OH, oxo, -OCi- ₄ alkyl, -Ci-6alkylene-OCi- ₄ alkyl, and -Ci-6alkylene-OH. For example, in some embodiments, R ⁶ is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with -C(0)OCi- ₄ alkyl, - C(0)OH, hydroxyl or 1-2 halogen. In one group of compounds, R ⁶ is cyclopropyl. In another group of compounds R ⁶ is cyclobutyl. In other embodiments, R ⁶ is 3,3- difluorocyclobutyl .

[00146] The foregoing formulas, embodiments, and groups of compounds may be further defined according to the following description.

[00147] In some embodiments according to formulas (Γ), (I), (II), (HA), (IIB), (X), or (X-l) - (X-l 1), R ² is -L ^l -G ^A . In some embodiments according to formulas (I), (II), (IIA),or (IIB), R ³ is -V-GP.

[00148] In some embodiments, G ^A or G ^B is -G^R ⁷ .

[00149] In some embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , the 4- to 12-membered heterocycle at R ⁷ may be a 4- to 8- membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, -CH2S(0)2phenyl, halogen, hydroxyl, oxo, -OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci-6alkylene-OH. In some embodiments R ⁷ is a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the

monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, -CH2S(0)2phenyl, halogen, hydroxyl, oxo, -OCi-4alkyl, -Ci- ₆ alkylene- OCi-4alkyl, and -Ci-6alkylene-OH. For example, in some embodiments, R ⁷ is an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl, a morpholinyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,4-oxazepanyl, 3-oxa- 8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, a pyrrolidinyl, piperidinyl, thiomorpholinyl, a thietanyl, piperazinyl, or azetidinyl, each being optionally substituted as described herein. In other embodiments, R ⁷ is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, or thietanyl, each being optionally substituted with 1-4 substituents independently selected from Ci- 4alkyl and oxo. In some embodiments, the oxetanyl, tetrahydrofuranyl,

tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, piperazinyl, and azetidinyl, are each optionally substituted with 1-4 substituents independently selected from halogen, Ci-4alkyl and oxo. In some embodiments, the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, thietanyl, and piperazinyl are each optionally substituted with Ci-4alkyl, and the pyrrolidinyl, piperazinyl, and thietanyl further optionally substituted with 1-2 oxo groups. In other embodiments, R ⁷ is a 4- to 8-membered monocyclic heterocycle containing 1 oxygen atom (e.g., an oxetanyl, a tetrahydrofuranyl, a tetrahydropyranyl). In other embodiments, R ⁷ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci- 4alkyl or -CH2S(0)2phenyl. In other embodiments, R ⁷ is a 4-membered monocyclic heterocycle containing 1 oxygen atom and optionally substituted with Ci-4alkyl. In other embodiments, R ⁷ is a 4- to 8-membered monocyclic heterocycle containing 1 sulfur atom (e.g., thietanyl, tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl). In other embodiments, R ⁷ is a 4-membered monocyclic heterocycle containing 1 sulfur atom and optionally substituted with 1-2 oxo groups. In other embodiments, R ⁷ is a 4- to 8-membered monocyclic heterocycle containing 1 nitrogen atom and optionally 1 oxygen atom or 1 sulfur atom (e.g., azetidinyl, pyrrolidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl) and optionally substituted with oxo (e.g., 2-oxopyrrolidin-l-yl). The heterocycles of R ⁷ may be appended to the parent molecule by any substitutable carbon atom or nitrogen atom in R ⁷ . Thus, in some embodiments, the oxygen-containing heterocycle is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, or tetrahydropyran-4-yl. In other embodiments, the sulfur- containing heterocycle is thietan-3-yl, tetrahydrothiophen-3-yl, tetrahydro-2H- thiopyran-3-yl, or tetany dro-2H-thiopyran-4-yl. In other embodiments, the heterocycle containing 1 nitrogen atom and optionally 1 oxygen or sulfur atom is e.g., piperidin-l-yl, morpholin-4-yl, azetidin-l-yl, piperazin-l-yl, 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, l,4-oxazepan-4- yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, thiomorpholin-4-yl, or 2-oxopyrrolidin-l-yl. In the embodiments of the invention, the oxygen- and sulfur-containing heterocycles may be unsubstituted or substituted as described herein. For example, the oxygen-containing heterocycle may be oxetan-3- yl, 3-methyloxetan-3-yl or 3 -((phenyl sulfonyl)methyl)oxetan-3-yl and the sulfur- containing heterocycle may be thietan-3-yl or l, l-dioxothietan-3-yl.

[00150] In the embodiments of formulas (Γ), (I), (II), (HA), (IIB), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , the 4- to 12-membered heterocycle at R ⁷ may be a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to G ¹ , the second ring being a C3-8cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, the spirocyclic R ⁷ is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, -CH2S(0)2phenyl, halogen, hydroxyl, oxo, - OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci-6alkylene-OH. In some

embodiments, R ⁷ is a 7- to 12-membered spiro heterocycle consisting of the first ring and a second ring, as described herein. The first ring is attached to G ¹ through any substitutable carbon or nitrogen atom in R ⁷ . In one embodiment, the first ring is attached to G ¹ through a nitrogen atom. The first ring of R ⁷ includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine. In some embodiments, the first ring of R ⁷ is a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. For example, in some embodiments, the first ring is morpholino, piperazin-l-yl, or piperidin-l-yl. The second ring includes a C3-scycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl. The second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common. For example, in some embodiments, R ⁷ is 4-oxa-7-azaspiro[2.5]octanyl (e.g., 4-oxa-7-azaspiro[2.5]octan-7-yl).

[00151] In the embodiments of formulas (Γ), (I), (II), (HA), (ΠΒ), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , the 4- to 12-membered heterocycle at R ⁷ may be a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, and oxo. In other embodiments, R ⁷ is a 7- to 12- membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, oxo, -OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- ₆ alkylene-OH. In some embodiments, the fused bicyclic heterocycle is a 7-12- membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocyclic heterocyclic ring. For example, in some embodiments, R ⁷ is 2- oxa-5-azabicyclo[4.1.OJheptanyl (e.g., 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl).

[00152] In other embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , R ⁷ may be a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from Ci-4alkyl, Ci-4haloalkyl, halogen, or hydroxyl. In other embodiments, R ⁷ is a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the

monocyclic heteroaryl being optionally substituted with 1-3 substituents

independently selected from Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, -OCi-4alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci-6alkylene-OH. For example, in some

embodiments, R ⁷ is a 5-membered heteroaryl containing 1-3 nitrogen atoms (e.g., pyrrolyl, imidazolyl, pyrazolyl, triazolyl). In certain embodiments, R ⁷ is pyrazol-l-yl. In other embodiments, R ⁷ is a 6-membered heteroaryl containing 1-3 nitrogen atoms (e.g., pyridine, pyrimidine, etc.). In some embodiments, R ⁷ is pyridin-2-yl or pyridin- 3-yl.

[00153] In embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X- 11) containing -G^R ⁷ , R ⁷ may be a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, hydroxyl, -C(0)OCi- ₄ alkyl, -C(0)OH, and oxo. In other embodiments, R ⁷ is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, - C(0)OCi- ₄ alkyl, -C(0)OH, oxo, -OCi- ₄ alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- 6alkylene-OH. For example, in some embodiments, R ⁷ is cyclopropyl, cyclobutyl, or cyclopentyl, each being optionally substituted with -C(0)OCi-4alkyl, -C(0)OH, hydroxyl or 1-2 halogen. In one group of compounds, R ⁷ is cyclopropyl. In another group of compounds R ⁷ is cyclobutyl. In other embodiments, R ⁷ is 3,3- difluorocyclobutyl. In other embodiments, R ⁷ is a cyclobutane carboxylic acid. [00154] In other embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , R ⁷ may be phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, -C(0)OCi-4alkyl, and -C(0)OH. In other

embodiments, R ⁷ is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, - C(0)OCi- ₄ alkyl, -C(0)OH, -OCi- ₄ alkyl, -Ci-6alkylene-OCi-4alkyl, and -Ci- 6alkylene-OH.

[00155] For example, in embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , R ⁷ may be represented by the following formulas, wherein R ^7a , R^, R ^7c , and R ^7d are the optional R ⁷ substituents, respectively for the 4- 12 membered heterocycle, C3-scycloalkyl, phenyl, and 5- or 6-membered heteroaryl of R ⁷ and s is an integer from 0-4:

[00156] In some embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) containing -G^R ⁷ , G ¹ may be a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a Ci- 3alkylene bridge between two non-adjacent ring atoms, G ¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, and oxo. In further embodiments, G ¹ is a 4- to 8-membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms. In some embodiments, G ¹ is connected to the parent molecular moiety (e.g., at L ¹ ) through the first nitrogen atom. In other embodiments, G ¹ is attached at a ring carbon atom of G ¹ . In further embodiments, G ¹ is a 4- to 6-membered optionally substituted monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms. In some embodiments, G ¹ is a 4- to 8- membered monocyclic heterocycle containing 1 or 2 nitrogen atoms, the monocyclic heterocycle optionally containing one double bond and/or a Ci-3alkylene bridge between two non-adjacent ring atoms, G ¹ being optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, hydroxyl, and oxo. In some embodiments, G ¹ contains one nitrogen atom. In other embodiments, G ¹ contains two nitrogen atoms. In some embodiments, G ¹ is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms. The heterocycles at G ¹ may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G ¹ , the heterocycle is unsubstituted. For example, in some embodiments, G ¹ may be piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH-pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl, each unsubstituted or substituted as described herein. In other embodiments, the piperazinyl, homopiperazinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-dihydro-lH- pyrrolyl, oxetanyl, morpholino, tetrahydropyranyl, or 1,2,3,6-tetrahydropyridinyl are optionally substituted with 1-4 substituents independently selected from 1 hydroxyl, 1-2 halogen, 1 oxo, and 1-4 Ci-4alkyl groups. In some embodiments, pyrrolidinyl and/or piperidinyl is optionally substituted with halogen, 1 hydroxyl, or 1 oxo and the piperazinyl is optionally substituted with oxo. In some embodiments, G ¹ is piperazin- 1-yl optionally substituted with oxo. In some embodiments, G ¹ may have a Ci- 3alkylene bridge between two non-adjacent ring atoms (e.g., 2,5- diazabicyclo[2.2.1]heptanyl). In other embodiments, G ¹ is without a Ci-3alkylene bridge between two non-adjacent ring atoms. The heterocycles of G ¹ may be appended to the parent molecule (e.g., at LVL ³ ) by any substitutable carbon or nitrogen atom. In some embodiments, LVL ³ is -0-, - R ¹⁰ -, C(0) R ¹⁰ -, - R ¹⁰ C(O)-, -NR ³⁰ -, C(0)NR ³⁰ -, -NR ³⁰ C(O)-, or -C(O)- and G ¹ is attached to LVL ³ at a ring carbon atom of G ¹ . In some embodiments, LVL ³ is a bond and G ¹ is attached to LVL ³ at a ring nitrogen atom of G ¹ . For example, non-limiting examples of G ¹ include piperazin-l-yl, 2-oxo-piperazin-l-yl, homopiperazin-l-yl, azetidin-l-yl, azetidin-3-yl, pyrrolidin-3-yl, 3-hydroxy-pyrrolidin-3-yl, 3-fluoro-pyrrolidin-3-yl, piperidin-l-yl, piperidin-3-yl, piperidin-4-yl, 3-hydroxypiperidin-4-yl, 4- hydroxypiperidin-4-yl, 3-fluoropiperidin-4-yl, 4-fluoropiperidin-4-yl, 3,3- difluoropiperidin-4-yl, azepan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,5-dihydro- lH-pyrrol-3-yl, or l,2,3,6-tetrahydropyridin-4-yl.

[00157] For example, in embodiments of formulas In some embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) -G^R ⁷ together may represent 4-(oxetan-3-yl)piperazin-l-yl, 4-(3-methyloxetan-3-yl)piperazin-l-yl, 4- (tetrahydrofuran-3-yl)piperazin-l-yl, 4-(2-methyltetrahydrofuran-3-yl)piperazin-l-yl, 4-(tetrahydro-2H-pyran-3 -yl)piperazin- 1 -yl, 4-(tetrahydro-2H-pyran-4-yl)piperazin- 1 - yl, 4-(oxetan-3-yl)-2-oxo-piperazin-l-yl, 4-(oxetan-3-yl)piperidin-l-yl, l-(oxetan-3- yl)piperidin-3-yl, l-(oxetan-3-yl)piperidin-4-yl, l-(3-methyloxetan-3-yl)piperidin-4- yl, 3 -hydroxy- l-(oxetan-3-yl)piperidin-4-yl, 3-fluoro-l-(oxetan-3-yl)piperidin-4-yl, 4- hydroxy-l-(oxetan-3-yl)piperidin-4-yl, 4-fluoro-l-(oxetan-3-yl)piperidin-4-yl, 3,3- difluoro- 1 -(oxetan-3 -yl)piperidin-4-yl, 4-(2-oxopyrrolidin- 1 -yl)piperidin- 1 -yl, 3 -(2- oxopyrrolidin- 1 -yl)piperidin- 1 -yl, 4-morpholinopiperidin- 1 -yl, (4-methylpiperazin- 1 - yl)piperidin- 1 -yl, 4-(3 ,3 -difluoroazetidin- 1 -yl)piperidin- 1 -yl, 3 -mo holinopyrrolidin 1-yl, l-(oxetan-3-yl)pyrrolidin-3-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2- yl, 1 -(oxetan-3 -yl)- 1 ,2, 3 ,6-tetrahy dropyridin-4-yl, 3 -hydroxy- 1 -(oxetan-3 -yl)- pyrrolidin-3-yl, 3 -fluoro-1 -(oxetan-3 -yl)pyrrolidin-3-yl, l-(oxetan-3-yl)azetidin-3-yl, 3 -(oxetan-3 -yl)azeti din- 1-yl, 3-(pyrrolidin-l-yl)azetidin-l-yl, 3-(4-fluoropiperidin-l- yl)azeti din- 1-yl, 3-morpholinoazetidin-l-yl, 3-methyl-3-morpholinoazetidin-l-yl, 3- (2-methylmorpholino)azetidin-l-yl, 3-(3-methylmorpholino)azetidin-l-yl, dimethylmorpholino)azeti din- 1-yl, 3-(2,6-dimethylmorpholino)azetidin-l-yl, 3-(l,4- oxazepan-4-yl)azeti din- 1-yl, 3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)azetidin-l-yl, (3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)azetidin-l-yl, 3-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)azetidin-l-yl, 3-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)azeti din- 1-yl, 3-(4-oxa-7-azaspiro[2.5]octan-7-yl)azetidin-l-yl, 3-(2-oxa-5- azabicyclo[4.1.0]heptan-5-yl)azetidin-l-yl, 3-(mo holinomethyl)azetidin-l-yl), 3- (1,1 -dioxidothiomorpholino)azetidin- 1 -yl, 4-(thietan-3 -yl)piperazin- 1 -yl, 4- (piperazin-l-yl)thietane 1, 1 -dioxide, 4-(oxetan-3-yl)-4-( ¹ -oxidanyl)-4 ⁴ -piperazin-l yl, 3-(lH-pyrazol-l-yl)azetidin-l-yl, 4-(oxetan-3-yl)mo holin-2-yl, 6-methyl-4- (oxetan-3-yl)mo holin-2-yl, 5-methyl-4-(oxetan-3-yl)moφholin-2-yl, 2-methyl-4- (oxetan-3-yl)moφholin-2-yl, 4-(oxetan-3-yl)-l,4-diazepan-l-yl, 2-phenylpyrrolidin- 1 -yl, 2-(pyridin-3-yl)pyrrolidin-l-yl, or 2-(pyridin-2-yl)pyrrolidin-l-yl.

[00158] In other embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1), -G^R ⁷ together may represent 3-(l-hydroxycyclobutyl)piperazin-l-yl; 4- cyclopropylpiperazin- 1 -yl; 4-cyclobutylpiperazin- 1 -yl; 4-cyclopentylpiperazin- 1 -yl; l-cyclopropylpiperidin-4-yl; l-cyclopropylpiperidin-3-yl; l-cyclobutylpiperidin-4-yl, l-cyclopentylpiperidin-4-yl, 4-(3,3-difluorocyclobutyl)piperazin-l-yl; or 5- cyclopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl.

[00159] In some embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X-l 1) wherein R ⁷ is an optionally substituted oxetan-3-yl, G ¹ may be represented by the following formulas, wherein R ^gl is the optional G ¹ substituent and m is an integer

[00160] In embodiments of formulas (Γ), (I), (II), (IIA), (IIB), (X), or (X-l) - (X- 11), G^R ⁷ may be represented by the following formulas, wherein R ^gl , R ^7a , R ^7b , R ^7c , R ^7d , m and s are as defined herein:

[00161] In some embodiments according to formulas (I) to (VIIB), R ² is -L ^l -G ^A and/or R ³ is -I^-G ⁶ , where G^ ⁴ is G ^2A and/or G ⁶ is G ²³ . In some embodiments, only one of -L ¹ -G ^2A and -L ³ -G ^2B is present. The heterocycles at G ^2A and G ^2B may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G ^2A and G ^2B , the heterocycle is unsubstituted. For example, G ^2A or G ^2B may be substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl (e.g., methyl, ethyl, isopropyl), Ci-4haloalkyl (e.g., -CF ₃ , -CH2CF3, -CH2CHF2), halogen (e.g., fluoro), hydroxyl, oxo, cyano, -C(0)Ci-4alkyl (e.g., -C(0)CH ₃ ), -C(0)OCi- ₄ alkyl (e.g., -C(0)OCH ₃ , -C(0)OCH ₂ CH ₃ , - C(0)OC(CH ₃ ) ₃ ), -OCi- ₄ alkyl (e.g., -OCH3), -Ci-6alkylene-OCi-4alkyl (e.g., - CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OCH ₃ ), and -Ci-ealkylene-OH (e.g., - CH ₂ OH, -C (OH)(CH ₃ ) ₂ , -CH ₂ C(OH)(CH ₃ ) ₂ , -C(OH)(CH ₃ )CH(CH ₃ ) ₂ ). & ^A or G ²¹³ may be an optionally substituted 4- to 8-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second nitrogen atom, an oxygen or sulfur atom, and optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms, G ^2A or G™ being connected to LVL ³ , respectively, through the first nitrogen atom. G ^2A or G ^2B may be an optionally substituted 4- to 6-membered monocyclic heterocycle containing a first nitrogen atom and optionally a second heteroatom independently selected from oxygen and nitrogen, and optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non-adjacent ring atoms. In some embodiments, G ^2A or G ^2B may be substituted with one substituent selected from the foregoing group and further optionally substituted with 1-3 substituents selected from the group consisting of Ci-4alkyl and halogen. In some embodiments, G ^2A or G ²³ is a 6-membered monocyclic heterocycle containing 1 or 2 nitrogen atoms and substituted with Ci-4alkyl. In some embodiments, G ^2A or G ^2B is piperazin-l-yl optionally substituted with Ci-4alkyl. For example, G ^2A or G ^2B may be 4-Ci-4alkyl-piperazin-l-yl. In other embodiments, G ^2A or G ^2B may be

unsubstituted. In some embodiments, G ^2A or G ^2B may have a Ci- ₃ alkylene bridge between two non-adjacent ring atoms (e.g., 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3- azabicyclo[3.2. ljoctanyl). In other embodiments, G ^2A or G ^2B is without a Ci- ₃ alkylene bridge between two non-adjacent ring atoms. The heterocycles of G ^2A or Gr ²³ are appended to the parent molecule (i.e., at LVL ³ ) by a nitrogen atom in G ^2A or G ^2B (e.g., morpholin-4-yl, homomorpholin-4-yl, thiomorpholin-4-yl, 4- thiomorpholine 1,1 -dioxide, piperazin-l-yl, homopiperazin-l-yl, azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, azepan-l-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 6- oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8- azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl).

[00162] In further examples according to formulas (I) to (VIIB), the optionally substituted G ^2A or G ^2B may be piperidin-l-yl, 3-fluoropiperidin-l-yl, 4- fluoropiperidin-l-yl, 3-methoxypiperidin-l-yl, 3-(methoxymethyl)piperidin-l-yl, 4- (methoxymethyl)piperidin- 1 -yl, 4-methylpiperidin- 1 -yl, 4-hydroxy-4- methylpiperidin-l-yl, 4-(ethoxycarbonyl)piperidin-l-yl, 4-(tert- butoxycarbonyl)piperidin-l-yl, 3-cyanopiperidin-l-yl, 4-cyanopiperidin-l-yl, 3- hydroxypiperidin-l-yl, 4-hydroxypiperidin-l-yl, 3-(hydroxymethyl)piperidin-l-yl, 4- (2-methoxyethyl)piperidin-l-yl, pyrrolidin-l-yl, 3-fluoropyrrolidin-l-yl, 3-(2- hydroxypropan-2-yl)pyrrolidin-l-yl, 3 -hydroxy-3 -methylpyrrolidin-l-yl, 4- methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4-isopropylpiperazin-l-yl, 4-(tert- butyl)piperazin- 1 -yl, 3 -(2-hydroxypropan-2-yl)piperazin- 1 -yl, 4- (ethoxycarbonyl)piperazin- 1 -yl, 4-(methoxycarbonyl)piperazin- 1 -yl, 4- acetylpiperazin-l-yl, 2,4,5-trimethylpiperazin-l-yl, 3,3,4-trimethylpiperazin-l-yl, piperazin-l-yl, 3-(trifluoromethyl)piperazin-l-yl, 4-(2-methoxyethyl)piperazin-l-yl, 4-(2,2,2-trifluoroethyl)piperazin- 1 -yl, 3 ,4, 5 -trimethylpiperazin- 1 -yl, 3 -(2-hy droxy-3 - methylbutan-2-yl)piperazin-l-yl, 2,5-dimethylpiperazin-l-yl, 3,4-dimethylpiperazin- 1-yl, 3-methylpiperazin-l-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-l-yl, 3- (hydroxymethyl)-4-methylpiperazin- 1 -yl, 3 -(hydroxymethyl)piperazin- 1 -yl, 4-(tert- butoxycarbonyl)piperazin-l-yl, 2-oxopiperazin-l-yl, 3-methylpiperazin-l-yl, (3- methoxypropyl)piperazin- 1 -yl, 4-methyl- 1 ,4-diazepan- 1 -yl, 4-acetyl- 1 ,4-diazepan- 1 - yl, l,4-oxazepan-4-yl, morpholin-4-yl, 2,6-dimethylmorpholino, 2- (methoxymethyl)mo holino, 1, 1-dioxidothiomorpholino, azetidin-l-yl, 3- methylazetidin- 1 -yl, 3 -hydroxy-3 -methylazetidin- 1 -yl, 3-ethyl-3 -hydroxyazetidin- 1 - yl, 3-hydroxy-3-isopropylazetidin-l-yl, 3-fluoroazetidin-l-yl, 3- (methoxymethyl)azetidin- 1 -yl, 3 -(hydroxymethyl)azetidin- 1 -yl, 3 -methoxyazetidin- 1 - yl, 3-hydroxyazetidin-l-yl, 3-(2-hydroxypropan-2-yl)azetidin-l-yl, 3-cyanoazetidin-l- yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3- oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, or 5-methyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[00163] In some embodiments of formulas (I) to (VIIB), G ^2A /G ^2B may be represented by the following formulas, wherein R ^g2a is the optional G ^2A /G ^2B substituent and m is an integer between 0 and 4.

[00164] In some embodiments of formulas (I), (II), (IIA), and (ΠΒ), G ^A is G ^3A and/or G ^B is G ^3B where G ^3A and G ^3B are as described above. In some embodiments, only one of -L ¹ -G ^3A and -L ³ -G ^3B is present. In other embodiments, G ^3A and G ^3B are both present. The heterocycles at G ^3A and G ^3B may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G ^3A or G ^3B , the heterocycle is unsubstituted. The optional G ^3A /G ^3B substituent may be bonded to the same atom, or a different atom, in G ^3A or G ^3B to which L ¹ or L ³ is bonded. G ^3A and G ^3B are attached to L ¹ and L ³ , respectively, at a ring carbon ring atom of G ^3A or G ^3B . In some embodiments, G ^3A and/or G ^3B are independently a 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl (e.g., methyl, isobutyl), Ci-4haloalkyl, halogen (e.g., fluoro), hydroxyl, oxo, cyano, -OCi- ₄ alkyl (e.g., -OCH3), -C(0)Ci- ₄ alkyl (e.g., -C(0)CH ₃ ), - C(0)OCi- ₄ alkyl (e.g., -C(O)O-t-butyl), -Ci-6alkylene-OCi- ₄ alkyl (e.g., -(CH ₂ ) ₃ - OCH ₃ ), and -Ci-6alkylene-OH. In some embodiments, the optional substituents include Ci- ₄ alkyl, hydroxyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, or -Ci-ealkylene-OCi- 4alkyl. G ^3A /G ^3B may be an optionally substituted 4- to 6-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen and nitrogen, G ^3A /G ^3B being connected to the parent molecular moiety through a ring carbon atom of G ^3A /G ^3B . For example, in some embodiments, G ^3A or G ^3B may be azetidin-3-yl, pyrrolidin-3-yl, 2-oxooxazolidin-3-yl, 2-oxooxazolidin-5-yl, piperidin- 3-yl, piperidin-4-yl, azepan-3-yl, l,2,3,6-tetrahydropyridin-4-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, 2,5-dihydrofuran-3- yl, or 3,6-dihydro-2H-pyran-4-yl, each optionally substituted. In still other embodiments, G ^3A or G ^3B may be piperidin-3-yl, piperidin-4-yl, l-methylpiperidin-3- yl, l-(methoxycarbonyl)piperidin-3-yl, l-(methoxycarbonyl)piperidin-4-yl, l-(3- methoxypropyl)piperidin-4-yl, l-acetylpiperidin-4-yl, 3-hydroxypiperidin-4-yl, 3- fluoro- 1 -methylpyrrolidin-3 -yl, 3 -hydroxy- 1 -methylpyrrolidin-3 -yl, 1 - acetyl pyrrolidin-3-yl, l-(2,2-difluoroethyl)pyrrolidin-3-yl, 2-oxooxazolidin-3-yl, 5- methyl-2-oxooxazolidin-5-yl, 3,5-dimethyl-2-oxooxazolidin-5-yl, tetrahydropyran-4- yl, tetrahydropyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 2,5-dihydrofuran-3-yl, tetrahydrofuran-3-yl, 2-methyltetrahydrofuran-2-yl, oxetan-3-yl, 3 -hydroxy oxetan-3- yl, 3-methyloxetan-3-yl, or azetidin-3-yl.

[00165] In some embodiments, G /G may be represented by the following formulas, wherein R ^g3a is the optional G ^3A /G ^3B substituent and m is an integer between 0 and 4.

[00166] In other embodiments of formulas (I), (II), (IIA), and (IIB), G ^A is G ^4A and/or G ^B is G ^4B where G ^4A and G ^4B are independently a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8- membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L ¹ or L ³ , respectively, the second ring being a C3-8cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G ^4A and G ^4B are each optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, oxo, and -OCi-4alkyl. In some embodiments, only one of -L ¹ -G ^4A and -L ³ -G ^4B is present. Unless substitution is indicated as present or optional for a specific spiro heterocyclic G ^4A or G ^4B , the spiro heterocycle is unsubstituted. In some embodiments, G ^4A or G ^4B is a 7- to 12- membered spiro heterocycle consisting of the first ring and a second ring, as described herein. The first ring of G ^4A or G ^4B includes, but is not limited to, heterocycles such as azetidine, pyrrolidine, piperidine, azepane, morpholine, azocane, piperazine, and homopiperazine. In a preferred embodiment, the first ring of G ^4A or G ^4B is a 4- to 8- membered monocyclic heterocycle containing 1-2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom. In another embodiment, the first ring of G ^4A or G ^4B is a 4- to 6- membered monocyclic heterocycle containing 1-2 nitrogen atoms. The first ring is attached to LVL ³ through any substitutable carbon or nitrogen atom. In one embodiment, the first ring is attached to LVL ³ through a nitrogen atom. For example, in some embodiments, the first ring is azetidin-l-yl, pyrrolidin-l-yl, piperazin-l-yl, or piperidin-l-yl. The second ring of G ^4A or G ^4B includes, but is not limited to, heterocycles such as oxetane, tetrahydrofuran, tetrahydropyran, dioxolane, etc. In some embodiments, the second ring has one oxygen atom. In other embodiments, the second ring has two oxygen atoms. In other embodiments, the second ring is a C ₃ - 8cycloalkyl, e.g., cyclopropyl, cyclobutyl cyclopentyl. The second ring is formed by the attachment of two atoms of the second ring to a single carbon atom of the first ring such that the first ring and the second ring share one carbon atom in common. For example, the second ring may be joined with the first ring at the 4-position of a first ring piperidin-l-yl or the 3 -position of a first ring azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, or piperazin-l-yl. In certain embodiments, G ^4A or G ^4B is l,4-dioxa-8- azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2- oxa-5,8-diazaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, l-oxa-8- azaspiro[4.5]decanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6- oxa-2-azaspiro[3.4]octanyl, l-oxa-6-azaspiro[3.3]heptanyl, or 2-oxa-6- azaspiro[3.3]heptanyl, 2-oxa-8-azaspiro[4.5]decanyl, 2,6-diazaspiro[3.3]heptanyl, 2- oxa-7-azaspiro[4.4]nonanyl, 2-oxa-5-azaspiro[3.4]octanyl, l-oxa-9- azaspiro[5.5]undecanyl, where the 2,6-diazaspiro[3.3]heptanyl and 2-oxa-5,8- diazaspiro[3.5]nonanyl are optionally substituted with Ci-4alkyl and/or oxo. The heterocycles of G ^4A or G ^4B may be appended to the parent molecule (i.e., at LVL ³ ) by any substitutable carbon or nitrogen atom. Other embodiments include l,4-dioxa-8- azaspiro[4.5]decan-8-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-7- azaspiro[4.4]nonan-7-yl, 5-methyl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-6- azaspiro[3.4]octan-6-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, l-oxa-6- azaspiro[3.3]heptan-6-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 2,5-dioxa-8- azaspiro[3.5]nonan-8-yl, l-oxa-8-azaspiro[4.5]decan-8-yl, 5-oxa-8- azaspiro[3.5]nonan-8-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 2-oxa-6- azaspiro[3.3]heptan-6-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, l-oxa-9- azaspiro[5.5]undecan-9-yl, 6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl, or 2,6- diazaspiro[3.3]heptan-2-yl. In further embodiments, G ² is selected from the group consisting of 2,6-diazaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, and 2- oxa-8-azaspiro[4.5]decan-8-yl.

[00167] In other embodiments of formulas (I), (II), (IIA), and (IIB), G ^A is G ^5A and/or G ^B is G ^5B , where G ^5A and/or G ^5B are as described above. In some

embodiments, only one of -L ¹ -G ^5A and -L ³ -G ^5B is present. The heterocycles at G ^5A and/or G ^5B may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific heterocyclic G ^5A and/or G ^5B , the heterocycle is unsubstituted. In some embodiments, the fused bicyclic heterocycle is a 7-12- membered ring system having a monocyclic heterocycle, as defined herein, fused to another monocycli

and/or G may be

, each being optionally substituted with 1-4 substituents selected from the group consisting of Ci-4alkyl (e.g., methyl, ethyl, isobutyl), Ci-4haloalkyl (e.g.,- CF ₃ , -CH2CF ₃ ), halogen (e.g., fluoro), hydroxyl, and oxo. In other embodiments G ^5A

with one Ci-4alkyl, Ci-4haloalkyl, halogen, or oxo. In some embodiments, G and/or G may be substituted with one substituent selected from the foregoing group. For example, in some embodiments, G and/or G is

[00168] In other embodiments of formulas (I) to (VIIB), G ^A , G ^B , and/or G ^c are each independently G ^6A , G ^6B , or G ^6C , respectively, where G ^6A , G ^6B , and G ^6C are as described above. In some embodiments, only one of G ^6A , G ^6B , and G ^6C is present. In some embodiments, G ^6A , G ^6B , or G ^6C are independently cyclopropyl, cyclobutyl, or cyclopentyl, each optionally substituted as defined herein. For example, in some embodiments G ^6A , G ^6B , or G ^6C may be substituted with Ci-4alkoxy (e.g., 3- methoxycyclobutane). The optional G ^6A , G ^6B , or G ^6C substituent may be bonded to the same atom, or a different atom, in G ^6A , G ^6B , or G ^6C , to which L ¹ , L ³ , or the parent molecular moiety is bonded.

[00169] In some embodiments of formulas (I) to (VIIB), G ^A and/or G ^B are G ^7A or G ^7B , respectively, where G ^7A and G ^7B are as described above. In some embodiments, only one of -L -G ^7A and -L ³ -G ^7B is present. The heteroaryls at G ^7A or G ^7B may be unsubstituted or substituted. Unless substitution is indicated as present or optional for a specific G ^7A or G ^7B , the heteroaryl is unsubstituted. For example, in some embodiments, G ^7A or G ^7B may be optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, hydroxyl, cyano, and -OCi-4alkyl. For example, in some embodiments G ^7A or G ^7B may be a thiazole, oxazole, triazole pyrazole, imidazole, pyridine, furan optionally substituted with Ci-4alkyl. Further exemplary G ^7A or G ^7B include 1 -methyl- 1H- 1,2,4- triazol-3-yl, l-ethyl-lH-l,2,4-triazol-3-yl, l-methyl-lH-pyrazol-3-yl, 1-ethyl-lH- pyrazol-3-yl, oxazol-2-yl, oxazol-5-yl, thiazol-2-yl, imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, and furan-3-yl. [00170] In some embodiments, R ² is not cyano when R ³ is an imidazolyl optionally substituted with one or two Ci-4alkyl. In some embodiments, R ² is not Ci-4alkyl, - OCi-4alkyl, hydroxy, halogen or cyano when R ³ is imidazolyl optionally substituted with one or two Ci-4alkyl. In some embodiments, R ² is not Ci-4alkyl, -OCi-4alkyl, hydroxy, halogen or cyano when R ³ is imidazolyl, oxazolyl, thiazolyl, pyrazolyl, thiadiazolyl, triazolyl, oxadiaolyl, pyrimidinyl, or pyridinyl, each optionally substituted with one or two Ci-4alkyl. In some embodiments, R ² is not Ci-4alkyl, - OCi-4alkyl, hydroxy, halogen or cyano when R ³ is a 5- or 6-membered heteroaryl optionally substituted with one or two Ci-4alkyl.

[00171] In some embodiments of formulas (I) to (VIIB), G ^A and/or G ^c is G ^8A or G ^8C respectively, where G ^8A and G ^8C are as described above. In some embodiments, only one of G ^8A and G ^8C is present. G ^8A and G ^8C may be unsubstituted or substituted. In some embodiments, G ^8A or G ^8C is phenyl.

[00172] In some embodiments, only one of -L ^l -G ^A , -L ³ -G ^B , and G ^c is present, as L ¹ , G ⁴ , L ³ , G ⁶ , and G ^c are defined herein. In some embodiments, one of G? ^A , G ^3A , G ^4A , G ^5A , G ^6A , G ^7A , G ^8A , and one of G ^6C and G ^8C are present. In other embodiments, G ^2A and G ^8C are both present. In other embodiments, G ^6A and G ^6C are both present.

[00173] According to the embodiments described herein above and below are further combinations of embodiments wherein L ¹ is a bond. In alternative

combinations of embodiments, L ¹ is -0-. In still further alternative combinations, L ¹ is - R ¹⁰ - and R ¹⁰ , at each occurrence, is independently selected from the group consisting of hydrogen, Ci-4alkyl, C(0)Ci-4alkyl, oxetanyl, cyclopropyl, and cyclobutyl. In still other embodiments, L ¹ is -NR ¹⁰ -Ci-4alkylene-, wherein R ¹⁰ is as defined herein. In other embodiments, L ¹ is -0-Ci-4alkylene- In other

embodiments, L ¹ is -Ci-4alkylene- In other embodiments, L ¹ is -C(O)-. In still other embodiments, L ¹ is - R ¹⁰ C(O)-. In other embodiments, L ¹ is -C(0) R ¹⁰ -.

[00174] According to the embodiments described herein above and below are further combinations of embodiments wherein L ³ is a bond. In alternative

combinations of embodiments, L ³ is -0-. In still further alternative combinations, L ³ is -NR ³⁰ - and R ³⁰ , at each occurrence, is independently selected from the group consisting of hydrogen, Ci-4alkyl, C(0)Ci-4alkyl, oxetanyl, cyclopropyl, and cyclobutyl. In still other embodiments, L ³ is -NR ³⁰ -Ci-4alkylene-, wherein R ³⁰ is as defined herein. In other embodiments, L ³ is -0-Ci-4alkylene- In other embodiments, L is -Ci-4alkylene- In other embodiments, L is -C(O)-. In still other embodiments, L ³ is - R ³⁰ C(O)-. In other embodiments, L ³ is -C(0) R ³⁰ -.

[00175] In some embodiments, L ^l -G ^A is -G , -O-G^, - R ¹⁰ -^, - R ¹⁰ -Ci- ₄ alkylene-G ^A , -0-Ci-4alkylene-G ^A , - R ¹⁰ C(O)-G ^A , -C(O) R ¹⁰ -G ^A , or -C(0)-G ^A . Subject to the description of formulas (I), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIIA), and (VIIB), V-G ^A includes, but is not limited to, -G ¹ - R ⁷ , G ^2A , G ^3A , -0-G ^3A , - R ¹⁰ -G ^3A , -0-Ci-4alkylene-G ^3A , -NR ¹⁰ -Ci-4alkylene-G ^3A , -Ci-4alkylene-G ^3A , -C(O) R ¹⁰ -G ^3A , G ^4A , G ^5A , G ^6A , -0-G ^6A , -0-Ci-4alkylene-G ^6A , - R ¹⁰ -Ci-4alkylene-G ^6A , -C(O)NR ¹⁰ -G ^6A , - R ¹⁰ C(O)-G ^6A , G ^7A , -0-Ci-4alkylene- G ^7A , - R ¹⁰ -Ci-4alkylene-G ^7A , G ^8A , -0-Ci-4alkylene-G ^8A , - R ¹⁰ -Ci-4alkylene-G ^8A , - R ¹⁰ C(O)-G ^8A , -C(O) R ¹⁰ -G ^8A , and -C(0)-G ^8A .

[00176] In some embodiments of formula (IIA) are compounds wherein X ¹ , X ³ , X ⁴ , and X ⁵ are each independently N or CH; and V-G ^A is -G^R ⁷ (IIA-1), G ^3A (IIA-2), - 0-G ^3A (ΠΑ-3), or -0-Ci- ₄ alkylene-G ^3A (IIA-4). In further embodiments, G ^3A is an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom. In the foregoing embodiments are further embodiments wherein X ³ and X ⁵ are independently N or CH, and X ¹ and X ⁴ are each CH. In each of the foregoing embodiments are further embodiments wherein X ⁵ is N and X ¹ , X ³ , and X ⁴ are each CH. In other embodiments, X ³ is N and X ¹ , X ⁴ , and X ⁵ are each CH. In yet other embodiments, X ¹ , X ³ , X ⁴ , and X ⁵ are each CH. Examples of monocyclic optionally substituted G ^3A heterocycles include oxetan-3-yl, piperidin-4-yl, piperidin- 3-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, and pyrrolidin- 3-yl.

(IIA-1) (IIA-2)

(IIA-3) (IIA-4)

[00177] In some embodiments of formula (IIA) are compounds wherein X ¹ and X ⁵ are each independently N or CH; X ³ is CR ³ ; R ³ is selected from the group consisting of -L ³ -G ^B , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; and L ¹ - G ^A is -G^R ⁷ (ΠΑ-5), G ^3A (IIA-6), or - R ¹⁰ -G ^3A (IIA-7). In further embodiments, G ^3A is an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom. In some embodiments according to the foregoing, X ¹ , X ⁴ , and X ⁵ are each independently N or CH. In further embodiments, X ¹ is N or CH, and X ⁴ and X ⁵ are each CH. In some embodiments, X ¹ , X ⁴ , and X ⁵ are each CH. In other embodiments, X ¹ is N, and X ⁴ and X ⁵ are each CH. Examples of monocyclic optionally substituted G ^3A heterocycles include oxetan-3-yl, piperidin-4-yl, piperidin- 3-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyrrolidin-2-yl, and rrolidin-3-yl.

(IIA-5) (IIA-6)

(IIA-7) [00178] In other embodiments of formula (IIA) are compounds wherein X ³ and X ⁴ are each independently N or CH; X ¹ is CR ¹ ; R ¹ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; and I^-G ⁴ is - G^R ⁷ (ΠΑ-8), G ^3A (ΠΑ-9), or - R ¹⁰ -G ^3A (IIA-10). In further embodiments, G ^3A is an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom. In some embodiments according to the foregoing, X ³ , X ⁴ , and X ⁵ are each independently N or CH. In some embodiments, X ³ , X ⁴ , and X ⁵ are each CH. In other embodiments are compounds wherein X ³ and X ⁴ are each independently N or CH; X ¹ is CR ¹ ; R ¹ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl. In some embodiments, X ³ and X ⁴ are each CH. Examples of monocyclic optionally substituted G ^3A heterocycles according to the foregoing include oxetan-3-yl, piperidin-4-yl, piperidin-3-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrah dropyran-4-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl.

(IIA-10)

[00179] In other embodiments are compounds of formula (IIA), wherein X ¹ is N or CH; X ³ is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; and -G is -G^R ⁷ (HA- 11), G ^3A (HA- 12), -0-G ^3A (IIA-13), -0-Ci- ₄ alkylene-G ^3A (IIA-14), - R ¹⁰ -G ^3A (IIA-15), - R ¹⁰ -Ci-4alkylene-G ^3A (IIA-16), -Ci- ₄ alkylene-G ^3A (IIA- 17), G ^4A (IIA- 18), and G ^5A (IIA- 19). In further embodiments, G ^3A is an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom. In other embodiments, X ¹ is CH; X ³ is N or CH; and X ⁴ is N or CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is N. In other embodiments, X ¹ is CH; X ³ is N; and X ⁴ is CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is CH. Examples of monocyclic optionally substituted G ^3A

heterocycles according to the foregoing include oxetan-3-yl, piperidin-4-yl, piperidin- 3-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl.

(II A- 11) (DA- 12)

(IIA-13) (IIA-14)

(IIA-15) (IIA-16)

IIA-17) (IIA-18)

(IIA-19)

[00180] In other embodiments are compounds of formula (IIA), wherein X ¹ is N or CH; X ⁴ is N or CH; X ³ is CR ³ ; R ³ is selected from the group consisting of -L ³ -G ^B , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi-4alkyl, -OCi-4haloalkyl, - C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi- ₄ alkyl, and -OCi- ₄ haloalkyl; and I^-G^ is G ^3A (IIA-20). In other embodiments according to the foregoing R ³ is selected from the group consisting of Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ . In further embodiments, G ^3A is an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom. In other embodiments according to the foregoing embodiments of formula (IIA), X ¹ is CH and X ⁴ is CH. Examples of monocyclic optionally substituted G ^3A heterocycles according to the foregoing include oxetan-3-yl, piped din-4-yl, piperidin-3-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl,

tetrahydropyran-4-yl, pyrrolidin-2- l, and pyrrolidin-3-yl.

(IIA-20)

[00181] In some embodiments, iAG ¹³ is -G ⁶ , -O-G ⁶ , - R ³⁰ -G ^B , - R ³⁰ -Ci- ₄ alkylene-G ^B , -0-Ci- ₄ alkylene-G ^B , - R ³⁰ C(O)-G ^B , -C(O) R ³⁰ -G ^B , or -C(0)-G ^B . Subject to the description of formulas (I), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VIA), (VIB), (VII), (VIIA), and (VIIB), L ³ -G ^B includes, but is not limited to, -G ¹ - R ⁷ , -O-G^R ⁷ , - R ³⁰ -G ¹ -R ⁷ , -0-Ci- ₄ alkylene-G ¹ -R ⁷ , - R ³⁰ -Ci- ₄ alkylene-G ¹ -R ⁷ , G ^2B , -C(0)-G ^2B , - R ³⁰ -Ci- ₄ alkylene-G ^2B , -0-Ci- ₄ alkylene-G ^2B , G ^3B , -0-G ^3B , - R ³⁰ -G ^3B , -0-Ci- ₄ alkylene-G ^3B , - R ³⁰ -Ci- ₄ alkylene-G ^3B , -C(O) R ³⁰ -G ^3B , G ^4B , G ^5B , G ^6B , -0-G ^6B , and G ^7B .

[00182] In other embodiments, are compounds of formula (IIB), wherein X ¹ and X ⁵ are each independently N or CH; X ² is CR ² ; R ² is selected from the group consisting of -L ^l -G ^A , Ci- ₄ alkyl, Ci- ₄ haloalkyl, halogen, cyano, nitro, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , -NR ²⁰ (Ci- ₄ haloalkyl), -NR ²⁰ C(O)(Ci- ₄ alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi- ₄ alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci- ₄ haloalkyl), -L ² -Ci- ₆ alkylene- R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi- ₄ alkyl)-Ci-3alkylene- R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-R ²¹ , -L ² -C2- ₄ alkylene-0-C2- ₄ alkylene-0-C2- 4alkylene-R ²¹ , -C3- ₈ alkenyl, -C3- ₈ alkenylene-OH, -C3- ₈ alkenylene-OCi-4alkyl, -C ₃ - ₈ alkynylene-OH, and -C3- ₈ alkynylene-OCi-4alkyl; and L ³ -G ^B is -G^R ⁷ (ΠΒ-l), -O- (ΠΒ-4), - R ³⁰ -Ci- ₄ alkylene-G ¹ -R ⁷ (IIB-5), G ^3B (ΠΒ-6), -0-G ^3B (ΠΒ-7), - R ³⁰ -G ^3B (ΠΒ-8), -O-Ci- ₄ alkylene-G ^3B (IIB-9), - R ³⁰ -Ci-4alkylene-G ^3B (IIB- 10), or -C(O) R ³⁰ -G ^3B (IIB- 11). In further embodiments, G ^3B is an optionally substituted 4- to 8-membered monocyclic heterocycle containing one nitrogen or oxygen atom. In some embodiments according to the foregoing, X ¹ , X ⁴ , and X ⁵ are each independently N or CH. In further embodiments, X ¹ is N or CH, and X ⁴ and X ⁵ are each CH. In some embodiments, X ¹ , X ⁴ , and X ⁵ are each CH. In other embodiments, X ¹ is N, and X ⁴ and X ⁵ are each CH. In other embodiments, X ¹ and X ⁵ are each independently N or CH; X ⁴ is CR ⁴ ; and R ⁴ is selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl. In further embodiments according to the foregoing definitions of X ⁴ and R ⁴ , one of X ¹ and X ⁵ is N and the other CH. In yet other embodiments, X ¹ and X ⁵ are each CH.

(IIB-1) (IIB-2)

(IIB-3)

(IIB-5) (IIB-6)

(IIB-8)

(IIB-9) (IIB- 10)

(IIB-11)

[00183] In other embodiments are compounds of formula (IIB), wherein X ¹ is N or CH; X ² is N or CH; X ⁴ is N or CH; X ⁵ is CR ⁵ ; R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; and L ³ -G ^B is -G^R ⁷ (ΠΒ-12 . In other embodiments, X ¹ is CH; X ² is CH; and X ⁴ is CH.

(IIB-12)

[00184] In some embodiments of formula (III), X ¹ , X ³ , X ⁴ , and X ⁵ are each independently N or CH; R ² is -L ¹ ^, and L ¹ -G ^A is G ^2A (III-l), G ^6A (III-2), -0-G ^6A (III-3), -0-Ci-4alkylene-G ^6A (III-4), - R ¹⁰ -Ci-4alkylene-G ^7A (III-5), G ^8A (III-6), - R ¹⁰ C(O)-G ^8A (III-7), -C(O) R ¹⁰ -G ^8A (III-8), or -C(0)-G ^8A (III-9); provided that L ^l -G ^A is not morpholino when X ³ is N, X ¹ , X ⁴ and X ⁵ are CH, and R ⁸ is phenyl or 4- cyanophenyl. In each of the foregoing embodiments are further groups of compounds wherein X ⁵ is N and X ¹ , X ³ , and X ⁴ are each CH. In other groups of compounds, X ³ is N and X ¹ , X ⁴ , and X ⁵ are each CH. In yet other groups of compounds, X ¹ , X ³ , X ⁴ , and X ⁵ are each CH.

(III-9)

[00185] In some embodiments, of formula (IV), X ¹ and X ⁵ are each independently N or CH; R ² is -L ^l -G ^A , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, nitro, hydroxyl, - OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -OCs-ealkenyl, -C(0)Ci- ₄ alkyl, COOH, -C(0)OCi- ₄ alkyl, - R ²⁰ R ²⁰ , - R ²⁰ (Ci-4haloalkyl), - R ²⁰ C(O)(Ci-4alkyl), - R ²⁰ C(O)(Ci- ₄ haloalkyl), - R ²⁰ C(O)OCi-4alkyl, -C(O) R ²⁰ R ²⁰ , -C(O)NR ²⁰ (Ci-4haloalkyl), -L ² - Ci-6alkylene-R ²¹ , -L ² -Ci-6haloalkylene-R ²¹ , -L ² -Ci-3alkylene-C(H)(OCi-4alkyl)-Ci- ₃ alkylene-R ²¹ , -L ² -C2-4alkylene-0-C2-4alkylene-R ²¹ , -C ₃ -8alkenyl, -C ₃ -8alkenylene- OH, -C ₃ -8alkenylene-OCi-4alkyl, -C ₃ -8alkynylene-OH, and -C ₃ -8alkynylene-OCi- 4alkyl; R ³ is selected from the group consisting of -L ³ -G ^B , Ci-4alkyl, Ci-4haloalkyl, halogen, cyano, hydroxyl, -OCi- ₄ alkyl, -OCi- ₄ haloalkyl, -C(0)Ci- ₄ alkyl, -C(0)OCi- ₄ alkyl, - R ⁴⁰ R ⁴⁰ , and -C(O) R ⁴⁰ R ⁴⁰ ; -L ¹ ^ is G ^2A (IV- 1), -C(O) R ¹⁰ -G ^6A (IV-2), or -0-Ci-4alkylene-G ^8A (IV-3); -L ³ -G ^B is G ^2B (IV-4), -C(0)-G ^2B (IV-5), - R ³⁰ -Ci- ₄ alkylene-G ^2B (IV-6), (IV-7), G ^6B (IV-8), -0-G ^6B (IV-9), and G ^7B (IV- 10); and R ⁸ and X ⁴ are as defined herein. In some embodiments according to the foregoing, X ⁴ is N or CH. In further embodiments, X ¹ is N or CH, and X ⁴ and X ⁵ are each CH. In some embodiments, X ¹ , X ⁴ , and X ⁵ are each CH. In other embodiments X ¹ is N, and X ⁴ and X ⁵ are each CH.

(IV-9) (IV- 10) [00186] In some embodiments of formulas (IV) and (IV-1) to (IV-10), as defined above, X ⁴ is CR ⁴ ; and R ⁴ is selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, -OCi-4alkyl, -OCi-4haloalkyl, and G ^c . In further embodiments, one of X ¹ and X ⁵ is N and the other CH. In yet other embodiments, X ¹ and X ⁵ are each CH. In some groups of compounds, R ⁴ is selected from the group consisting of Ci-4alkyl, halogen, and -OCi-4alkyl.

[00187] In some embodiments of formula (V), X ³ and X ⁴ are each independently N or CH; X ⁵ is N or CR ⁵ ; R ¹ is selected from the group consisting of Ci-4alkyl, Ci- 4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl; R ² is -L ^l -G ^A and -L ^l -G ^A is G ^2A (V-l), G ^6A (V-2), G ^7A (V-3), or G ^8A (V-4). In some embodiments, X ⁵ is N or CH. In some embodiments X ³ , X ⁴ , and X ⁵ are each CH.

[00188] In some embodiments of formulas (V), (V-l), (V-2), (V-3), or (V-4), as defined above, X ⁵ is CR ⁵ ; and R ⁵ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, and -OCi-4haloalkyl. In further embodiments, X ³ and X ⁴ are each CH. In further embodiments, R ¹ is selected from the group consisting of Ci-4alkyl and -OCi-4alkyl.

[00189] In some embodiments of formula (VIB), X ¹ , X ³ , and X ⁴ are N or CH; R ⁵ and R ⁸ are as defined in formula (VI); R ² is -L ¹ -^; and -L ¹ ^ is G ^2A (VIB-1), G ^7A (Vm-2), -0-Ci- ₄ alkylene-G ^7A (VIB-3), and - R ¹⁰ -Ci-4alkylene-G ^7A (VIB-4). In some groups of compounds, R ⁵ is selected from the group consisting of Ci-4alkyl, halogen, and -OCi-4alkyl. In other embodiments, X ¹ is CH; X ³ is N or CH; and X ⁴ is N or CH. In other embodiments, X ¹ is CH; X ³ is CH; and X ⁴ is N. In other embodiments, X ¹ is CH; X ³ is N; and X ⁴ is CH. In other embodiments, X ¹ is CH; X is CH and X ⁴ is CH.

(VIB-4) [00190] In some embodiments of the compounds of formula (VII), as defined herein, X ¹ , X ³ , and X ⁵ are each independently N or CH; R ² is -L ^l -G ^A R ⁴ is selected from the group consisting of Ci-4alkyl, Ci-4haloalkyl, halogen, -OCi-4alkyl, -OCi- ₄ haloalkyl, and G ^c ; and L ¹ ^ is G ^2A (VII-1), G ^6A (VII-2), -0-Ci-4alkylene-G ^6A (VII-3), - R ¹⁰ -Ci-4alkylene-G ^6A (VII-4), or - R ¹⁰ C(O)-G ^6A (VII-5); and G ^c is G ^6C or G ^8C . In further embodiments, X ¹ is CH; X ³ is CH; and X ⁵ is CH. In other embodiments, X ¹ is CH; X ³ is N; and X ⁵ is CH. In other embodiments, X ¹ is CH; X ^: is CH; and X ⁵ is N. In other embodiments, X ¹ is N; X ³ is CH; and X ⁵ is CH.

(VII-5)

[00191] The formulas (I), (II), and (IIB) to (VIIB), and corresponding embodiments, and groups of compounds may be further defined according to the following description.

[00192] In some embodiments, X ² is CR ² , where R ² may be:

[00193] hydrogen;

[00194] Ci-4alkyl (e.g., methyl, ethyl, tert-butyl);

[00195] Ci-4haloalkyl (e.g., CF ₃ );

[00196] halogen (e.g., bromo, fluoro);

[00197] cyano;

[00198] nitro;

[00199] hydroxyl;

[00200] -OCi- ₄ alkyl (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH ₃ ) ₂ , - OCH2CH2CH2CH3, -OCH ₂ CH(CH ₃ )2, -OCH(CH ₃ )CH ₂ CH3);

[00201] -OCi-4haloalkyl (e.g., -OCF3, -OCH2CHF2);

[00202] -OC ₃ -6alkenyl (e.g., -OCH ₂ CH=CH ₂ );

[00203] -C(0)Ci- ₄ alkyl (e.g., -C(0)CH ₃ );

[00204] -COOH; [00205] -C(0)OCi- ₄ alkyl (e.g., -C(0)OCH ₃ );

[00206] - R ²⁰ R ²⁰ (e.g., - H ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , - HCH(CH ₃ ) ₂ , - NCH ₃ CH(CH ₃ ) ₂ ,);

[00207] - R ²⁰ (Ci-4haloalkyl) (e.g., - HCH2CH2CH2F, - HCH ₂ CF ₃ );

[00208] - R ²⁰ C(O)(Ci-4alkyl) (e.g., - HC(0)CH ₃ , - HC(0)CH(CH ₃ ) ₂ );

[00209] - R ²⁰ C(O)(Ci-4haloalkyl) (e.g., - HC(0)CH ₂ CF ₃ );

[00210] - R ²⁰ C(O)OCi-4alkyl (e.g., - HC(O)O-tert-butyl);

[00211] -C(O) R ²⁰ R ²⁰ (e.g., -C(0) H ₂ , -C(0) HCH ₃ , -C(0) HCH ₂ CH ₃ , - C(0)N(CH ₃ ) ₂ , -C(0)NCH(CH ₃ ) ₂ );

[00212] -C(O) R ²⁰ (Ci-4haloalkyl) (e.g., -C(0) HCH ₂ CF ₃ );

[00213] -L ² -Ci- ₆ alkylene-R ²¹ ;

[00214] -L ² -Ci- ₆ haloalkylene-R ²¹ ;

[00215] -L ² -Ci- ₃ alkylene-C(H)(OCi-4alkyl)-Ci- ₃ alkylene-R ²¹ , (e.g., - H-Ci- ₃ alkylene-C(H)(OCi-4alkyl)-Ci- ₃ alkylene-OCi-4alkyl, such as - HCH ₂ -CH(OCH ₃ )- CH ₂ -OCH ₃ );

[00216] -L ² -C ₂ -4alkylene-0-C ₂ -4alkylene-R ²¹ (e.g., - H-C ₂ -4alkylene-0-C ₂ - 4alkylene-N(Ci-4alkyl)(Ci-4alkyl), such as - H-CH ₂ CH ₂ OCH2CH2N(CH ₃ )2);

[00217] -L ² -C2-4alkylene-0-C ₂ -4alkylene-0-C ₂ -4alkylene-R ²¹ (e.g., -O- CH2CH2-O-CH2CH2-O-CH2CH2- H2);

[00218] -C _3-8 alkenyl (e.g., -CH=CHC(CH ₃ ) ₃ );

[00219] -C _3-8 alkenylene-OH (e.g., -CH=CHCH ₂ -OH);

[00220] -C ₃ - ₈ alkenylene-OCi-4alkyl (e.g., -CH=CHCH ₂ -OCH ₃ );

[00221] -C ₃ - ₈ alkynylene-OH (e.g., -C≡C-C(CH ₃ )(OH)CH ₂ CH ₃ ); or

[00222] -C ₃ - ₈ alkynylene-OCi-4alkyl (e.g., -C≡C-C(CH ₃ )(OCH ₃ )CH ₂ CH ₃ ).

[00223] In some embodiments where R ² is -L ² -Ci- ₆ alkylene-R ²¹ , L ² is a bond (e.g., -Ci-6alkylene-OCi-4alkyl, -Ci-6alkylene-OH, -Ci-6alkylene- H ₂ , -Ci- ₆ alkylene- HC(0)Ci-4alkyl, -Ci-6alkylene- HC(0)OCi-4alkyl, -Ci-ealkylene- HS(0) ₂ Ci-4alkyl, -Ci- ₆ alkylene— C(0)Ci-4alkyl). In some embodiments where L ² is a bond, the L ² -Ci- ₆ alkylene-R ²¹ is Ci- ₃ alkylene-R ²¹ . Examples include -CH2OCH3, -C(CH ₃ ) ₂ OH, -CH2OH, -CH(CH ₃ )OH, -CH ₂ CH(CH ₃ )OH, -CH ₂ HC(0)0-t-butyl, - CH2 H2, -CH ₂ HC(0)CH ₃ , -CH ₂ HS(0) ₂ CH ₃ , and -CH ₂ C(0)CH ₃ .

[00224] In some embodiments where R ² is -L ² -Ci- ₆ alkylene-R ²¹ , L ² is -O- (e.g., - 0-Ci-6alkylene-OCi-4alkyl). In some embodiments where L ² is -0-, the L ² -Ci- ealkylene-R ²¹ is -O-Ci-salkylene-R ²¹ . Examples include -O-CH2CH2-OCH3 and -

[00225] In some embodiments where R ² is -L ² -Ci- ₆ alkylene-R ²¹ , L ² is - H- (e.g., - H-Ci-6alkylene-OCi-4alkyl, -NH-Ci-6alkylene-N(Ci-4alkyl)(Ci-4alkyl), - H-Ci- 6alkylene-C(0)N(Ci-4alkyl)(Ci-4alkyl), - H-Ci-6alkylene-N(Ci-4alkyl)C(0)OCi- 4alkyl, - H-Ci-6alkylene-CN). In some embodiments where L ² is -NH- the L ² -Ci- ₆ alkylene-R ²¹ is -NH-Ci-3alkylene-R ²¹ or -NH-C2-5alkylene-R ²¹ . Examples include -NH-CH ₂ CH ₂ CH2-0-t-butyl, -NH-CH2CH2CH2-OCH3, -NH-CH(CH ₃ )CH ₂ -OCH3, -NH-CH(CH3)CH(CH ₃ )-OCH3, -NH-CH(CH ₃ )CH2-OCH ₂ CH3, -NH- CH ₂ CH(CH3)-OCH ₂ CH3, -NH-CH ₂ C(CH ₃ )2-OCH3, -NH-CH ₂ CH ₂ CH(CH3)-OCH3, -NH-CH ₂ CH2CH2N(CH ₂ CH3)2, -NH-CH ₂ CH ₂ N(CH3)2, -NH- CH ₂ C(CH3)2CH ₂ N(CH3)2, -NH-CH ₂ C(0)N(CH ₂ CH3)2, -NH- CH(CH3)C(0)N(CH ₃ )2, -NH-CH ₂ C(CH ₃ )2CN, and -NH-CH ₂ CH ₂ N(CH3)C(0)0-t- butyl.

[00226] In some embodiments where R ² is -L ² -Ci-6alkylene-R ²¹ , L ² is -N(Ci- 4alkyl)- (e.g., N(Ci-4alkyl)-Ci-6alkylene-OCi-4alkyl, -N(Ci-4alkyl)-Ci-6alkylene- OH). In some embodiments where L ² is -N(Ci-4alkyl)-, the L ² -Ci- ₆ alkylene-R ²¹ is - N(Ci-4alkyl)-Ci-3alkylene-R ²¹ or -N(Ci-4alkyl)-C2-5alkylene-R ²¹ . Examples include -NCH3-CH2CH2CH2-OCH3 and -NCH3-CH ₂ CH(CH ₃ )-OH.

[00227] In some embodiments where R ² is -L ² -Ci-6alkylene-R ²¹ , L ² is -NHC(O)- (e.g., -NHC(0)-Ci-6alkylene-OCi-4alkyl, such as -NHC(0)-CH ₂ -OCH ₃ ). In some embodiments where L ² is -NHC(O)-, the L ² -Ci- ₆ alkylene-R ²¹ is -NHC(0)-Ci- 3alkylene-R ²¹ .

[00228] In some embodiments where R ² is -L ² -Ci-6haloalkylene-R ²¹ , L ² is -NH- (e.g., -NH-Ci-6haloalkylene-OCi-4alkyl, such as NH-CH ₂ CH(CF3)-OCH ₃ ). In some embodiments where L ² is -NH- the L ² -Ci-6haloalkylene-R ²¹ is -NH-C2- shaloalkylene-R ²¹ .

[00229] In some embodiments where R ² is -L ² -Ci-6haloalkylene-R ²¹ , L ² is -O- (e.g., -O-Ci-ehaloalkylene-OH, such as -0-CH2CH(CH ₂ Cl)CH ₂ OH and -O- CH2C(CH3)(CH ₂ C1)CH ₂ 0H). In some embodiments where L ² is -0-, the L ² -Ci- ₆ haloalkylene-R ²¹ is -0-C2-shaloalkylene-R ²¹ . [00230] In embodiments according to formula (III) where R ² is -L ² -Ci-6alkylene- R ²¹ , the -L ² -Ci- ₆ alkylene-R ²¹ may be Ci-3alkylene-OH or -O-Ci-salkylene-OCi- 4alkyl.

[00231] In embodiments according to formula (V) where R ² is -L ² -Ci- ₆ alkylene- R ²¹ , the -L ² -Ci- ₆ alkylene-R ²¹ may be Ci- ₃ alkylene-OH or - H-Ci-salkylene-OCi- 4alkyl.

[00232] In embodiments according to formula (VI), (VIA), or (VIB) where R ² is - L ² -Ci- ₆ alkylene-R ²¹ , the -L ² -Ci- ₆ alkylene-R ²¹ may be Ci- ₃ alkylene-OH or - H-C2- 5alkylene-OCi-4alkyl.

[00233] In embodiments according to formula (VII), (VIIA), or (VIIB) where R ² is -L ² -Ci- ₆ alkylene-R ²¹ , the -L ² -Ci- ₆ alkylene-R ²¹ may be -Ci- ₃ alkylene-OH, -Ci- ₃ alkylene-OCi- ₄ alkyl, -Ci- ₃ alkylene- H ₂ , -Ci- ₃ alkylene- HC(0)Ci-4alkyl, -Ci- ₃ alkylene- HC(0)OCi-4alkyl, -Ci- ₃ alkylene- HS(0) ₂ Ci-4alkyl, -Ci- ₃ alkylene- C(0)Ci- ₄ alkyl, -0-C ₂ -5alkylene-OCi-4alkyl, - H-C ₂ -5alkylene-OCi-4alkyl, -N(Ci- 4alkyl)-C ₂ -5alkylene-OCi-4alkyl, -N(Ci-4alkyl)-C ₂ -5alkylene-OH, - H-C ₂ - ₅ alkylene- N(Ci-4alkyl)(Ci-4alkyl), - HCi- ₃ alkylene-C(0)N(Ci-4alkyl)(Ci-4alkyl), - H-Ci- ealkylene-CN, - H-C ₂ -5alkylene-N(Ci-4alkyl)C(0)OCi-4alkyl, or - HC(0)-Ci- ₃ alkylene-OCi-4alkyl.

[00234] In some embodiments of formulas (I) - (VIIB), X ⁴ is CR ⁴ , where R ⁴ may be:

[00235] hydrogen;

[00236] Ci- ₄ alkyl;

[00237] Ci- ₄ haloalkyl;

[00238] halogen;

[00239] -OCi- ₄ alkyl;

[00240] -OCi- ₄ haloalkyl; or

[00241] G ^c (i.e., G ^6C or G ^8C ).

[00242] For example, G ^6C may be a cyclopropyl. G ^8C may be a phenyl group.

[00243] Further according to each of the foregoing embodiments, R ⁸ is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R ⁸ being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen (e.g., fluoro, chloro), hydroxyl, cyano, -S(0) ₂ Ci-4alkyl (e.g., -S0 ₂ CH ₃ ), -S(0)Ci- ₄ alkyl (e.g., -SOCH ₃ ), -SCi- ₄ alkyl (e.g., -SCH ₃ ), Ci- ₄ alkyl (e.g., methyl, ethyl), Ci- ₄ haloalkyl (e.g., -CF ₃ ), -C ₃ - ₆ alkenyl (e.g., -CH ₂ CH=CH ₂ ), -OCi- ₄ alkyl (e.g., -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ ), -OCi- ₄ haloalkyl (e.g., -OCF ₃ ), -Ci- ₄ alkylene-OCi- ₄ alkyl (e.g., -CH ₂ OCH ₃ ), -Ci- ₄ alkylene-N(Ci- ₄ alkyl)(Ci- ₄ alkyl) (e.g., - CH ₂ N(CH ₃ )(CH ₂ CH ₃ )), - H(Ci- ₄ alkylene-OCi- ₄ alkyl) (e.g., - H(CH ₂ CH ₂ OCH ₃ )), - H(Ci- ₄ alkylene-OH) (e.g., - H(CH ₂ CH ₂ OH)), -N(Ci- ₄ alkyl)(Ci- ₄ alkylene-OCi- ₄ alkyl) (e.g., -N(CH ₃ )(CH ₂ CH ₂ OCH ₃ )), -N(Ci- ₄ alkyl)(Ci- ₄ alkylene-OH)(e.g., - N(CH ₃ )(CH ₂ CH ₂ OH)), - H ₂ , - H(Ci- ₄ alkyl), -N(Ci- ₄ alkyl)(Ci- ₄ alkyl)), -C(0) H ₂ , -C(0) H(Ci- ₄ alkyl), -C(0)N(Ci- ₄ alkyl)(Ci- ₄ alkyl), -L ⁴ -G ¹⁰ , C ₃ - ₆ cycloalkyl, Cs- 6cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, and optionally an oxygen or sulfur atom, the monocyclic heterocycle optionally containing one double bond and/or a Ci- ₃ alkylene bridge between two non- adjacent ring atoms, (e.g., azetidin-l-yl, pyrrolidin-l-yl, azepan-l-yl, 3,9- diazabicyclo[4.2.1]nonan-3-yl), the C ₃ -6cycloalkyl, the C5-6cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-4 substituents independently selected from the group consisting of halogen (e.g., fluoro), hydroxyl, -OCi- ₄ alkyl (e.g., -OCH ₃ ), Ci- ₄ alkyl (e.g., ethyl), Ci- ₄ haloalkyl, -Ci- ₄ alkylene-OCi- ₄ alkyl (e.g., -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ ), and -Ci- ₄ alkylene-OH (e.g., -CH ₂ OH, -C(OH)(CH ₃ ) ₂ ), wherein L ⁴ and G ¹⁰ are as defined herein. In further embodiments, R ⁸ is phenyl, or a 6-membered heteroaryl such as pyrazinyl, pyrimidinyl, pyridazinyl, or pyridinyl, each optionally substituted as defined above. The 6-membered heteroaryl at R ⁸ includes a pyridone ring, which is defined herein by the tautomeric hydroxypyridine form, whether or not the pyridone or the hydroxypyridine tautomer predominates. In some embodiments, R ⁸ is phenyl, the phenyl being optionally substituted with one substituent selected from the group consisting of halogen, hydroxyl, cyano, Ci- ₄ alkyl, Ci- ₄ haloalkyl, -C ₃ - ₆ alkenyl, -OCi- ₄ alkyl, -C(0)NH ₂ , -L ⁴ -G ¹⁰ , or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, and optionally a Ci- ₃ alkylene bridge between two non- adjacent ring atoms, the 4- to 8-membered monocyclic heterocycle being

independently optionally substituted with 1-2 substituents independently selected from the group consisting of Ci- ₄ alkyl (e.g., CH ₃ ) and -Ci- ₄ alkylene-OH (e.g.,

CH ₂ OH), and the phenyl being further optionally substituted with 1-2 substituents independently selected from the group consisting of halogen and Ci- ₄ alkyl. [00244] According to the foregoing description of R ⁸ , L ⁴ -G ¹⁰ may be - R ⁹ -Ci- 4alkylene-phenyl (e.g., -NHCH ₂ -phenyl) or - R ⁹ -Ci-4alkylene-pyridinyl (e.g., - HCH(CH ₃ )-pyridin-2-yl, HCH(CH ₃ )-5-fluoropyridin-2-yl).

[00245] Alternatively, R ⁸ is pyrazinyl, the pyrazinyl being optionally substituted with 1-3 Ci-4alkyl groups. In another alternative, R ⁸ is pyrimidinyl (e.g., pyrimidin-4- yl, pyrimidin-5-yl), the pyrimidinyl being optionally substituted with one substituent selected from halogen, -S(0) ₂ Ci- ₄ alkyl, -S(0)Ci- ₄ alkyl, -SCi- ₄ alkyl, Ci- ₄ alkyl, -OCi- ₄ alkyl, or -Ci- ₄ alkylene-OCi- ₄ alkyl, the pyrimidinyl being further optionally substituted with Ci- ₄ alkyl. In still a further alternative, R ⁸ is pyridazinyl (e.g., pyridazin-4-yl). In another alternative, R ⁸ is pyridinyl (e.g., pyridin-2-yl, pyridin-3- yl, pyridin-4-yl), the pyridinyl being optionally substituted with one substituent selected from the group consisting of halogen, hydroxyl, Ci- ₄ alkyl, and a 4- to 8- membered monocyclic heterocycle containing 1-2 nitrogen atoms, the pyridinyl being further optionally substituted with 1-2 substituents selected from halogen and Ci- ₄ alkyl.

[00246] In further embodiments according to the foregoing, R ⁸ is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci- ₄ alkyl. For example, in certain embodiments, R ⁸ is phenyl optionally substituted with 1-2 fluoro atoms or 1 fluoro and 1 methyl group. In certain embodiments, R ⁸ is independently any of phenyl, 3,5-difluorophenyl, 3 -fluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, or 3-fluoro-5-methylphenyl.

[00247] In further embodiments according to the foregoing, R ⁸ is pyrazine, which is unsubstituted.

[00248] In other embodiments, the compouds of the present invention include 5- isopropoxy-2-methyl-N-(l -phenyl- l,2,4-triazol-3-yl)pyridin-3 -amine; 2-ethyl-5- isopropoxy-N-(l-phenyl-l,2,4-triazol-3-yl)pyridin-3-amine; N-[l-(3,5- difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-2-(oxetan-3-yl) -3,4-dihydro-lH- i soquinolin-7-amine; 1 -(3 , 5 -difluorophenyl)-N- [3 ,4-dimethyl-5 -(3 - morpholinoazeti din- l-yl)phenyl]-l,2,4-triazol-3 -amine; l-(3,4-difluorophenyl)-N-[3- methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]phenyl]-l,2,4-triazo l-3-amine; 1 -(3,5- difluorophenyl)-N-(3-isopropoxy-5-methyl-phenyl)-l,2,4-triaz ol-3-amine; l-(3,4- difluorophenyl)-N-(3-isopropoxy-5-methyl-phenyl)-l,2,4-triaz ol-3-amine; N-[3- methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]acetamid e; N-(3-isopropoxy-5- methyl-phenyl)-l-(3-pyridyl)-l,2,4-triazol-3-amine; N-(3-isopropoxy-5-methyl- phenyl)- 1 -(2-pyridyl)- 1 ,2,4-triazol-3 -amine; N-(3 -isopropoxy-5-methyl-phenyl)- 1 - phenyl- l,2,4-triazol-3 -amine; and l-[4-methyl-3-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]ethanol.

[00249] In another embodiment, the compounds of formula (Γ) include isotope- labelled forms thereof. An isotope-labelled form of a compound of formula (Γ) is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of formula (Γ) by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ C1, respectively.

[00250] In another embodiment, a compound of formula (Γ) or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.

[00251] In another embodiment, the present invention features a compound of formula (Γ) and the attendant definitions, wherein one or more hydrogen atoms are replaced by a deuterium atom.

[00252] In another embodiment, an isotope-labelled compound of formula (Γ) can be used in a number of beneficial ways. In one embodiment, an isotope-labelled compound of formula (Γ) into which, for example, a radioisotope, such as ³ H or ¹⁴ C, has been incorporated is suitable for a medicament and/or for substrate tissue distribution assays. In one embodiment, tritium ( ³ H) and carbon-14 ( ¹⁴ C) are particularly preferred owing to simple preparation and excellent detectability.

[00253] In yet another embodiment, incorporation of heavier isotopes, for example deuterium ( ² H), into a compound of formula (Γ) have therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of formula (Γ) can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[00254] In another embodiment, Deuterium ( ² H) can also be incorporated into a compound of formula (Γ) for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.

Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non- exchangeable position, rate differences of kM/kD = 2-7 are typical. If this rate difference is successfully applied to a compound of formula (Γ) that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.

[00255] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of formula (Γ) with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of compounds of formula (Γ) are thereby obtained, and can be expressed

quantitatively in terms of increases in the in vivo half-life (ti/2), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs. [00256] The following is intended to illustrate the above: a compound of formula (Γ) which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium- hydrogen exchange of this type.

[00257] In another embodiment, deuterium-hydrogen exchange in a compound of formula (Γ) can be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683- 688, 1993.

[00258] In another embodiment, the invention features a compound of formula (Γ), wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1 below.

[00259] Table 1. Compound Table

75

76

97 98

99 100

101 102

103 104

105 106

107 108

85

92

95

331 332

333 334

335 336

337 338

339 340

341 342

411 412

413 414

416

417 418

419 420

117

118

119

120

121

636

638

639 640

641 642

643 644

645 646

659

260] Table 2. Compound Names (IUPAC Nomenclature)

Cmpd

Cmpd Name

No.

23 N-(3-fluoro-5-methyl-phenyl)-l-phenyl-l,2,4-triazol-3-amine

24 N-(3 -isopropoxyphenyl)- 1 -(2-pyridyl)- 1 ,2,4-triazol-3 -amine

25 l-phenyl-N-(3-phenylphenyl)-l,2,4-triazol-3 -amine

26 N-[3-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]benzamide

27 N-(m-tolyl)- 1 -phenyl- 1 ,2,4-triazol-3 -amine

28 N-(3-bromophenyl)-l -phenyl- l,2,4-triazol-3 -amine

29 3-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzoic acid

30 Nl -( 1 -phenyl- 1 ,2,4-triazol-3 -yl)benzene- 1 ,3 -diamine

31 [2-[(l-phenyl-l,2,4-triazol-3-yl)amino]-4-pyridyl]methanol

32 4-methyl-N-(l -phenyl- l,2,4-triazol-3-yl)pyridin-2-amine

33 2-methyl-N-(l -phenyl- l,2,4-triazol-3-yl)pyridin-4-amine

34 N-phenyl-3-[(l -phenyl- l,2,4-triazol-3-yl)amino]benzamide

35 phenyl-[3-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]methanone

36 N-(2-fluoro-5-isopropoxy-phenyl)-l-phenyl-l,2,4-triazol-3- amine

37 N-(4-fluoro-3-isopropoxy-phenyl)-l-phenyl-l,2,4-triazol-3- amine

38 3-[(l -phenyl- l,2,4-triazol-3-yl)amino]benzonitrile

39 N-[4-chloro-3 -(trifluoromethoxy)phenyl]- 1 -phenyl- 1 ,2,4- triazol-3 -amine

40 N-[4-fluoro-3-(trifluoromethoxy)phenyl]-l -phenyl- 1,2,4- triazol-3 -amine

41 N-[3-methyl-5-(trifluoromethoxy)phenyl]- 1 -phenyl- 1 ,2,4- triazol-3 -amine

42 N-(3-isopropoxyphenyl)-l-(3-pyridyl)-l,2,4-triazol-3-amine

43 4-ethoxy-N-(l -phenyl- l,2,4-triazol-3-yl)pyridin-2-amine

44 4-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-2,3-dihydro-l,4- benzoxazin-7-amine

45 N-(2,3 -dihydro- 1 ,4-benzodioxin-6-yl)- 1 -(3 -pyridyl)- 1 ,2,4- triazol-3 -amine

46 N-(l,3-benzodioxol-5-yl)-l-(3-pyridyl)-l,2,4-triazol-3-amine

47 N-(3,5-dimethoxyphenyl)-l-(3-pyridyl)-l,2,4-triazol-3-amine

48 N-(3,5-dimethylphenyl)-l-(3-pyridyl)-l,2,4-triazol-3-amine

49 N-[3-(cyclopentoxy)phenyl]-l-phenyl-l,2,4-triazol-3-amine

50 N-(3-benzyloxy-4-methyl-phenyl)-l -phenyl- l,2,4-triazol-3 - amine Cmpd

Cmpd Name

No.

51 N-[2-fluoro-5-(trifluoromethoxy)phenyl]-l -phenyl- 1 ,2,4- triazol-3 -amine

52 2-methoxy-N-methyl-5-[( 1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]benzamide

53 N-(5-isopropoxy-2-methyl-phenyl)-l-phenyl-l,2,4-triazol-3- amine

54 N-[3 -(cyclopropylmethoxy)phenyl]- 1 -(3 -pyridyl)- 1 ,2,4-triazol- 3 -amine

55 l-(3-pyridyl)-N-[3-(trifluoromethoxy)phenyl]-l,2,4-triazol-3 - amine

56 N-(3-methoxy-5-methyl-phenyl)-l-(3-pyridyl)-l,2,4-triazol-3- amine

57 2-isopropoxy-4-[( 1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]benzonitrile

58 N-(3-methoxy-4-oxazol-5-yl-phenyl)-l -phenyl- l,2,4-triazol-3- amine

59 4-[3-(5-methoxy-2-methyl-anilino)-l,2,4-triazol-l-yl]pyridin -2- ol

60 N-[3-(4-methylpiperazin-l-yl)phenyl]-l-phenyl-l,2,4-triazol- 3- amine

61 N-[3-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]acetamide

62 Nl ,N1 -dimethyl-N3 -( 1 -phenyl- 1 ,2,4-triazol-3 -yl)benzene- 1,3- diamine

63 4-methyl-Nl-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3-diamine

64 4-methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3-diamine

65 N-[3-methoxy-5-(trifluoromethoxy)phenyl]-l-phenyl-l,2,4- triazol-3 -amine

66 [3-[(l-phenyl-l,2,4-triazol-3-yl)amino]-5- (trifluoromethoxy )pheny 1 ] methanol

67 3-isobutoxy-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzoic acid

68 N-(5-ethoxy-2,3-dimethyl-phenyl)-l -phenyl- l,2,4-triazol-3- amine

69 N-(3-methoxyphenyl)-l -phenyl- l,2,4-triazol-3 -amine

70 Nl-methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3- diamine

71 4-fluoro-Nl -(1 -phenyl- 1 ,2,4-triazol-3 -yl)benzene- 1 ,3 -diamine

72 3 -[(1 -phenyl- 1 ,2,4-triazol-3 -yl)amino]phenol

73 l-phenyl-N-(2,4,5-trimethylphenyl)-l,2,4-triazol-3-amine

74 N-(4-fluoro-2,5-dimethyl-phenyl)-l-phenyl-l,2,4-triazol-3- amine

75 N-(4,5-difluoro-2-methoxy-phenyl)- 1 -phenyl- 1 ,2,4-triazol-3 - amine Cmpd

Cmpd Name

No.

76 N-(2,5-difluoro-4-methoxy-phenyl)- 1 -phenyl- 1 ,2,4-triazol-3 - amine

77 l-phenyl-N-(2,4,5-trifluorophenyl)-l,2,4-triazol-3-amine

78 N-(3-methoxy-5-methyl-phenyl)-l-phenyl-l,2,4-triazol-3-amine

79 N-(3,5-dimethoxyphenyl)-l -phenyl- l,2,4-triazol-3 -amine

80 N-[3-(cyclopropylmethoxy)-5-methyl-phenyl]-l-phenyl-l,2,4- triazol-3 -amine

81 N-(3-fluoro-5-sec-butoxy-phenyl)-l-phenyl-l,2,4-triazol-3- amine

82 2, 5-dimethyl-Nl -( 1 -phenyl- 1 ,2,4-triazol-3 -yl)benzene- 1 ,4- diamine

83 N-(5-methoxy-2-methyl-phenyl)-l-(2-methoxy-4-pyridyl)- l,2,4-triazol-3 -amine

84 N-(3 -isopropoxyphenyl)- 1 -(2-methoxy-4-pyridyl)- 1 ,2,4-triazol- 3 -amine

85 N-benzyl-4-[3-(5-methoxy-2-methyl-anilino)-l,2,4-triazol-l- yl]pyridin-2-amine

86 N-benzyl-4-[3-(3-isopropoxyanilino)-l,2,4-triazol-l-yl]pyrid in- 2-amine

88 methyl 2-methoxy-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzoate

89 N-(3 -isopropoxyphenyl)- 1 -(4-pyridyl)- 1 ,2,4-triazol-3 -amine

90 4-methoxy-Nl-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3- diamine

91 N-(3 -morpholinophenyl)- 1 -phenyl- 1 ,2,4-triazol-3 -amine

92 Nl ,4-dimethyl-N3 -(1 -phenyl- 1 ,2,4-triazol-3 -yl)benzene- 1,3- diamine

93 N-(3,5-dimethylphenyl)-l-(4-pyridyl)-l,2,4-triazol-3-amine

94 5-isopropoxy-2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)pyridin - 3 -amine

95 N-(5-ethoxy-2-methyl-phenyl)-l-phenyl-l,2,4-triazol-3-amine

96 4-fluoro-6-methyl-Nl -(1 -phenyl- 1 ,2,4-triazol-3 -yl)benzene- 1,3- diamine

97 N-[4-ethyl-3 -[( 1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]phenyl]acetamide

98 N-(4-isopropoxy-3 -morpholino-phenyl)- 1 -phenyl- 1 ,2,4-triazol- 3 -amine

99 N-(3,5-diisopropoxyphenyl)-l-phenyl-l,2,4-triazol-3-amine

100 2-methoxy-N,N-dimethyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzamide

101 2- methoxy-N-(l-methylcyclopropyl)-5-[(l-phenyl-l,2,4-triazol-

3- yl)amino]benzamide Cmpd

Cmpd Name

No.

102 N-isopropyl-2-methoxy-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzamide

103 2-methoxy-5-[(l -phenyl- l,2,4-triazol-3-yl)amino]benzamide

104 N-ethyl-2-methoxy-4-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzamide

105 N-ethyl-2-fluoro-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzamide

106 2-methoxy-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-N-(2,2,2- trifluoroethyl)benzamide

107 N-methyl-3 -[(1 -phenyl- l,2,4-triazol-3-yl)amino]benzamide

108 N-ethyl-2-methoxy-5-[( 1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]benzamide

109 2-methoxy-5-[(l -phenyl- l,2,4-triazol-3-yl)amino]benzoic acid

1 10 N-[3 -(cyclopropoxy)phenyl]- 1 -phenyl- 1 ,2,4-triazol-3 -amine

1 1 1 N-[3-(oxetan-3-yloxy)phenyl]-l-phenyl-l,2,4-triazol-3-amine

1 12 l-phenyl-N-(3-tetrahydrofuran-3-yloxyphenyl)-l,2,4-triazol-3 - amine

1 13 l-phenyl-N-(3-tetrahydropyran-4-yloxyphenyl)-l,2,4-triazol-3 - amine

1 14 N-[5-(lH-imidazol-2-yl)-2-methyl-phenyl]-l-phenyl-l,2,4- triazol-3 -amine

1 15 N-(3-isopropoxy-4-methyl-phenyl)-l-phenyl-l,2,4-triazol-3- amine

1 16 N-(5-isopropoxy-2-isopropyl-phenyl)-l-phenyl-l,2,4-triazol-3 - amine

1 17 N-[4-(3-furyl)-3-methoxy -phenyl]- 1-phenyl-l, 2,4-triazol-3- amine

1 18 N-(3-methoxy-4-tetrahydrofuran-3-yl-phenyl)- 1-phenyl-l, 2,4- triazol-3 -amine

1 19 N-ethyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-2,3- dihydrobenzofuran-7-carboxamide

120 1 -phenyl-N-(3 -pyrrolidin- 1 -ylphenyl)- 1 ,2,4-triazol-3 -amine

121 N2-[(l S)-l -(5-fluoro-2-pyridyl)ethyl]-N4-(l-phenyl-l,2,4- triazol-3-yl)pyridine-2,4-diamine

122 tert-butyl 3-[3-[(l-phenyl-l,2,4-triazol-3- yl)aminolphenyl]piperidine-l-carboxylate

123 l-phenyl-N-[3 -(3 -piped dyl)phenyl]-l,2,4-triazol-3 -amine

124 methyl 2-methoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzoate

125 2-methoxy-N-(oxetan-3-yl)-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzamide

126 rel-N- [3 -methoxy-4- [(3 S)-tetrahy drofuran-3 -yljphenyl] - 1 - phenyl- 1 ,2,4-triazol-3 -amine Cmpd

Cmpd Name

No.

127 re/-N-[3-methoxy-4-[(3R)-tetrahydrofuran-3-yl]phenyl]-l- phenyl- 1 ,2,4-triazol-3 -amine

128 tert-butyl 3-[2-methoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)aminolphenyl]pyrrolidine- 1 -carboxylate

129 N-(3 -methoxy-4-pyrrolidin-3 -yl-phenyl)- 1 -phenyl- 1 ,2,4-triazol - 3 -amine

130 1 -[3 -[2-methoxy-4-[(l -phenyl- 1 ,2,4-triazol-3 - yl)aminolphenyllpyrrolidin-l-yl]ethanone

131 l-(4-fluorophenyl)-N-(3-isopropoxyphenyl)-l,2,4-triazol-3- amine

132 4-[3-(3-methoxy-4-tetrahydrofuran-3-yl-anilino)-l,2,4-triazo l- l-yl]benzonitrile

133 4-[3-(3-methoxy-4-tetrahydrofuran-3-yl-anilino)-l,2,4-triazo l- l-yl]benzamide

134 4-[3 -(3 -isopropoxyanilino)- 1 ,2,4-triazol- 1 -yljbenzonitnle

135 l-(3-fluorophenyl)-N-(3-isopropoxyphenyl)-l,2,4-triazol-3- amine

136 N-[(l S)-l-(5-fluoro-2-pyridyl)ethyl]-4-[3-(3- isopropoxyanilino)- 1 ,2,4-triazol- 1 -yl]pyridin-2-amine

137 3-methyl-5-[(l -phenyl- l,2,4-triazol-3-yl)amino]benzonitrile

138 N-(3-fluoro-4-tetrahydrofuran-3 -yl-phenyl)- 1 -phenyl- 1,2,4- triazol-3 -amine

139 N-(3,5-diethoxyphenyl)-l -phenyl- l,2,4-triazol-3 -amine

140 N-(3 -isopropoxyphenyl)- 1 -[4-(trifluoromethyl)phenyl]- 1 ,2,4- triazol-3 -amine

141 N- [3 -chloro-4-(2, 5 -dihy dro- 1 H-pyrrol-3 -yl)phenyl] - 1 -phenyl- l,2,4-triazol-3 -amine

142 N-(3-chloro-4-pyrrolidin-3 -yl-phenyl)- 1 -phenyl- l,2,4-triazol-3 - amine

143 [2-methoxy-4-[(l -phenyl- 1,2,4-tri azol-3-yl)amino]phenyl]- morpholino-methanone

144 [4-[[l-(4-fluorophenyl)-l,2,4-triazol-3-yl]amino]-2-isopropo xy- phenyl]-morpholino-methanone

145 N-(3 ,5-difluoro-4-tetrahydrofuran-3 -yl-phenyl)- 1 -phenyl- 1 ,2,4- triazol-3 -amine

146 N-[3,5-difluoro-4-(3-furyl)phenyl]-l-phenyl-l,2,4-triazol-3- amine

147 N-(3 -methoxy-4-pyrrolidin-2-yl-phenyl)- 1 -phenyl- 1 ,2,4-triazol- 3 -amine

148 4-[[l-(4-fluorophenyl)-l,2,4-triazol-3-yl]amino]-2-isopropox y- N-(oxetan-3-yl)benzamide

149 N-(3 -isopropoxyphenyl)- 1 -[3 -(trifluoromethyl)phenyl]- 1 ,2,4- triazol-3 -amine

150 N-(4-fluoro-3-tetrahydrofuran-3 -yl-phenyl)- 1 -phenyl- 1,2,4- tri azol-3 -amine Cmpd

Cmpd Name

No.

151 N-(2,4-difluoro-5-tetrahy drofuran-3 -yl-phenyl)- 1 -phenyl- 1 ,2,4- triazol-3 -amine

152 tert-butyl 2-[2-fluoro-5-[(l-phenyl-l,2,4-triazol-3- yl)aminolphenyl]pyrrolidine- 1 -carboxylate

153 N-(4-fluoro-3-pyrrolidin-2-yl-phenyl)-l -phenyl- l,2,4-triazol-3 - amine

154 N2-[(lR)-l-(5-fluoro-2-pyridyl)ethyl]-N4-(l -phenyl- 1,2,4- triazol-3-yl)pyridine-2,4-diamine

155 N4-( 1 -phenyl- 1 ,2,4-triazol-3 -yl)-N2- [( 1 S) - 1 - (2- pyridyl)ethyl]pyridine-2,4-diamine

156 tert-butyl 3-[2-fluoro-5-[[l-(3-fluorophenyl)-l,2,4-triazol-3- yl]amino]phenyl]pyrrolidine-l -carboxylate

157 1 -(3 -fluorophenyl)-N-(4-methoxy-3 -tetrahy drofuran-3 -yl- phenyl)- 1 ,2,4-triazol-3 -amine

158 1 -(3 -fluorophenyl)-N-(4-fluoro-3 -pyrrolidin-3 -yl-phenyl)- 1 ,2,4- triazol-3 -amine

160 N4-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-N2-[( 1R)- 1 -(2- pyridyl)ethyl]pyridine-2,4-diamine

161 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5- morpholino-pyridin-3 -amine

162 1 -(3 ,4-difluorophenyl)-N-(3 -methoxy-4-tetrahy drofuran-3 -yl- phenyl)- 1 ,2,4-triazol-3 -amine

163 2- methyl-5-morpholino-N-(l -phenyl- 1,2,4-tri azol-3-yl)pyri din-

3 - amine

164 2-methyl-5-(4-methylpiperazin- 1 -yl)-N-(l -phenyl- 1 ,2,4-triazol- 3 -yl)pyridin-3 -amine

165 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5-(4- methylpiperazin- 1 -yl)pyridin-3 -amine

166 2-ethyl-5-morpholino-N-(l -phenyl- 1,2,4-tri azol-3-yl)pyridin-3- amine

167 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-ethyl-5- morpholino-pyridin-3 -amine

168 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-tetrahydropyran-4 - yl-pyridin-3 -amine

169 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5- pyrrolidin- 1 -yl-pyridin-3 -amine

170 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5-(9- methyl-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-3-amine

171 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-5-isopropoxy-2- methyl-pyridin-3 -amine

172 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-isopropoxy-2 - methyl-pyridin-3 -amine

173 2- chloro-5-morpholino-N-(l -phenyl- 1,2,4-tri azol-3-yl)pyri din-

3 - amine

174 2-chloro-N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-5- morpholino-pyridin-3 -amine Cmpd

Cmpd Name

No.

175 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5-(l - piped dyl)pyridin-3 -amine

176 2-phenyl-N-(l -phenyl- 1 ,2,4-triazol-3 -yl)-6-pyrrolidin- 1 -yl- pyridin-4-amine

177 N-[l-(2-fluoro-4-pyridyl)-l,2,4-triazol-3-yl]-5-isopropoxy-2 - methyl-pyridin-3 -amine

178 4-[3-[(5-isopropoxy-2-methyl-3-pyridyl)amino]-l,2,4-triazol- l- yl]pyridin-2-ol

179 5-isopropoxy-2-methyl-N-[l-(2-methyl-4-pyridyl)-l,2,4-triazo l- 3 -yl]pyridin-3 -amine

180 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(4- piperidyl)pyridin-3 -amine

181 2-methyl-5-(l-methyl-4-piperidyl)-N-(l-phenyl-l,2,4-triazol- 3- yl)pyridin-3 -amine

182 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5-(l - methyl-4-piperidyl)pyridin-3-amine

185 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-morpholino- pyridin-4-amine

186 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5-(2- methylmo holin-4-yl)pyridin-3-amine

187 2-chloro-N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-6- methyl-pyridin-4-amine

188 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-tetrahydrofuran-3 - yl-pyridin-3 -amine

189 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5- tetrahydrofuran-3-yl-pyridin-3 -amine

190 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5- tetrahydropyran-4-yl-pyridin-3-amine

191 2-chloro-N-[ 1 -(4-fluoro-3 -mo holino-phenyl)- 1 ,2,4-triazol-3 - yl]-6-methyl-pyridin-4-amine

192 6-methyl-5-[(l -phenyl- l,2,4-triazol-3-yl)amino]pyridin-3-ol

193 5-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-6-methy l- pyridin-3-ol

194 2-ethyl-5-isopropoxy-N-(l-phenyl-l,2,4-triazol-3-yl)pyridin- 3- amine

195 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-ethyl-5- isopropoxy-pyridin-3-amine

196 2- chloro-5-isopropoxy-N-(l-phenyl-l,2,4-triazol-3-yl)pyridin-

3 - amine

197 2-chloro-N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5- isopropoxy-pyridin-3-amine

198 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-5-[(l - methyl-4-piperidyl)oxy]pyridin-3-amine

199 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-tetrahydrofuran-3 - yloxy-pyridin-3 -amine Cmpd

Cmpd Name

No.

200 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-tetrahydropyran-4 - yloxy-pyridin-3 -amine

201 2-methyl-5-( 1 -methylpyrrolidin-3 -yl)oxy-N-(l -phenyl- 1 ,2,4- triazol-3-yl)pyridin-3 -amine

202 5-[(E)-3 -methoxyprop- 1 -enyl]-2-methyl-N-( 1 -phenyl- 1 ,2,4- triazol-3-yl)pyridin-3 -amine

203 5-[(E)-3 ,3 -dimethylbut- 1 -enyl]-2-methyl-N-( 1 -phenyl- 1 ,2,4- triazol-3-yl)pyridin-3 -amine

204 2-methyl-5-[(l-methyl-4-piperidyl)oxy]-N-(l-phenyl-l,2,4- triazol-3-yl)pyridin-3 -amine

205 5-isopropoxy-2-methoxy-N-(l-phenyl-l,2,4-triazol-3- yl)pyridin-3 -amine

206 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-isopropoxy-2 - methoxy-pyridin-3 -amine

207 2-methyl-5-(oxetan-3-ylmethoxy)-N-(l-phenyl-l,2,4-triazol-3- yl)pyridin-3 -amine

208 2-(chloromethyl)-3-[[6-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]-3 -pyridyl]oxy]propan- 1 -ol

209 tert-butyl 4-[[6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]- 3-pyridyl]oxy]piperidine-l-carboxylate

210 N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-methyl-5- tetrahydropyran-4-yloxy-pyridin-3-amine

211 N5-isopropyl-2-methyl-N3-(l-phenyl-l,2,4-triazol-3- yl)pyridine-3 , 5 -diamine

212 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N5-isopropyl- 2- methyl-pyridine-3,5-diamine

213 N5-isopropyl-N5,2-dimethyl-N3-(l-phenyl-l,2,4-triazol-3- yl)pyridine-3 , 5 -diamine

214 l-(5-bromo-3-pyridyl)-N-(4-fluoro-2-methyl-phenyl)-l,2,4- triazol-3 -amine

215 tert-butyl 4-[[6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]- 3-pyridyllmethyllpiperidine-l-carboxylate

216 tert-butyl 4-[[5-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3- yllaminol-6-methyl-3-pyridyllmethyllpiperidine-l-carboxylate

217 3-[2-[6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-3- py ri dy 1 ] ethyl ] oxetan-3 -ol

218 3-[2-[5-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-6 - methyl-3-pyridyl]ethyl]oxetan-3-ol

219 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(4- piperidylmethyl)pyridin-3 -amine

220 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-5-(4- piperidylmethyl)pyridin-3 -amine

221 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(tetrahydropyran- 4- ylmethoxy)pyridin-3 -amine

222 2-methyl-5-(l-methyl-2-morpholino-ethoxy)-N-(l-phenyl- l,2,4-triazol-3-yl)pyridin-3 -amine Cmpd

Cmpd Name

No.

223 2-(chloromethyl)-2-methyl-3-[[6-methyl-5-[(l-phenyl-l,2,4- triazol-3-yl)aminol-3-pyridylloxy]propan-l-ol

224 2- methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(2-tetrahydrofuran-

3- ylethoxy)pyridin-3-amine

225 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(2-tetrahydropyra n- 4-ylethoxy)pyridin-3 -amine

226 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(tetrahydrofuran- 2- ylmethoxy)pyridin-3 -amine

227 N-(3 -fluoro-5 -i sopropoxy-phenyl)- 1 -(5 -fluoro-3 -pyridyl)- 1,2,4- triazol-3 -amine

228 2-methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)-N5-(4- piperidylmethyl)pyridine-3,5-diamine

229 2-methyl-N3 -( 1 -phenyl- 1 ,2,4-triazol-3 -yl)-N5-(3 - piperidylmethyl)pyridine-3,5-diamine

230 2-methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)-N5- (tetrahydropyran-4-ylmethyl)pyridine-3,5-diamine

231 2-methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)-N5- (tetrahy dropyran-3 -ylmethyl)pyridine-3 , 5 -diamine

232 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-(tetrahydropyran- 2- ylmethoxy)pyridin-3 -amine

233 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-5-[(l - methyl-4-piperidyl)methyl]pyridin-3-amine

234 2-methyl-5-[(l-methyl-4-piperidyl)methyl]-N-(l-phenyl-l,2,4- triazol-3-yl)pyridin-3 -amine

235 l-[3-[[[6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-3- pyridyl]amino]methyl]-l-piperidyl]ethanone

236 2- methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)-N5-(tetrahydrofuran-

3- ylmethyl)pyridine-3,5-diamine

237 2-methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)-N5-(pyrrolidin-3- ylmethyl)pyridine-3,5-diamine

238 2-methyl-N-( 1 -phenyl- 1 ,2,4-triazol-3 -yl)-5-[ 1 -(3 - pyridyl)ethoxy]pyridin-3 -amine

239 5-[2-(lH-imidazol-2-yl)ethoxy]-2-methyl-N-(l-phenyl-l,2,4- triazol-3-yl)pyridin-3 -amine

240 2-methyl-N-( 1 -phenyl- 1 ,2,4-triazol-3 -yl)-5-[ 1 -(4- pyridyl)ethoxy]pyridin-3 -amine

241 N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-5-methyl-2- tetrahydrofuran-3-yl-pyridin-4-amine

242 5-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-2-tetrahydrofuran-3 - yl-pyridin-4-amine

243 2-(3-furyl)-5-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)pyridin- 4- amine

244 N5,2-dimethyl-N5-[(lR)-l-phenylethyl]-N3-(l-phenyl-l,2,4- triazol-3-yl)pyridine-3,5-diamine

245 N-[3 -( 1 , 1 ,2,2,2-pentadeuterioethoxy)phenyl]- 1 -phenyl- 1 ,2,4- triazol-3 -amine Cmpd

Cmpd Name

No.

246 [(3S,5R)-l-[4-[3-(3-isopropoxyanilino)-l,2,4-triazol-l-yl]-2 - pyridyll-5-methyl-3-piperidyllmethanol

247 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-pyrrolidin-3-yl- pyridin-3 -amine

248 2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-pyrrolidin-2-yl- pyridin-3 -amine

249 5-(l-isobutylpyrrolidin-3-yl)-2-methyl-N-(l-phenyl-l,2,4- triazol-3-yl)pyridin-3 -amine

250 [ 1 - [4-[3 -(3 -isopropoxyanilino)- 1 ,2,4-triazol- 1 -yl]-2-pyridyl]-2- piperidyl]methanol

251 4-morpholino-N-(l -phenyl- 1 ,2,4-triazol-3 -yl)pyridin-2-amine

252 1 -[3-[6-methyl-5-[(l -phenyl- 1,2,4-tri azol-3-yl)amino]-3- py ri dy 1 ] py rroli din- 1 -y 1 ] ethanone

253 l-[2-[6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-3- py ri dy 1 ] py rroli din- 1 -y 1 ] ethanone

254 5-(l-isobutylpyrrolidin-2-yl)-2-methyl-N-(l-phenyl-l,2,4- triazol-3-yl)pyridin-3 -amine

255 N-(3-isopropoxyphenyl)-l-[2-[(3S,5R)-3,4,5- trimethylpiperazin-l-yl]-4-pyridyl]-l,2,4-triazol-3-amine

256 rel-2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-[(3R)- tetrahydrofuran-3-yl]pyridin-3 -amine

257 re/-2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-[(3S)- tetrahydrofuran-3-yl]pyridin-3 -amine

258 4-(2-phenylpyrrolidin- 1 -yl)-N-(l -phenyl- 1 ,2,4-triazol-3 - yl)pyridin-2-amine

259 N-(l-phenyl-l,2,4-triazol-3-yl)-4-[2-(3-pyridyl)pyrrolidin-l - yl]pyridin-2-amine

260 4-(2-methylpyrrolidin-l-yl)-N-(l -phenyl- 1,2,4-tri azol-3- yl)pyridin-2-amine

261 4-(2-isopropylpyrrolidin- 1 -yl)-N-( 1 -phenyl- 1 ,2,4-triazol-3 - yl)pyridin-2-amine

262 N-(l-phenyl-l,2,4-triazol-3-yl)-4-[2-(2-pyridyl)pyrrolidin-l - yl]pyridin-2-amine

263 N5-[(l S)-l-(5-fluoro-2-pyridyl)ethyl]-2-methyl-N3-(l-phenyl- l,2,4-triazol-3-yl)pyridine-3,5-diamine

264 2-isopropoxy-4-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzamide

265 5-[l-(3-methoxypropyl)pyrrolidin-2-yl]-2-methyl-N-(l-phenyl- l,2,4-triazol-3-yl)pyridin-3 -amine

266 N-[ 1 -[2-(azepan- 1 -yl)-4-pyridyl]- 1 ,2,4-triazol-3 -yl]-4,6- dimethyl-pyridin-2-amine

267 l-[2-(azepan-l-yl)-4-pyridyl]-N-(3,5-dimethylphenyl)-l,2,4- triazol-3 -amine

268 N-[ 1 -[2-(azepan- 1 -yl)-4-pyridyl]- 1 ,2,4-triazol-3 -yl]- 1 -methyl- indazol-6-amine

269 N-[ 1 -[6-(azepan- 1 -yl)pyrimidin-4-yl]- 1 ,2,4-triazol-3 -yl]- 1 - Cmpd

Cmpd Name

No.

methyl-indazol-6-amine

270 1 -[6-[(l -phenyl- 1 ,2,4-triazol-3 -yl)amino]indolin- 1 -yljethanone

271 N-[ 1 -(2-fluoro-4-pyridyl)- 1 ,2,4-triazol-3 -yl]-4,6-dimethyl- pyridin-2-amine

272 2-[4-[(l-phenyl-l,2,4-triazol-3-yl)amino]-2-pyridyl]propan-2 -ol

273 2-[4-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-2- pyridyl]propan-2-ol

274 1 -(3 -ethoxyphenyl)-N-(3 -methoxyphenyl)- 1 ,2,4-triazol-3 -amine

275 N-(3-bromo-5-tert-butyl-phenyl)-l-phenyl-l,2,4-triazol-3- amine

276 l-(3,5-difluorophenyl)-N-(3-isopropoxy-4-tetrahydropyran-4- yl-phenyl)-l,2,4-triazol-3 -amine

277 N- [4-fluoro-3 -methyl-5 -(4-methylpiperazin- 1 -yl)phenyl] - 1 - phenyl- 1 ,2,4-triazol-3 -amine

278 N-(3-isopropoxy-4-tetrahydropyran-4-yl-phenyl)-l-phenyl- l,2,4-triazol-3 -amine

279 N-(3-isopropoxy-4-tetrahydropyran-4-yl-phenyl)-l-(3-pyridyl) - l,2,4-triazol-3 -amine

280 N-(3-isopropoxy-4-tetrahydropyran-4-yl-phenyl)-l-(2-pyridyl) - l,2,4-triazol-3 -amine

281 N-[4-(3, 6-dihy dro-2H-pyran-4-yl)-3-(trifluoromethoxy)phenyl]- 1 -(2-pyridyl)- 1 ,2,4-triazol-3 -amine

282 N-(3-isopropoxy-4-tetrahydrofuran-3-yl-phenyl)-l-phenyl- l,2,4-triazol-3 -amine

283 N-(3 -i sopropoxy-4-tetrahy drofuran-3 -yl-phenyl)- 1 -(2-pyridy 1)- l,2,4-triazol-3 -amine

284 l-(3,5-difluorophenyl)-N-(3-isopropoxy-4-tetrahydrofuran-3-y l- phenyl)- 1 ,2,4-triazol-3 -amine

285 N-[4-(3, 6-dihy dro-2H-pyran-4-yl)-3-(trifluoromethoxy)phenyl]- 1 -phenyl- 1 ,2,4-triazol-3 -amine

286 l-(2-pyridyl)-N-[4-tetrahydropyran-4-yl-3- (trifluoromethoxy )pheny 1 ] - 1 , 2,4 -tri azol -3 -amine

287 N-[3,4-bis(3,6-dihydro-2H-pyran-4-yl)phenyl]-l-phenyl-l,2,4- triazol-3 -amine

288 N-[3-isopropoxy-4-(l-methyl-4-piperidyl)phenyl]-l-phenyl- l,2,4-triazol-3 -amine

289 l-(3,5-difluorophenyl)-N-[3-isopropoxy-4-(l-methyl-4- piperidyl)phenyl]- 1 ,2,4-triazol-3 -amine

290 l-phenyl-N-[4-tetrahydropyran-4-yl-3- (trifluoromethoxy )pheny 1 ] - 1 , 2,4 -tri azol -3 -amine

291 N-[3,4-di(tetrahydropyran-4-yl)phenyl]-l-phenyl-l,2,4-triazo l- 3 -amine

292 N-(3,4-dimethoxyphenyl)-l -phenyl- l,2,4-triazol-3 -amine

293 N-( 1 -phenyl- 1 ,2,4-triazol-3 -yl)spiro[indoline-3 ,4'- Cmpd

Cmpd Name

No.

tetrahydropyran]-6-amine

294 l-[6-[(l-phenyl-l,2,4-triazol-3-yl)amino]spiro[indoline-3,4' - tetrahydropyran]- 1 -yljethanone

295 l-isopropyl-N-(l-phenyl-l,2,4-triazol-3-yl)spiro[indoline-3, 4'- tetrahydropyran]-6-amine

296 N-[ 1 -(2-fluoro-4-pyridyl)- 1 ,2,4-triazol-3 -yl]- 1 -isopropyl- spiro[indoline-3,4'-tetrahydropyran]-6-amine

297 l-isopropyl-N-(l-phenyl-l,2,4-triazol-3-yl)indolin-6-amine

298 1 -isopropyl -N-[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 -yl] spiro[indoline- 3,4'-tetrahydropyran]-6-amine

299 N-(3-allyloxy-4-tetrahydropyran-4-yl-phenyl)-l-(3-allyl-2- pyridyl)- 1 ,2,4-triazol-3 -amine

300 l-(oxetan-3-yl)-N-(l -phenyl- l,2,4-triazol-3 -yl)spiro[indoline- 3,4'-tetrahydropyran]-6-amine

301 l-(l-methylpyrrolidin-3-yl)-N-(l -phenyl- l,2,4-triazol-3 - yl)spiro[indoline-3,4'-tetrahydropyran]-6-amine

302 l-(oxetan-3-yl)-N-(l -phenyl- l,2,4-triazol-3-yl)indolin-6-amine

303 l-(l-methylpyrrolidin-3-yl)-N-(l -phenyl- l,2,4-triazol-3 - yl)indolin-6-amine

304 l-isopropyl-N-(l-phenyl-l,2,4-triazol-3-yl)indol-6-amine

305 l-[5-[(l-phenyl-l,2,4-triazol-3-yl)amino]spiro[indoline-3,4' - piperidine]-l-yl]ethanone

306 1 -[ 1 '-isopropyl-5-[( 1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]spiro[indoline-3,4'-piperidine]-l-yl]ethanone

307 N3,4-dimethyl-N3-(oxetan-3-yl)-Nl-(l-phenyl-l,2,4-triazol-3- yl)benzene- 1 ,3 -diamine

308 1 -(3 -methoxy- 1 -methyl-propyl)-N-(l -phenyl- 1 ,2,4-triazol-3 - yl)indolin-6-amine

309 1 -isopropyl- 1 '-(oxetan-3 -yl)-N-(l -phenyl- 1 ,2,4-triazol-3 - yl)spiro[indoline-3,4'-piperidine]-5-amine

310 1 -(2-methoxyethyl)-N-( 1 -phenyl- 1 ,2,4-triazol-3 -yl)indazol-6- amine

311 l-(2-methoxyethyl)-N-(l -phenyl- l,2,4-triazol-3-yl)-3, 4- dihydro-2H-quinolin-7-amine

312 l-isopropyl-N-(l-phenyl-l,2,4-triazol-3-yl)spiro[indoline-3, 4'- tetrahydropyran]-5-amine

313 N-[ 1 -(2-fluoro-4-pyridyl)- 1 ,2,4-triazol-3 -yl]- 1 -isopropyl- spiro[indoline-3,4'-tetrahydropyran]-5-amine

314 4-[3-[(l-isopropylspiro[indoline-3,4'-tetrahydropyran]-5- yl)amino]- 1 ,2,4-triazol- 1 -yl]- lH-pyridin-2-one

315 N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]- 1 -isopropyl- spiro[indoline-3,4'-tetrahydropyran]-5-amine

316 N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]- 1 -(2- methoxyethyl)-3,4-dihydro-2H-quinolin-7-amine Cmpd

Cmpd Name

No.

317 N-[ 1 -(2-fluoro-4-pyridyl)- 1 ,2,4-triazol-3 -yl]- 1 -(2- methoxyethyl)-3,4-dihydro-2H-quinolin-7-amine

318 4-[3-[[l-(2-methoxyethyl)-3,4-dihydro-2H-quinolin-7- yl]amino]- 1 ,2,4-triazol- 1 -yl]- lH-pyridin-2-one

319 N-[ 1 -(3 ,5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]- 1 -isopropyl- 1 '- (oxetan-3-yl)spiro[indoline-3,4'-piperidine]-5-amine

320 1 '-(oxetan-3 -yl)-N-(l -phenyl- l,2,4-triazol-3 -yl)spiro[indane- 3,4'-piperidine]-5-amine

321 1 '-(oxetan-3 -yl)-N-[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 - yl]spiro[indane-3,4'-piperidine]-5-amine

322 1 -isopropyl- 1 '-(oxetan-3 -yl)-N-[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 - yl]spiro[indoline-3,4'-piperidine]-5-amine

323 N-[ 1 -(2-fluoro-4-pyridyl)- 1 ,2,4-triazol-3 -yl]- 1 '-(oxetan-3 - yl)spiro[indane-3,4'-piperidine]-5-amine

324 N-[ 1 -(3 -fluorophenyl)- 1 ,2,4-triazol-3 -yl]- 1 '-(oxetan-3 - yl)spiro[indane-3,4'-piperidine]-5-amine

325 1 -(3 , 5 -difluorophenyl)-N- [4-fluoro-3 - [3 -fluoro- 1 -(oxetan-3 - yl)pyrrolidin-3-yl]phenyl]-l,2,4-triazol-3-amine

326 l-(3,5-difluorophenyl)-N-[4-methyl-3-[4-(oxetan-3- yl)piperazin- 1 -yl]phenyl]- 1 ,2,4-triazol-3 -amine

327 l-(3,5-difluorophenyl)-N-(2,3-dimethyl-5-nitro-phenyl)-l,2,4 - triazol-3 -amine

328 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4,5-dimethyl- benzene- 1 ,3 -diamine

329 1 -(3 , 5 -difluorophenyl)-N- [3 ,4-dimethy 1-5 - [4-(oxetan-3 - yl)piperazin- 1 -yl]phenyl]- 1 ,2,4-triazol-3 -amine

330 1 -(3 , 5 -difluorophenyl)-N- [3 -[4-(oxetan-3 -yl)piperazin- 1 - yl]phenyl]-l,2,4-triazol-3-amine

331 l-(3,5-difluorophenyl)-N-[2-methoxy-3-methyl-5-[4-(oxetan-3- yl)piperazin- 1 -yl]phenyl]- 1 ,2,4-triazol-3 -amine

332 N-[3 -[4-(oxetan-3 -yl)piperazin- 1 -yl]phenyl]- 1 -pyrazin-2-yl- l,2,4-triazol-3 -amine

333 N-[3-[4-(oxetan-3-yl)piperazin-l-yl]phenyl]-l-(2,3,5- trifluorophenyl)- 1 ,2,4-triazol-3 -amine

334 1 -(3 ,4-difluorophenyl)-N- [3 -[4-(oxetan-3 -yl)piperazin- 1 - yl]phenyl]-l,2,4-triazol-3-amine

335 l-(4-fluorophenyl)-N-[3-[4-(oxetan-3-yl)piperazin-l- yl]phenyl]-l,2,4-triazol-3-amine

336 N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-5-methyl-2- (oxetan-3-yl)-3,4-dihydro-lH-isoquinolin-7-amine

337 N-[ 1 -(2, 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-5-methyl-2- (oxetan-3-yl)-3,4-dihydro-lH-isoquinolin-7-amine

338 5-methyl-2-(oxetan-3-yl)-N-[l-(2,3,5-trifluorophenyl)-l,2,4- triazol-3-yl]-3,4-dihydro-lH-isoquinolin-7-amine

339 5-methyl-2-(oxetan-3-yl)-N-(l-pyrazin-2-yl-l,2,4-triazol-3-y l)- 3,4-dihydro-lH-isoquinolin-7-amine Cmpd

Cmpd Name

No.

340 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-5-methyl-2- (oxetan-3-yl)-3,4-dihydro-lH-isoquinolin-7-amine

341 N-[l-(4-fluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-2-(oxetan -3- yl)-3,4-dihydro-lH-isoquinolin-7-amine

342 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(3- methoxypropyl)-Nl ,5-dimethyl-benzene- 1 ,3-diamine

343 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl,Nl,5- trimethyl-benzene- 1 ,3-diamine

344 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-(3- fluoropropyl)-5-methyl-benzene-l,3-diamine

345 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2- ethoxypropyl)-5-methyl-benzene-l,3-diamine

346 N3-[ 1 -(3,5-difluorophenyl)- 1 ,2,4-triazol-3-yl]-Nl -(2-ethoxy-l - methyl-ethyl)-5-methyl-benzene-l,3-diamine

347 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2-methoxy - l-methyl-ethyl)-5-methyl-benzene-l,3-diamine

348 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-N,5- dimethyl-anilino]propan-2-ol

349 1 -(3 , 5 -difluorophenyl)-N- [3 - [4-(oxetan-3 -yl)morpholin-2- yl]phenyl]-l,2,4-triazol-3-amine

350 rel- 1 -(3 , 5 -difluorophenyl)-N- [3 - [(2R)-4-(oxetan-3 - yl)morpholin-2-yl]phenyl]-l,2,4-triazol-3-amine

351 rel- 1 -(3 , 5 -difluorophenyl)-N- [3 - [(2 S)-4-(oxetan-3 - yl)morpholin-2-yl]phenyl]-l,2,4-triazol-3-amine

352 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-[(l S)-2- methoxy- 1 -methyl-ethyl]-5-methyl-benzene- 1 ,3-diamine

353 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-[(lR)-2- methoxy- 1 -methyl-ethyl]-5-methyl-benzene- 1 ,3-diamine

354 l-(3,5-difluorophenyl)-N-(m-tolyl)-l,2,4-triazol-3-amine

355 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4-methyl-pyrid in- 2-amine

356 N-(3-chloro-5-methyl-phenyl)-l -(3,5-difluorophenyl)- 1,2,4- triazol-3 -amine

357 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5,6-dimethoxy- pyridin-2-amine

358 l-(3,5-difluorophenyl)-N-(2,3-dimethylphenyl)-l,2,4-triazol- 3- amine

359 N2-(2-methoxy- 1 -methyl-ethyl)-4-methyl-N6-[ 1 -[3- (trifluoromethyl)phenyl]-l,2,4-triazol-3-yl]pyridine-2,6-dia mine

360 l-(3,5-difluorophenyl)-N-(2,5-dimethylphenyl)-l,2,4-triazol- 3- amine

361 N6-[l-[3-(difluoromethyl)phenyl]-l,2,4-triazol-3-yl]-N2-(2- methoxy-l-methyl-ethyl)-4-methyl-pyridine-2,6-diamine

362 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-phenyl]-3 -methyl-pent- l-yn-3-ol Cmpd

Cmpd Name

No.

363 l-[3-[[l-(3-fluorophenyl)-l,2,4-triazol-3-yl]amino]-5-methyl - phenyl] -3 -methyl-pent- 1 -yn-3 -ol

364 1 -(3 , 5 -difluorophenyl)-N- [4-methyl-3 -(3 -morpholinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

365 1 -(3 , 5 -difluorophenyl)-N- [3 ,4-dimethy 1-5 - (3 - morpholinoazetidin-l-yl)phenyl]-l,2,4-triazol-3-amine

366 1 -(3 ,4-difluorophenyl)-N- [4-methyl-3 -(3 -morpholinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

367 1 -(3 ,4-difluorophenyl)-N- [3 ,4-dimethy 1-5 - (3 - morpholinoazetidin-l-yl)phenyl]-l,2,4-triazol-3-amine

368 6-chloro-4-(methoxymethyl)-N-[l-[3-(trifluoromethyl)phenyl]- l,2,4-triazol-3-yl]pyridin-2-amine

369 1 -(3 , 5 -difluorophenyl)-N- [3 -methyl-4-[4-(oxetan-3 - yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

370 l-(3,4-difluorophenyl)-N-[3-methyl-4-[4-(oxetan-3- yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

371 1 -(3 , 5 -difluorophenyl)-N- [3 -methyl-4-(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

372 1 -(3 ,4-difluorophenyl)-N- [3 -methyl-4-(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

373 N- [3 -(cy clopentoxy)phenyl] - 1 -(3 , 5 -difluorophenyl)- 1,2,4- triazol-3 -amine

374 1 -(3 , 5 -difluorophenyl)-N-(3 -methoxy-4-morpholino-phenyl)- l,2,4-triazol-3 -amine

375 l-(3,5-difluorophenyl)-N-(5-isopropoxy-2-methyl-phenyl)- l,2,4-triazol-3 -amine

376 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-6-[4- (oxetan-3-yl)piperazin-l-yl]pyridin-2-amine

377 1 -(3 , 5 -difluorophenyl)-N-(3 -propoxyphenyl)- 1 ,2,4-triazol-3 - amine

378 N-(2,5-diethoxyphenyl)-l-(3,5-difluorophenyl)-l,2,4-triazol- 3- amine

379 l-(3,5-difluorophenyl)-N-(3,4,5-trimethoxyphenyl)-l,2,4- triazol-3 -amine

380 l-(3,5-difluorophenyl)-N-(3,5-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

381 l-(3,5-difluorophenyl)-N-(3-methoxyphenyl)-l,2,4-triazol-3- amine

382 N-(2,2-difluoro-l,3-benzodioxol-5-yl)-l-(3,5-difluorophenyl) - l,2,4-triazol-3 -amine

383 l-(3,5-difluorophenyl)-N-(2,5-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

384 1 -(3 , 5 -difluorophenyl)-N- [3 -methoxy-5 - (trifluoromethyl)phenyl]-l,2,4-triazol-3-amine

385 l-(3,5-difluorophenyl)-N-(2,3-dihydro-l,4-benzodioxin-6-yl)- l,2,4-triazol-3 -amine Cmpd

Cmpd Name

No.

386 l-(3,5-difluorophenyl)-N-(3,4-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

387 l-(3,5-difluorophenyl)-N-(5-methoxy-2-methyl-phenyl)-l,2,4- triazol-3 -amine

388 l-(3,5-difluorophenyl)-N-(2,3-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

389 N-(l,3-benzodioxol-5-yl)-l-(3,5-difluorophenyl)-l,2,4-triazo l- 3 -amine

390 l-(3,5-difluorophenyl)-N-(3-ethoxyphenyl)-l,2,4-triazol-3- amine

391 N-(2,2-difluoro- 1 ,3 -benzodioxol-4-yl)- 1 -(3 ,5-difluorophenyl)- l,2,4-triazol-3 -amine

392 1 -(3 , 5 -difluorophenyl)-N- [3 -(trifluoromethoxy)phenyl] - 1,2,4- triazol-3 -amine

393 l-(3,5-difluorophenyl)-N-(2,2,3,3-tetrafluoro-l,4-benzodioxi n- 6-yl)-l,2,4-triazol-3 -amine

394 1 -(3 , 5 -difluorophenyl)-N-(3 ,4-dihy dro-2H- 1 , 5 -benzodioxepin- 7-yl)-l,2,4-triazol-3 -amine

395 l-(3,5-difluorophenyl)-N-(3-isopropoxyphenyl)-l,2,4-triazol- 3- amine

396 1 -(3 , 5 -difluorophenyl)-N-(4-fluoro-3 -methoxy -phenyl)- 1,2,4- triazol-3 -amine

397 l-(3,5-difluorophenyl)-N-(3-methoxy-4-methyl-phenyl)-l,2,4- triazol-3 -amine

398 l-(3,5-difluorophenyl)-N-[3-(2-methoxyethoxy)phenyl]-l,2,4- triazol-3 -amine

399 N-(4-cyclopropyl-3-methoxy-phenyl)-l-(3,5-difluorophenyl)- l,2,4-triazol-3 -amine

400 1 -(3 , 5 -difluorophenyl)-N-(3 -fluoro-5 -methoxy -phenyl)- 1,2,4- triazol-3 -amine

401 l-(3,5-difluorophenyl)-N-(3-isobutoxyphenyl)-l,2,4-triazol-3 - amine

402 l-(3,5-difluorophenyl)-N-[3-methoxy-4- (trifluoromethyl)phenyll-l,2,4-triazol-3-amine

403 N-(3-butoxyphenyl)-l-(3,5-difluorophenyl)-l,2,4-triazol-3- amine

404 1 -(3 , 5 -difluorophenyl)-N- [3 -(tetrahy drofuran-2- ylmethoxy)phenyl]- 1 ,2,4-triazol-3 -amine

405 1 -(3 , 5 -difluorophenyl)-N- [2-methy 1-5 - (trifluoromethoxy )pheny 1 ] - 1 , 2,4 -tri azol -3 -amine

406 l-(3,5-difluorophenyl)-N-(5-methoxy-2,3-dimethyl-phenyl)- l,2,4-triazol-3 -amine

407 l-(3,5-difluorophenyl)-N-(3-isopropoxy-5-methyl-phenyl)- l,2,4-triazol-3 -amine

408 l-(3,4-difluorophenyl)-N-(5-methoxy-2,3-dimethyl-phenyl)- l,2,4-triazol-3 -amine Cmpd

Cmpd Name

No.

409 1 -(3 ,4-difluorophenyl)-N-(3 -methoxy-4-morpholino-phenyl)- l,2,4-triazol-3 -amine

410 l-(3,4-difluorophenyl)-N-(3-isopropoxy-5-methyl-phenyl)- l,2,4-triazol-3 -amine

411 N-[3 -(cyclopentoxy)phenyl]- 1 -(3 ,4-difluorophenyl)- 1 ,2,4- triazol-3 -amine

412 l-(3,4-difluorophenyl)-N-(5-isopropoxy-2-methyl-phenyl)- l,2,4-triazol-3 -amine

413 N-[l-(3,4-difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-6-[4- (oxetan-3-yl)piperazin-l-yl]pyridin-2-amine

414 N-[l-(3-fluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-6-[4- (oxetan-3-yl)piperazin-l-yl]pyridin-2-amine

416 5-methyl-6-[4-(oxetan-3-yl)piperazin-l-yl]-N-(l-phenyl-l,2,4 - triazol-3-yl)pyridin-2-amine

417 1 -(3 , 5 -difluorophenyl)-N- [4-i sopropoxy-3 -(3 - morpholinoazetidin-l-yl)phenyl]-l,2,4-triazol-3-amine

418 l-(3,5-difluorophenyl)-N-[4-isopropoxy-3-[4-(oxetan-3- yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

419 1 -(3 , 5 -difluorophenyl)-N- [4-fluoro-3 -(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

420 1 -(3 ,4-difluorophenyl)-N- [4-i sopropoxy-3 -(3 - morpholinoazetidin-l-yl)phenyl]-l,2,4-triazol-3-amine

421 l-(3,4-difluorophenyl)-N-[4-isopropoxy-3-[4-(oxetan-3- yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

422 1 -(3 ,4-difluorophenyl)-N- [4-fluoro-3 -(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

423 N-(2,5-diethoxyphenyl)-l-(3,4-difluorophenyl)-l,2,4-triazol- 3- amine

424 1 -(3 ,4-difluorophenyl)-N-(3 ,4,5 -trimethoxyphenyl)- 1,2,4- triazol-3 -amine

425 l-(3,4-difluorophenyl)-N-(3,5-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

426 l-(3,4-difluorophenyl)-N-(3-methoxyphenyl)-l,2,4-triazol-3- amine

427 l-(3,4-difluorophenyl)-N-(2,5-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

428 l-(3,4-difluorophenyl)-N-(2,3-dihydro-l,4-benzodioxin-6-yl)- l,2,4-triazol-3 -amine

429 l-(3,4-difluorophenyl)-N-(3,4-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

430 l-(3,4-difluorophenyl)-N-(5-methoxy-2-methyl-phenyl)-l,2,4- triazol-3 -amine

431 l-(3,4-difluorophenyl)-N-(2,3-dimethoxyphenyl)-l,2,4-triazol - 3 -amine

432 N-(l,3-benzodioxol-5-yl)-l-(3,4-difluorophenyl)-l,2,4-triazo l- 3 -amine Cmpd

Cmpd Name

No.

433 l-(3,4-difluorophenyl)-N-(3-ethoxyphenyl)-l,2,4-triazol-3- amine

434 l-(3,4-difluorophenyl)-N-[3-(trifluoromethoxy)phenyl]-l,2,4- triazol-3 -amine

435 l-(3,4-difluorophenyl)-N-(2,2,3,3-tetrafluoro-l,4-benzodioxi n- 6-yl)-l,2,4-triazol-3 -amine

436 1 -(3 ,4-difluorophenyl)-N-(3 ,4-dihy dro-2H- 1 , 5 -benzodioxepin- 7-yl)-l,2,4-triazol-3 -amine

437 1 -(3 ,4-difluorophenyl)-N-(4-fluoro-3 -methoxy -phenyl)- 1,2,4- triazol-3 -amine

438 1 -(3 ,4-difluorophenyl)-N-[3 -(2-methoxyethoxy)phenyl]- 1 ,2,4- triazol-3 -amine

439 1 -(3 ,4-difluorophenyl)-N-(3 -fluoro-5 -methoxy -phenyl)- 1,2,4- triazol-3 -amine

440 l-(3,4-difluorophenyl)-N-(3-isobutoxyphenyl)-l,2,4-triazol-3 - amine

441 N-(3-butoxyphenyl)-l-(3,4-difluorophenyl)-l,2,4-triazol-3- amine

442 l-(3,4-difluorophenyl)-N-[3-(tetrahydrofuran-2- ylmethoxy)phenyl]- 1 ,2,4-triazol-3 -amine

443 l-(3,4-difluorophenyl)-N-[2-methyl-5- (trifluoromethoxy )pheny 1 ] - 1 , 2,4 -tri azol -3 -amine

444 l-(3,4-difluorophenyl)-N-(3-isopropoxyphenyl)-l,2,4-triazol- 3- amine

445 l-(3,4-difluorophenyl)-N-(3-isopropoxy-4-morpholino-phenyl)- l,2,4-triazol-3 -amine

446 1 -(3 , 5 -difluorophenyl)-N-(3 -i sopropoxy-4-morpholino-phenyl)- l,2,4-triazol-3 -amine

447 l-(3,5-difluorophenyl)-N-[4-methoxy-3-methyl-5-[4-(oxetan-3- yl)piperazin- 1 -yl]phenyl]- 1 ,2,4-triazol-3 -amine

448 l-(3,4-difluorophenyl)-N-[4-methoxy-3-methyl-5-[4-(oxetan-3- yl)piperazin- 1 -yl]phenyl]- 1 ,2,4-triazol-3 -amine

449 l-(3-fluorophenyl)-N-[4-methoxy-3-methyl-5-[4-(oxetan-3- yl)piperazin- 1 -yl]phenyl]- 1 ,2,4-triazol-3 -amine

450 N-[4-methoxy-3-methyl-5-[4-(oxetan-3-yl)piperazin-l- yl]phenyl]-l-(3-pyridyl)-l,2,4-triazol-3-amine

451 N-(5-chloro-2-methyl-phenyl)-l-(3,5-difluorophenyl)-l,2,4- triazol-3 -amine

452 1 -(3 , 5 -difluorophenyl)-N- [2-methy 1-5 -[4-(oxetan-3 - yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

453 1- (3,5-difluorophenyl)-N-[5-[4-(methoxymethyl)-l-piperidyl]-

2- methyl-phenyl]- 1 ,2,4-triazol-3 -amine

454 1 -(3 , 5 -difluorophenyl)-N- [2-methy 1-5 -(2-oxa-7- azaspiro[4.4]nonan-7-yl)phenyl]-l,2,4-triazol-3-amine

455 1 -(3 , 5 -difluorophenyl)-N- [2-methy 1-5 -(2-oxa-5 - azaspiro[3.4]octan-5-yl)phenyl]-l,2,4-triazol-3-amine Cmpd

Cmpd Name

No.

456 N-[5-(l,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-2-methy l- phenyl]- 1 -(3 ,5-difluorophenyl)- 1 ,2,4-triazol-3 -amine

457 l-(3,5-difluorophenyl)-N-[2-methyl-5-[3-(oxetan-3-yl)azetidi n- 1 -yllphenyl]- 1 ,2,4-triazol-3 -amine

458 1 -(3 , 5 -difluorophenyl)-N- [5 - [(3R)-3 -i sopropoxypyrrolidin- 1 - yll-2-methyl-phenyl]-l,2,4-triazol-3-amine

459 1 -(3 , 5 -difluorophenyl)-N- [5 -(4-i sopropoxy- 1 -piped dyl)-2- methyl-phenyl]- 1 ,2,4-triazol-3 -amine

460 2-[ 1 -[3 -[[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino]-4- methyl-phenyl]-4-piperidyl]propan-2-ol

461 l-(3,5-difluorophenyl)-N-[2-methyl-5-[4-(oxetan-3-yl)-l- piperidyl]phenyl]- 1 ,2,4-triazol-3 -amine

462 l-(3,5-difluorophenyl)-N-[2-methyl-5-[4-(2,2,2- trifluoroethyl)piperazin-l-yl]phenyl]-l,2,4-triazol-3 -amine

463 N-[5-(4-cyclopropylpiperazin-l-yl)-2-methyl-phenyl]-l-(3,5- difluorophenyl)- 1 ,2,4-triazol-3 -amine

464 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4- methyl-phenyl]-4-(methoxymethyl)piperidin-4-ol

465 N-[5-(4-tert-butylpiperazin-l-yl)-2-methyl-phenyl]-l-(3,5- difluorophenyl)- 1 ,2,4-triazol-3 -amine

466 1 -(3 , 5 -difluorophenyl)-N- [2-methyl-5 -( 1 -oxa-9- azaspiro[5.5]undecan-9-yl)phenyl]-l,2,4-triazol-3-amine

467 l-(3,5-difluorophenyl)-N-[2-methyl-5-(2-oxa-8- azaspiro[4.5]decan-8-yl)phenyl]-l,2,4-triazol-3-amine

468 l-(3,5-difluorophenyl)-N-[5-(4-methoxy-l-piperidyl)-2-methyl - phenyl]- 1 ,2,4-triazol-3 -amine

469 N- [5 -(3 , 3 -difluoroazetidin- 1 -yl)-2-methyl-pheny 1] - 1 -(3 , 5 - difluorophenyl)- 1 ,2,4-triazol-3 -amine

470 l-(3,5-difluorophenyl)-N-[5-(3-ethoxyazetidin-l-yl)-2-methyl - phenyl]- 1 ,2,4-triazol-3 -amine

471 1 -(3 , 5 -difluorophenyl)-N- [5 - [3 -(2,2-dimethylmorpholin-4- yl)azetidin-l-yll-2-methyl-phenyll-l,2,4-triazol-3-amine

472 1 -(3 , 5 -difluorophenyl)-N- [2-methyl-5 - [3 -( 1 -piped dyl)azetidin- 1 -yllphenyl]- 1 ,2,4-triazol-3 -amine

473 2-[ 1 -[3 -[[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino]-4- methyl-phenyl]azetidin-3-yl]propan-2-ol

474 1 -(3 , 5 -difluorophenyl)-N- [5 - [3 -(2, 6-dimethylmorpholin-4- yl)azetidin-l-yl]-2-methyl-phenyl]-l,2,4-triazol-3-amine

1 -(3 , 5 -difluorophenyl)-N- [5 -(2-isopropyl-2, 6-

475 diazaspiro[3.3]heptan-6-yl)-2-methyl-phenyl]-l,2,4-triazol-3 - amine

476 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4-methyl-Nl- tetrahy drofuran-3 -yl-benzene- 1 , 3 -diamine

477 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2-methoxy - l-methyl-ethyl)-4-methyl-benzene-l,3-diamine

478 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2- Cmpd

Cmpd Name

No.

ethoxypropyl)-4-methyl-benzene-l,3-diamine

479 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4-methyl-Nl- tetrahydropyran-3-yl-benzene- 1,3 -diamine

480 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4-methyl-Nl-( 2- tetrahydropyran-2-ylethyl)benzene-l,3-diamine

481 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4-methyl-Nl-[ (2- methyltetrahydrofuran-2-yl)methyl]benzene- 1,3 -diamine

482 1 -(3 , 5 -difluorophenyl)-N- [2-methyl-5 -(2-oxa-7- azaspiro[3.5]nonan-7-yl)phenyl]-l,2,4-triazol-3-amine

483 N-[5-(2,3,4,4a,5,7,8,8a-octahydropyrano[3,2-c]pyridin-6-yl)- 2- methyl-phenyl]-l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine

484 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-6-(3- morpholinoazetidin- 1 -yl)pyridin-2-amine

485 N-[l-(3-fluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-6-(3- morpholinoazetidin- 1 -yl)pyridin-2-amine

486 5-methyl-6-(3 -morpholinoazetidin- 1 -yl)-N-[ 1 -(3 -pyridyl)- 1 ,2,4- triazol-3-yl]pyridin-2-amine

487 N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-( 2- morpholinoethyl)benzene- 1 ,4-diamine

488 1 -[4-[4-[[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino]-2- methyl-anilino]-l-piperidyl]ethanone

489 l-(3,5-difluorophenyl)-N-[2-methyl-5-(3-mo holinoazetidin-l- yl)phenyl]-l,2,4-triazol-3-amine

490 N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-(3- methoxypropoxy)-6-(trifluoromethyl)pyridin-4-amine

491 N-[ 1 -(3 ,4-difluorophenyl)- 1 ,2,4-triazol-3 -yl]-2-(3 - methoxypropoxy)-6-(trifluoromethyl)pyridin-4-amine

492 l-(3,5-difluorophenyl)-N-[3-(3-methoxypropoxy)-5-methyl- phenyl]- 1 ,2,4-triazol-3 -amine

493 l-(3,4-difluorophenyl)-N-[3-(3-methoxypropoxy)-5-methyl- phenyl]- 1 ,2,4-triazol-3 -amine

494 N- [3 -(3 -methoxypropoxy)-5 -methyl-phenyl] - 1 - [3 - (trifluoromethyl)phenyl]-l,2,4-triazol-3-amine

495 l-(3,5-difluorophenyl)-N-[3-methyl-4-(2- morpholinoethoxy)phenyl]-l,2,4-triazol-3 -amine

496 1 -(3 , 5 -difluorophenyl)-N- [3 -methyl-4-[ [ 1 -(oxetan-3 -yl)-3 - piperidyl]methoxy]phenyl]-l,2,4-triazol-3-amine

497 1 -(3 , 5 -difluorophenyl)-N- [3 -methyl-4-[ [ 1 -(oxetan-3 -yl)-4- piperidyl]oxy]phenyl]-l,2,4-triazol-3-amine

498 1 -(3 , 5 -difluorophenyl)-N- [3 -methyl-4-[ [ 1 -(oxetan-3 - yl)pyrrolidin-3-yl]methoxy]phenyl]-l,2,4-triazol-3-amine

499 1 -(3 , 5 -difluorophenyl)-N- [3 -methyl-4-[ 1 -(oxetan-3 - yl)pyrrolidin-3-yl]oxy -phenyl]- l,2,4-triazol-3 -amine

500 l-(3,5-difluorophenyl)-N-[3-methyl-4-[l-(oxetan-3-yl)azetidi n- 3-yl]oxy -phenyl]- l,2,4-triazol-3 -amine

501 l-(3,5-difluorophenyl)-N-[3-methyl-4-[[l-(oxetan-3-yl)azetid in- Cmpd

Cmpd Name

No.

3-yl]methoxy]phenyl]-l,2,4-triazol-3-amine

502 1 -(3 , 5 -difluorophenyl)-N- [3 -methy l-4-[ [ 1 -(oxetan-3 -yl)-4- piperidyl]methoxy]phenyl]-l,2,4-triazol-3-amine

503 1 -(3 , 5 -difluorophenyl)-N- [3 -methy l-4-[ [ 1 -(oxetan-3 -yl)-3 - piperidyl]oxy]phenyl]-l,2,4-triazol-3-amine

504 N-(3 -chloro-2-methyl-phenyl)- 1 -(3 ,5-difluorophenyl)- 1 ,2,4- triazol-3 -amine

505 N-[3-(2,2-difluoroethoxy)-5-methyl-phenyl]-l-(3,5- difluorophenyl)- 1 ,2,4-triazol-3 -amine

506 N-[3-(2,2-difluoroethoxy)-5-methyl-phenyl]-l-(3,4- difluorophenyl)- 1 ,2,4-triazol-3 -amine

507 N-[3-(2,2-difluoroethoxy)-5-methyl-phenyl]-l-[3- (trifluoromethyl)phenyl]-l,2,4-triazol-3-amine

508 N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-[ l- (oxetan-3-yl)-4-piperidyl]benzene-l,4-diamine

509 rac-N- [3 - [4- [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] - 2-methy 1 -phenoxy 1 cycl obuty 1 ] acetami de

510 l-[3-[[4-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]- 2- methy 1 -phenoxy ] methy 1 ] - 1 -piped dy 1 ] ethanone

511 1 - [4-[4-[[ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino]-2- methyl-phenoxy]-l-piperidyl]ethanone

512 l-[3-[[4-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]- 2- methyl-phenoxy]methyl]pyrrolidin-l-yl]ethanone

513 l-[4-[[4-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]- 2- methy 1 -phenoxy ] methy 1 ] - 1 -piped dy 1 ] ethanone

514 l-[3-[[4-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]- 2- methy 1 -phenoxy ] methy 1 ] azeti din- 1 -y 1 ] ethanone

515 1 -[3 -[4-[[ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino]-2- methyl-phenoxy]-l-piperidyl]ethanone

516 1 -(3 , 5 -difluorophenyl)-N-(3 -isopropoxy-2, 5 -dimethyl-phenyl)- l,2,4-triazol-3 -amine

517 l-(3,4-difluorophenyl)-N-(3-isopropoxy-2,5-dimethyl-phenyl)- l,2,4-triazol-3 -amine

518 l-(3,5-difluorophenyl)-N-[2-methyl-3-[4-(oxetan-3- yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

519 1 -(3 , 5 -difluorophenyl)-N- [2-methyl-3 -(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

520 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl- (oxetan-3-yl)benzene- 1,3 -diamine

521 1 -(3 , 5 -difluorophenyl)-N-(2-methyl-3 -morpholino-phenyl)- l,2,4-triazol-3 -amine

522 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2-methoxy - l-methyl-ethyl)-2-methyl-benzene-l,3-diamine

523 1 -(3 , 5 -difluorophenyl)-N-(2-fluoro-3 -i sopropoxy-5 -methyl- phenyl)- 1 ,2,4-triazol-3 -amine

524 l-(3,4-difluorophenyl)-N-(2-fluoro-3-isopropoxy-5-methyl- Cmpd

Cmpd Name

No.

phenyl)- 1 ,2,4-triazol-3 -amine

N-[(l-acetylazetidin-3-yl)methyl]-N-[4-[[l-(3,5-

525 difluorophenyl)-l,2,4-triazol-3-yl]amino]-2-methyl- phenyl]acetamide

N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-

526 (oxetan-3 -yl)-N 1 - [[ 1 -(oxetan-3 -yl)azetidin-3 - yl]methyl]benzene- 1 ,4-diamine

527 1 -(3 , 5 -difluorophenyl)-N- [2-methyl-4-(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

528 N-[2-methyl-4-(3-mo holinoazetidin-l-yl)phenyl]-l-(2- pyridyl)- 1 ,2,4-triazol-3 -amine

529 N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-[ [l- (oxetan-3-yl)pyrrolidin-3-yl]methyl]benzene-l,4-diamine

530 N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-[ l- (oxetan-3-yl)pyrrolidin-3-yl]benzene-l,4-diamine

531 N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-[ [l- (oxetan-3-yl)-3-piperidyllmethyl]benzene-l,4-diamine

532 N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-[ l- (oxetan-3-yl)-3 -piped dyl]benzene-l,4-diamine

533 l-(3,5-difluorophenyl)-N-[2-methyl-4-[4-(oxetan-3- yl)piperazin- 1 -yllphenyl]- 1 ,2,4-triazol-3 -amine

534 1 -(3 -fluoro-4-methoxy-phenyl)-N- [3 -(3 -morpholinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

535 1 -(3 , 5 -difluorophenyl)-N- [2-fluoro-4-(3 -mo holinoazetidin- 1 - yl)phenyl]-l,2,4-triazol-3-amine

536 N-(3-chloro-2,6-dimethyl-phenyl)-l-(3,5-difluorophenyl)-l,2, 4- triazol-3 -amine

537 1 -(3 , 5 -difluorophenyl)-N- [2,6-dimethyl-3 - [4-(oxetan-3 - yl)piperazin- 1 -yljphenyl]- 1 ,2,4-triazol-3 -amine

538 N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]acetamide

539 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2- ethoxypropyl)-2-fluoro-5-methyl-benzene-l,3-diamine

540 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-fluoro-Nl-( 2- methoxy- 1 -methyl-ethyl)-5-methyl-benzene- 1 ,3 -diamine

541 N-(3 -bromo-2-fluoro-5 -methyl-phenyl)- 1 -(3 , 5 -difluorophenyl)- l,2,4-triazol-3 -amine

542 N-(3-bromo-2-fluoro-5-methyl-phenyl)-l-(3,4-difluorophenyl)- l,2,4-triazol-3 -amine

543 N-[3 -methyl-5-[[ 1 -(3 -pyridyl)- 1 ,2,4-triazol-3 - yl]amino]phenyl]acetamide

544 6-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-8-[4- (oxetan-3-yl)piperazin-l-yl]-4H-l,4-benzoxazin-3-one

545 6-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-8-(3- morpholinoazetidin-l-yl)-4H-l,4-benzoxazin-3-one

546 1 -(3 , 5 -difluorophenyl)-N-(2-fluoro-5 -methyl-phenyl)- 1,2,4- Cmpd

Cmpd Name

No.

triazol-3 -amine

547 2-methoxy-N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]acetamide

548 N-(3-isopropoxy-5-methyl-phenyl)-l-(3-pyridyl)-l,2,4-triazol - 3 -amine

549 tert-butyl N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]carbamate

550 5-methyl-Nl-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3-diamine

551 3,3,3-trifluoro-N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)aminolphenyl]propanamide

552 N-(3 -bromo-5 -methyl-phenyl)- 1 -(3 , 5 -difluorophenyl)- 1,2,4- triazol-3 -amine

553 2-methyl-N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]propanamide

554 N-(5 -chloro-2-fluoro-3 -methyl-phenyl)- 1 -(3 , 5 -difluorophenyl)- l,2,4-triazol-3 -amine

555 N-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methy 1 -phenyl ] acetami de

556 N-[3-ethyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]acetamide

557 N-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-et hyl- phenyl] acetami de

558 N-(3-isopropoxy-5-methyl-phenyl)-l-(2-pyridyl)-l,2,4-triazol - 3 -amine

559 N-(3-isopropoxy-5-methyl-phenyl)-l-phenyl-l,2,4-triazol-3- amine

560 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-4-fluoro-Nl-( 2- methoxy- 1 -methyl-ethyl)-5-methyl-benzene- 1 ,3 -diamine

561 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(2- ethoxypropyl)-4-fluoro-5-methyl-benzene-l,3-diamine

562 N-[3 -ethyl-5-[[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 - yl]amino]phenyl]acetamide

563 N-[3-methyl-5-(trifluoromethoxy)phenyl]-l-(2-pyridyl)-l,2,4- triazol-3 -amine

564 N-[3-methyl-5-(trifluoromethoxy)phenyl]-l-(3-pyridyl)-l,2,4- triazol-3 -amine

565 3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] -4,5- dimethyl-phenol

566 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-fluoro-N3-( 3- fluoropropyl)-5-methyl-benzene-l,3-diamine

567 N-(5-methoxy-2,3-dimethyl-phenyl)-l-phenyl-l,2,4-triazol-3- amine

568 l-(3-fluorophenyl)-N-(5-methoxy-2,3-dimethyl-phenyl)-l,2,4- triazol-3 -amine

569 N-(5-methoxy-2,3 -dimethyl-phenyl)- 1 -(2-pyridyl)- 1 ,2,4-triazol- 3 -amine Cmpd

Cmpd Name

No.

570 N-(5-methoxy-2,3 -dimethyl-phenyl)- 1 -(3 -pyridyl)- 1 ,2,4-triazol- 3 -amine

571 N-[5-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-2,3-dimethyl- phenyl]- 1 -(3 ,5-difluorophenyl)- 1 ,2,4-triazol-3 -amine

572 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4- methy 1 -phenyl ] ethanone

573 1 -[4-methyl-3 -[(1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]phenyl]ethanone

574 l-[3-[[l-(3-fluorophenyl)-l,2,4-triazol-3-yl]amino]-4-methyl - phenyl] ethanone

575 1 -[4-methyl-3 -[[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 - yl]amino]phenyl]ethanone

576 1 -[4-methyl-3 -[[ 1 -(3 -pyridyl)- 1 ,2,4-triazol-3 - yl]amino]phenyl]ethanone

577 3, 4-dimethyl-5-[(l -phenyl- l,2,4-triazol-3-yl)amino]phenol

578 3-[[l-(3-fluorophenyl)-l,2,4-triazol-3-yl]amino]-4,5-dimethy l- phenol

579 3 ,4-dimethyl-5-[[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 -yl]amino]phenol

580 3,4-dimethyl-5-[[l-(3-pyridyl)-l,2,4-triazol-3-yl]amino]phen ol

581 4-methyl-N2-(l -phenyl- l,2,4-triazol-3-yl)pyridine-2,6-diamine

582 3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] -2-fluoro-5 - methyl-phenol

583 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4- methy 1 -phenyl ] ethanol

584 1 -[4-methyl-3 -[(1 -phenyl- 1 ,2,4-triazol-3 - yl)amino]phenyl]ethanol

585 l-[3-[[l-(3-fluorophenyl)-l,2,4-triazol-3-yl]amino]-4-methyl - phenyl] ethanol

586 1 -[4-methyl-3 -[[ 1 -(2-pyridyl)- 1 ,2,4-triazol-3 - yl]amino]phenyl]ethanol

587 1 -[4-methyl-3 -[[ 1 -(3 -pyridyl)- 1 ,2,4-triazol-3 - yl]amino]phenyl]ethanol

588 2-fluoro-5-methyl-3-[(l -phenyl- l,2,4-triazol-3-yl)amino]phenol

589 6-methyl-N2-(l -phenyl- l,2,4-triazol-3-yl)pyridine-2,4-diamine

590 3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] -2,5- dimethyl-phenol

591 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methy 1 -phenyl ] ethanone

592 l-(3,4-difluorophenyl)-N-(3-isopropoxy-2-methyl-phenyl)- l,2,4-triazol-3 -amine

593 l-(3,5-difluorophenyl)-N-(3-isopropoxy-2-methyl-phenyl)- l,2,4-triazol-3 -amine

594 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- Cmpd

Cmpd Name

No.

methyl -phenyl ] ethanol

595 2-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-phenyl]propan-2-ol

596 N-(3-bromo-5-methyl-phenyl)-l -phenyl- l,2,4-triazol-3 -amine

597 3-fluoro-5-[3-(2-fluoro-3-isopropoxy-5-methyl-anilino)- 1,2,4- triazol- 1 -yl] phenol

598 N-(2-fluoro-3-isopropoxy-5-methyl-phenyl)-l-phenyl-l,2,4- triazol-3 -amine

599 N-(2-fluoro-3 -i sopropoxy-5 -methyl-phenyl)- 1 -(3 - fluorophenyl)- 1 ,2,4-triazol-3 -amine

600 3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-methy l- benzonitrile

601 1 -(3 , 5 -difluorophenyl)-N-(5 -isopropoxy-2, 3 -dimethyl-phenyl)- l,2,4-triazol-3 -amine

602 3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] -2-fluoro-5 - methyl-benzonitrile

603 N-(2-fluoro-3-isopropoxy-5-methyl-phenyl)-l-(3-pyridyl)- l,2,4-triazol-3 -amine

604 Nl -[3 -(diethylamino)propyl]-N3 -[ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4- triazol-3-yl]-5-methyl-benzene-l,3-diamine

605 2-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-anilino]-N,N-diethyl-acetamide

606 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-(2-methoxy - 2-methyl-propyl)-5-methyl-benzene-l,3-diamine

607 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-N3- (2,2,2-trifluoroethyl)benzene- 1 ,3 -diamine

608 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-[2-[2- (dimethylamino)ethoxy]ethyl]-5-methyl-benzene-l,3-diamine

609 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-(3- methoxybutyl)-5-methyl-benzene-l,3-diamine

610 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-[2- (dimethylamino)ethyl]-5-methyl-benzene-l,3-diamine

Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-[3-

611 (dimethylamino)-2,2-dimethyl-propyl]-5-methyl-benzene-l,3- diamine

612 N3 -(3 -tert-butoxypropyl)-N 1 - [ 1 -(3 , 5 -difluorophenyl)- 1,2,4- triazol-3-yl]-5-methyl-benzene-l,3-diamine

613 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-N3- (3 ,3 ,3 -trifluoro-2-methoxy-propyl)benzene- 1 ,3 -diamine

614 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methy 1 -phenyl ] -3 -methyl -azeti dine-3 -carb onitril e

615 (2S)-2-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino] -5- methyl-anilino]-N,N-dimethyl-propanamide

616 3-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-anilino]-2,2-dimethyl-propanenitrile Cmpd

Cmpd Name

No.

617 Nl-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-N3-(2,3- dimethoxypropyl)-5-methyl-benzene-l,3-diamine

618 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-[(l S)-2- methoxy- 1 -methyl-propyl]-5-methyl-benzene- 1 ,3 -diamine

619 tert-butyl N- [2- [3 -[ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 - yllaminol-5-methyl-anilinolethyl]-N-methyl-carbamate

620 N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-(3- ethoxypropyl)-5-methyl-benzene-l,3-diamine

621 2-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4,5- dimethyl-phenoxy]-N,N-dimethyl-acetamide

622 tert-butyl N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3- y 1 ] amino] - 5 -methyl -phenyl Jmethyl ] carb am ate

623 tert-butyl N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3- yl]amino]-2-fluoro-5-methyl-phenyl]methyl]carbamate

624 N-[3-(aminomethyl)-5-methyl-phenyl]-l-(3,5-difluorophenyl)- l,2,4-triazol-3 -amine

l-(3,5-difluorophenyl)-N-[2-fluoro-5-methyl-3-[l,2,2,2-

625 tetradeuterio- 1 -(trideuteriomethyl)ethoxy]phenyl]- 1 ,2,4-triazol- 3 -amine

626 N- [3 -(aminomethyl)-2-fluoro-5 -methyl-phenyl] - 1 -(3,5- difluorophenyl)- 1 ,2,4-triazol-3 -amine

627 N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methy 1 -phenyl ] methyl ] acetami de

628 N-[4-isopropoxy-3-[4-(oxetan-3-yl)piperazin-l-yl]phenyl]-l- (2,3,4,5,6-pentadeuteriophenyl)-l,2,4-triazol-3-amine

629 N-(3-ethyl-5-methoxy-phenyl)-l-(2,3,4,5,6- pentadeuteriophenyl)-l,2,4-triazol-3 -amine

630 N-(3-isopropoxy-5-methyl-phenyl)-l-(2,3,4,5,6- pentadeuteriophenyl)-l,2,4-triazol-3 -amine

631 N-(3-methoxy-5-methyl-phenyl)-l-(2,3,4,5,6- pentadeuteriophenyl)-l,2,4-triazol-3 -amine

632 N-(3 -fluoro-5 -methoxy-phenyl)- 1 -(2, 3 ,4, 5 ,6- pentadeuteriophenyl)-l,2,4-triazol-3 -amine

633 N-(3,5-dimethoxyphenyl)-l-(2,3,4,5,6-pentadeuteriophenyl)- l,2,4-triazol-3 -amine

1 -(3 ,4-difluorophenyl)-N- [2-fluoro-5 -methyl-3 - [ 1 ,2,2,2-

634 tetradeuterio- 1 -(trideuteriomethyl)ethoxy]phenyl]- 1 ,2,4-triazol- 3 -amine

N-[2-fluoro-5-methyl-3 -[ 1 ,2,2,2-tetradeuterio- 1 -

635 (trideuteriomethyl)ethoxy]phenyl]- 1 -(3 -pyridyl)- 1 ,2,4-triazol-3 - amine

636 N- [ [3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino] -2- fluoro-5-methyl-phenyl]methyl]acetamide

N-[2-fluoro-5-methyl-3 -[ 1 ,2,2,2-tetradeuterio- 1 -

637 (trideuteriomethyl)ethoxy]phenyl]- 1 -phenyl- 1 ,2,4-triazol-3 - amine Cmpd

Cmpd Name

No.

N-[2-fluoro-5-methyl-3 -[ 1 ,2,2,2-tetradeuterio- 1 -

638 (trideuteriomethyl)ethoxy]phenyl]-l-(3-fluorophenyl)-l,2,4- triazol-3 -amine

639 3 - [ [ 1 -(2, 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] -2,5- dimethyl-phenol

640 3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl] amino] -2,5- dimethyl-benzonitrile

641 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-2- fluoro-pheny 1 ] ethanone

642 N- [3 -(aminomethyl)-2, 5 -dimethyl-phenyl]- 1 -(3,5- difluorophenyl)- 1 ,2,4-triazol-3 -amine

643 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-2- fluoro-pheny 1 ] ethanol

644 N- [ [3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1 ,2,4-triazol-3 -yl]amino] -2,5- dimethy 1 -phenyl ] methyl ] acetami de

645 N-(3-chloro-2,4,6-trideuterio-5-fluoro-phenyl)-l-phenyl-l,2, 4- triazol-3 -amine

646 N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-phenyl]methyl]methanesulfonamide

647 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-2,5- dimethy 1 -phenyl ] ethanone

648 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-2,5- dimethy 1 -phenyl ] ethanol

649 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4,5- dimethy 1 -phenyl ] ethanol

650 N-(3-bromo-2-fluoro-5-methyl-phenyl)-l -phenyl- 1,2,4-triazol- 3 -amine

651 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4,5- dimethy 1 -phenyl ] ethanone

652 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-phenyl]propan-2-one

653 l-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]propan-2-one

654 l-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]propan-2-ol

655 l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-phenyl]propan-2-ol

656 1, 1,1,2,3,3 -hexadeuterio-3 - [3 - [ [ 1 -(3 , 5 -difluorophenyl)- 1,2,4- triazol-3-yl]amino]-5-methyl-phenyl]propan-2-ol

657 1, 1, 1,2,3, 3-hexadeuterio-3-[3-methyl-5-[(l-phenyl-l,2,4-triazol- 3-yl)amino]phenyl]propan-2-ol

658 l, l,l,2,3,3-hexadeuterio-3-[3-methyl-5-[[l-(3-pyridyl)-l,2,4- triazol-3-yl]amino]phenyl]propan-2-ol

659 N-(3-chloro-2,5-difluoro-phenyl)-l -phenyl- l,2,4-triazol-3- amine Salts, Compositions, Uses, Formulation, Administration and Additional Agents

Pharmaceutically acceptable salts and compositions

[00261] As discussed herein, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for the treatment of neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy. In one embodiment, said

neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy include, but are not limited to spinal cord injury, stroke, multiple sclerosis, progressive multifocal 1 eu k oen cep h a 1 opat hy , congenital hypomyelination, encephalomyelitis, acute disseminated

encephalomyelitis, central pontine myelolysis, hypoxic demyeli nation, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher' s disease, Hurler Syndrome, traumatic brain injury, post radiation injur}', neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy /Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic

leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia. Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic vi us 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia.

[00262] In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, pallesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression,

dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy,

[00263] Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[00264] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also useful for treating or lessening the severity of, in a subject, a disease or disorder selected from neurodegenerative or neurological diseases or disorders related to axonal damage, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, a leukoencephalopathy or a leukodystrophy. [00265] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J.

Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of

pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (Ci-4 alkyl) ₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.

Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[00266] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the

pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as

pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;

powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[00267] In another aspect, the invention features a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

[00268] In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of the compounds of formula (Γ) and one or more

pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[00269] In one embodiment, the methods described herein also provide a method of promoting oligodendrocyte proliferation, differentiation or survival comprising contacting oligodendrocytes with a compound of formula (Γ) or a composition thereof.

[00270] In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival. In another embodiment, a method of the present invention comprises promoting oligodendrocyte proliferation, differentiation or survival with a compound of formula (Γ) or a composition thereof. In another embodiment, a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or disorder associated with a lack of oligodendrocyte proliferation, differentiation or survival comprising administering a therapeutically effective amount of the compounds of formula (Γ) or compositions thereof to a subject in need thereof.

[00271] In another embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells, oligodendrocyte cells or oligodendrocyte precursor cells. In one embodiment, a method of the present invention comprises promoting myelination by contacting neuronal cells,

oligodendrocyte cells or oligodendrocyte precursor cells with a compound of formula (Γ) or a composition thereof.

[00272] In another embodiment, a method of the present invention comprises promoting survival of cells of the nervous system. In another embodiment, a method of the present invention comprises promoting survival of cells of the nervous system comprising contacting the cells with a compound or composition of formula (Γ). In one embodiment, the cells of the nervous system comprise brain cells, cortical neurons, oligodendroctyes or oligodendrocyte precursor cells.

[00273] In another embodiment, a method of the present invention is useful for treating or lessening the severity of a disease or disorder selected from a disease or condition associated with demyelination comprising administering a therapeutically effective amount of the compounds of formula (Γ) or compositions thereof to a subject in need thereof. In one embodiment, the disease or condition associated with demyelination is a CNS disorder or a CNS demyelinating disease as described herein. In one embodiment, the disease is multiple sclerosis.

[00274] In another embodiment, the subject has, or is at risk of having, multiple sclerosis. The subject with multiple sclerosis can be at any stage of treatment or disease. In one embodiment, the subject with multiple sclerosis has one or more of: benign multiple sclerosis, relapsing remitting multiple sclerosis, quiescent relapsing remitting multiple sclerosis, active relapsing remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis, clinically isolated syndrome, or clinically defined multiple sclerosis. In one embodiment, the type of multiple sclerosis is primary progressive multiple sclerosis. In another embodiment, the type of multiple sclerosis is rel apsi ng-rem i tti ng multiple sclerosis. In yet another embodiment, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further embodiment, the type of multiple sclerosis is progressive relapsing multiple sclerosis. In another embodiment, the subject is asymptomatic. In another embodiment, the subject has one or more multiple sclerosis-like symptoms, such as those having clinically isolated syndrome or clinically defined multiple sclerosis. In yet other embodiments, the subject has one or more multiple sclerosis relapses.

[00275] In another embodiment, the subject has a relapsing form of multiple sclerosis such as relapsing remitting multiple sclerosis or relapsing secondary progressive multiple sclerosis. In one embodiment, the subject has relapsing remitting multiple sclerosis and has one or more ongoing clinical exacerbations. In another embodiment, the subject has relapsing remitting multiple sclerosis and one or more subclinical activities. In one embodiment, the clinical exacerbation or subclinical activity is shown by gadolinium enhancement of white matter lesions using T1/T2 magnetic resonance imaging. In another embodiment, the clinical exacerbation or subclinical activity is shown by development of new or enlarged white matter lesions on magnetic resonance imaging of the brain or spinal cord. In one embodiment, the development of new or enlarged white matter lesions is monitored by ΊΊ /Τ2 magnetic resonance imaging. In another embodiment, the development of new or enlarged white matter lesions is monitored by Proton Density magnetic resonance imaging. In yet another embodiment, the development of new or enlarged white matter lesions is monitored by MTR magnetic resonance imaging. See also, Gaitan, M. I. and Reich, D. S. (2014) MR I in Diagnosis and Disease Monitoring, in Multiple Sclerosis and CNS Inflammatory Disorders (eds L. M. Samkoff and A. D. Goodman), John Wiley & Sons, Ltd., Chichester, UK.

doi: 10.1002/9781118298633. ch4 which is incorporated herein in its entirety by reference.

[00276] In another embodiment, the clinical exacerbations or subclinical activities are monitored by a functional readout such as ambulatory changes (gait changes, sway changes, etc.), T25W changes and/or EDSS changes. In another embodiment, the clinical exacerbations or subclinical activities are monitored by a visual evoked potential assay, a visual acuity assay or a measurement of optic nerve thickness, in another embodiment, the clinical exacerbations or subclinical activities are monitored by a myelin labelling assay.

[00277] In another embodiment, the subject with multiple sclerosis can be at any stage of treatment or disease and treatment with compounds of formula (Γ) of the present invention result in improvement of the disease or symptoms. In one embodiment, improvement in the disease or symptoms is evidenced by a reduction or disappearance of one or more white matter lesions in the brain. In another

embodiment, improvement in the disease or symptoms is evidenced by improved function such as improved ambulation, improved gait, reduced sway, improved T25W scores or improved EDSS scores. In another embodiment, improvement in the disease or symptoms is evidenced by improvements in a visual acuity assay or a visual evoked potential assay. In another embodiment, improvement in the disease or symptoms is evidenced by enhanced optic nerve thickness. In another embodiment, improvement in the disease or symptoms is evidenced by increased myelination in a myelin labelling assay.

[00278] In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive demyelinating diseases. In one embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in primary progressive multiple sclerosis. In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in secondary progressive multiple sclerosis. In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in re lap sing-remitting multiple sclerosis. In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting myelin regeneration in progressive relapsing multiple sclerosis.

[00279] In yet another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein oligodendrocyte cells are stimulated to regenerate or differentiate. In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level wherein

oligodendrocyte cells are stimulated to remyelinate axons.

[00280] In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby oligodendrocyte cells are stimulated to regenerate or differentiate thereby treating demyelinating diseases or disorders. In yet another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for promoting remyelination at the cellular level whereby axons are remyelinated by oligodendrocyte cells thereby treating demyelinating diseases or disorders.

[00281] In another embodiment, the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein are useful for inducing endogenous oligodendrocytes or oligodendrocyte precursor cells to contact an axon and produce myelin.

[00282] In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukodystrophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (Γ). [00283] In one aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated

encephalomyelitis, central pontine myelolysis, hypoxic demyeli nation, ischemic demyelination, neuromyelitis optics, adrenol eukody strophy , Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher di sease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease ), Wallerian degeneration, optic neuritis, transverse myeliti s, amyotrophic lateral sclerosis (Lou Gehrig ^' s diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher ^' s disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 1 2 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic

leukody strophy, acute hemorrhagic leukoencephaliti s, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesi s/human T-lymphotropic v irus 1 (HTLV-1) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effectiv e amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (Γ).

[00284] In another aspect, the present inv ention prov ides a method of treating, prev enting or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, mov ement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesi s, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptiv e dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression. dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (Γ).

[00285] In yet another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or disorder selected from a

demvelinating di sease, central pontine myelinolysis, a nerve injury disease or disorder, a leukoencephalopathy or a leukody strophy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (Γ) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition .

[00286] In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a disease or di sorder selected from spinal cord inj ury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyeliti s, acute di sseminated

encephalomyelitis, central pontine myelolysis, hypoxic demyeli nation, ischemic demyelination, neuromyelitis optics, adrenoleukody strophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuriti s, transverse myelitis, amylotrophic lateral sclerosi s (Lou Gehrig' s di seae ), Huntington's disease, Alzheimer's disease, Parkinson's di sease, Tay-Sacks disease, Gaucher' s disease, Hurler Syndrome, traumatic brain inj ury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromy elitis optica, vitamin B 1 2 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic

leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia. Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic vi us 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (Γ) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition,

[00287] In another aspect, the present invention provides a method of treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, refapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis. In one aspect, the type of multiple sclerosis is primary progressive multiple sclerosis. In another aspect, the type of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another aspect, the type of multiple sclerosis is secondary

progressive multiple sclerosis. In still a further aspect, the type of multiple sclerosis is progressive relapsing multiple sclerosis.

[00288] In another aspect, the present invention provides a method for treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop, dysfunctional reflexes, pallesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression,

dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula (Γ) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

Manufacture of Medicaments

[00289] In one aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a leukoencephalopathy.

[00290] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal

leukoencephalopathy, congenital hypomyeli nation, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leukodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher' s disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 12 deficiency, isolated vitamin E deficiency syndrome, Bassen-K omzwei syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia.

[002911 In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemi paresis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop. dysfunctional reflexes, pallesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmy.

[00292] In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00293] In one aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from a demyelinating disease, central pontine myelinolysis, a nerv e injury disease or disorder or a leukoencephalopathy with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00294] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a disease or disorder selected from spinal cord injury, stroke, multiple sclerosis, progressive multifocal

leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, hypoxic demyelination, ischemic demyelination, neuromyelitis optics, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalatia, globoid cell leucodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amylotrophic lateral sclerosis (Lou Gehrig's diseae), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher' s disease, Hurler Syndrome, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, neuropathy, acute ischemic optic neuropathy, neuromyelitis optica, vitamin B 12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Leber's hereditary optic atrophy/Leber congenital amaurosis, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, schizophrenia, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis/human T-lymphotropic virus 1 (HTLV- 1 ) associated myelopathy, essential tremor or osmotic hyponatremia in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

[00295] In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of, in a subject, a type of multiple sclerosis selected from primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis or progressive relapsing multiple sclerosis. In one aspect, the type of multiple sclerosis is primary progressive multiple sclerosis. In another aspect, the type of multiple sclerosis is relapsing-remitting multiple sclerosis. In yet another aspect, the type of multiple sclerosis is secondary progressive multiple sclerosis. In still a further aspect, the type of multiple sclerosis is progressive relapsing multiple sclerosis.

[00296] In yet another aspect, the present the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating, preventing or ameliorating one or more symptoms of multiple sclerosis or another neurodegenerative disease selected from auditory impairment, optic neuritis, decreased visual acuity, diplopia, nystagmus, ocular dysmetria, internuclear ophthalmoplegia, movement and sound phosphenes, afferent pupillary defect, paresis, monoparesis, paraparesis, hemiparesis, quadraparesis, plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, motor dysfunction, walking impairment, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, gait disturbances, footdrop,

dysfunctional reflexes, paraesthesia, anaesthesia, neuralgia, neuropathic and neurogenic pain, L'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, disability progression, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction or anorgasmyin combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

Administration of Pharmaceutically acceptable salts and Compositions

[00297] In certain embodiments of the invention an "effective amount" of the compound, a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of, in a subject, a disease or disorder selected from one or more of a demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder or a

leukoencephalopathy.

[00298] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human

[00299] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally,

intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[00300] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain 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 (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,

polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00301] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00302] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00303] In order to prolong the effect of a compound of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming

microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00304] Compositions for rectal or vaginal administration are preferably

suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00305] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, 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 also comprise buffering agents.

[00306] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00307] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00308] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.

Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Additional Therapeutic Agents

[00309] It will also be appreciated that the the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[00310] In one embodiment, the additional therapeutic agents is an

immunomodulatory agent, such as an IFN-β 1 molecule including but not limited to an interferon beta la (Avonex®, Rebif®) or an interferon beta lb (Betaseron®, Betaferon®, Extavia®). Immunomodulatory agents also include other interferons and fragments, analogues, homologues, derivatives, and natural variants thereof with substantially similar biological activity to interferon beta la molecules.

[00311] In another embodiment, the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).

[00312] In another embodiment, the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)).

[00313] In another embodiment, the additional therapeutic agent is an

anthracenedione molecule such as mitoxantrone (Novantrone®). [00314] In another embodiment, the additional therapeutic agent is a sphingosine 1- phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.

[00315] In another embodiment, the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).

[00316] In another embodiment, the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).

[00317] In another embodiment, the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).

[00318] In another embodiment, the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).

[00319] In another embodiment, the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.

[00320] In another embodiment, the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.

[00321] In another embodiment, the additional therapeutic agent is an anti-VLA4 antibody, such as Natalizumab (Tysabri®) or a related VLA-4 antibodies such as those described in US 5,840,299, US 6,602,503, Sanchez-Madrid et al, (1986) Eur. J. Immunol 16: 1343-1349; Hemler et al, (1987) J Biol. Chem. 2: 11478-11485; Issekutz et al. (1991) J Immunol 147: 109 (TA-2 mab); Pulido et al. (1991) J Biol. Chem. 266: 10241-10245; and U.S. Pat. No. 5,888,507 the entire contents of each patent or publication hereby incorporated by reference in their entirety.

[00322] In another embodiment, the additional therapeutic agent is a LINGO-1 antagonist (e.g., an antibody against LINGO (e.g., LINGO-1, LINGO-2, LINGO-3, LINGO-4) or a Nogo receptor-1 (NgRl) modulator and compositions thereof such as those disclosed in WO2004/085648, WO2006/002437, WO2007/008547,

WO2007/025219, WO2007/064882, WO2007/056161, WO2007/133746,

WO2007/098283, WO2008/086006, WO2009/061500, WO2010/005570,

WO2010/062904, WO 2013/173364, WO2014/058875, each of which is hereby incorporated by reference in its entirety. [00323] In another embodiment, the additional therapeutic agent is a TAJ modulator, such as those disclosed in WO2006/017673, which is hereby incorporated by reference in its entirety.

[00324] In another embodiment, the additional therapeutic agent is a TrkA antagonist such as those disclosed in WO2008/013782 or a TrkB antagonist such as those disclosed in WO2009/048605, each of which is hereby incorporated by reference in its entirety.

[00325] In another embodiment, the additional therapeutic agent is a sclerostin modulator such as those disclosed in WO2013/063095, which is hereby incorporated by reference in its entirety.

[00326] In another embodiment, the additional therapeutic agent is an autotaxin (ATX) inhibitor or LPA receptor antagonist, such as those described in

WO2015048301, WO2015042053, WO2015042052, WO2015008230,

WO2015008229, WO2014202458, WO2014139882, WO2014133112,

WO2014097151, WO2014110000, WO2014/081756, WO2014/081752,

WO2014/048865, WO2014168824 , WO2014143583, WO2014139978,

WO2013/186159, WO2012/024620, WO2012/166415, WO2012078593,

WO2012078805, WO2012024620,WO2013070879, WO2013/061297,

WO2013/054185, WO2014/018881, WO2014/018887, WO2014/018891,

WO2014/025708, W02104/025709, WO2014/152725, WO2012028243,

WO2012005227, WO2011/159635, WO2011/159550, WO2011116867,

WO2011053948, WO2011041729, WO2011041694, WO2011041462,

WO2011041461, WO2011017561, WO2011017350, WO2010115491,

WO2011006569, WO20110141761, WO2010112124, WO2010112116,

WO2010077883, WO2010077882, WO2010068775, WO2010063352,

WO2010051031, WO2010051030, WO2009046841, WO2009046842,

WO2009046804, WO2009023854, WO2009/135590, WO2008/014286, WO

2010/141768, US2006/194850, US 2003/114505, US 2004/122236, US 2006/194850, US 6964945, US2005/0256160, US 2006/148830, US 2008/0293764,

US2010/0249157, the disclosure of each patent application and patent hereby incorporated by reference in its entirety. [00327] In another embodiment, the additional therapeutic agent is a Nox4 modulator such as those described in WO2013/037499, which is hereby incorporated by reference in its entirety.

[00328] In another embodiment, the additional therapeutic agent is a remyelinating antibody such as rHIgM22.

[00329] In another embodiment, the additional therapeutic agent is dalfampridine (Ampyra®)

[00330] In another embodiment, the additional therapeutic agent is a death receptor 6 (DR6) antagonist, a p75 antagonist or a combination thereof such as those disclosed in US8894999 and WO2014106104 each of which is incorporated herein by reference in its entirety.

[00331] In another embodiment, the additional therapeutic agent is Cethrin™.

[00332] In another embodiment, the additional therapeutic agent is an activin receptor modulator such as those described in WO2015/001352, which is hereby incorporated by reference in its entirety.

[00333] In another embodiment, the additional therapeutic agent is a GLP-1 like peptide or a derivative of GLP-1 like peptides such as those disclosed in

WO2015/000942, WO2014/202727, WO2012/1401 17, WO2012/062803, WO 2012/062804, WO2011/080102 and WO2009/030771, each of which is incorporated herein by reference in its entirety. In another embodiment, the GLP-1 derivative is Liraglutide or Semaglutide.

[00334] In another embodiment, the additional therapeutic agent is a RXR modulator such as those disclosed in US2015/0038585 and WO2013056232 each of which is incorporated herein by reference in its entirety. In another embodiment, the RXR modulator is HX630.

[00335] In another embodiment, the additional therapeutic agent is an activator of the RF2/KE API/ARE pathway such as those disclosed in WO2014/197818 which is hereby incorporated by reference in its entirety.

[00336] In another embodiment, the additional therapeutic agent is a PPAR agonist such as those disclosed in WO2014/165827 which is hereby incorporated by reference in its entirety. [00337] In another embodiment, the additional therapeutic agent is an inhibitor of HDAC4 such as those disclosed in WO2013/080120 which is hereby incorporated by reference in its entirety.

[00338] In another embodiment, the additional therapeutic agent is a gamma secretase inhibitor such as DAPT.

[00339] In another embodiment, the additional therapeutic agent is an antipsychotic medication such as quetiapine.

[00340] In another embodiment, the additional therapeutic agent is a thyroid hormone.

[00341] In another embodiment, the additional therapeutic agent is a thyroid translocator protein (TSPO) such as etifoxine.

[00342] In another embodiment, the additional therapeutic agent is insulin-like growth factor 1 (IGF-1).

[00343] In another embodiment, the additional therapeutic agent is an

anticholinergic such as benzatropine.

[00344] In another embodiment, the additional therapeutic agent is an

antihistamine/anticholinergic such as clemastine or clemastine fumarate.

[00345] In another embodiment, the additional therapeutic agent is one that removes antiaquaporin by plasmapheresis.

[00346] In another embodiment, the additional therapeutic agent is a hyaluronan inhibitor or antagonist such as those described in WO2015023691, which is hereby incorporated by reference in its entirety.

[00347] In another embodiment, the additional therapeutic agent is a hyaluronidase inhibitor such as a PH20 inhibitor or those described in WO2013/102144,

WO2011/133862, and WO2010/007729 each of which is hereby incorporated by reference in its entirety.

[00348] In another embodiment, the additional therapeutic agent is a Toll-Like Receptor-2 (TLR-2) inhibitor.

[00349] In another embodiment, the additional therapeutic agent is a Semaphorin 3A antagonist or antibody such as those disclosed in WO2014123186, which is hereby incorporated by reference in its entirety.

[00350] In another embodiment, the additional therapeutic agent is a CXCR2 inhibitor or antagonist. [00351] In another embodiment, the additional therapeutic agent is a Semaphorin 3F agonist.

[00352] In another embodiment, the additional therapeutic agent is a Wnt polypeptide or Wnt inhibitor such as those disclosed in WO 2013/040309 and WO 2012/097093, each of which is hereby incorporated by reference in its entirety.

[00353] In another embodiment, the additional therapeutic agent is a mitochondrial pore modulator such as Olesoxime.

[00354] In another embodiment, the additional therapeutic agent is a PSA NCAM antagonist, a CXCR2 inhibitor or antagonist, a MRF agonist, a GM-98 agonist, a Tcf4 inhibitor, a retinoid, a neuregulin 1-erbB signaling modulator, a zpfl91 activator, an miR219 activator, an miR338 activator or an miR138 activator.

[00355] In certain embodiments, the additional agent is an immunomodulatory agent such as an IFN-β 1 molecule which is administered intravenously, subcutaneously or intramuscularly. In one embodiment, the IFN-β 1 molecule is administered at 20-45 microgram once a week by intramuscular injection. In another embodiment, the IFN- β 1 molecule is administered at 20-30 microgram three times a week by intramuscular injection. In another embodiment, the IFN-β 1 molecule is administered at 40-50 micrograms once a week, by subcutaneous injection.

[00356] In another embodiment, the IFN-β 1 molecule is administered in an amount of between 10 and 50 μg intramuscularly three times a week.

[00357] In another embodiment, the IFN-β 1 molecule is administered in an amount of between 10 and 50 μg intramuscularly every five to ten days.

[00358] In another embodiment, the IFN-β 1 molecule is administered in an amount between 200 and 600 μg every other day by subcutaneous injection. In one embodiment, the IFN-β 1 molecule is an interferon β-lb (Betaseron®, Betaferon®, or Extavia®).

[00359] These combinations are useful for treating or lessening the severity of, in a subject, the diseases described herein including neurodegenerative diseases such as multiple sclerosis. These combinations are also useful in the kits described herein.

[00360] it will also be appreciated that the the compounds of formula (Γ) of the present invention and the methods, compositions and kits disclosed herein can be employed in combination therapies to not only treat or lessen the severity of, in a subject, the diseases described herein but may also be used in symptom management. Those additional agents include those useful for treating symptoms such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®, Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesi®a, glycerin suppositories);

depression (Cymbalta®, Effexor®, Paxil®, Prozac®, Wellbutrin®, Zoloft®);

dizziness and vertigo (Antivert®); emotional changes (Nuedexta®), Fatigue

(Amantadine®, Provigil®, Prozac®), itching (Atarax®); pain (Dilantin®, Elavil®, Klonipin®, Neurontin®, Pamelor®, Aventyl®, Tegetrol®); sexual problems

(Cialis®, Levitra®, Papaverine®, MUSE®, Prostin VR®, Viagra®); spasticity (Dantrium®, Gablofen®, Klonipin®, Lioresal®, Valium®, Zanaflex®); tremors (Laniazid®, Nydrazid®, Klonopin®, Rivotril®); and walking or gait difficulties (Ampyra®).

[00361] The amount of additional therapeutic agent present in or with the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00362] In another aspect, the present invention features a kit comprising a compound and/or pharmaceutical composition of formula (Γ) of the present invention and instructions for use thereof.

[00363] In another embodiment, the kits of the present invention further comprise one or more additional therapeutic agent(s). In another embodiment, the additional therapeutic agent is selected from an immunomodulatory agent, such as an IFN-β 1 molecule including but not limited to an interferon beta la (Avonex®, Rebif®) or an interferon beta lb (Betaseron®, Betaferon®, Extavia®).

[00364] In another embodiment, the additional therapeutic agent is a polymer of glutamic acid, lysine, alanine and tyrosine such as glatiramer acetate (Copaxone®).

[00365] In another embodiment, the additional therapeutic agent is an antibody or fragment thereof against alpha-4 integrin (e.g., natalizumab (Tysabri®)). [00366] In another embodiment, the additional therapeutic agent is an

anthracenedione molecule such as mitoxantrone (Novantrone®).

[00367] In another embodiment, the additional therapeutic agent is a sphingosine 1- phosphate receptor modulator such as fingolimod (Gilenya®) and those described in WO 2012/109108 the entire contents of which is hereby incorporated by reference.

[00368] In another embodiment, the additional therapeutic agent is a dimethyl fumarate such as an oral dimethyl fumarate (Tecfidera®).

[00369] In another embodiment, the additional therapeutic agent is an antibody to the alpha subunit of the IL-2 receptor of T cells such as daclizumab (Zenapax®).

[00370] In another embodiment, the additional therapeutic agent is an antibody against CD52 such as alemtuzumab (Lemtrada®).

[00371] In another embodiment, the additional therapeutic agent is an inhibitor of a dihydroorotate dehydrogenase such as teriflunomide (Aubagio®).

[00372] In another embodiment, the additional therapeutic agent is an antibody to CD20 such as ocrelizumab, rituximab or ofatumumab.

[00373] In another embodiment, the additional therapeutic agent is a corticosteroid such as, but not limited to methylprednisolone, Depo-Medrol®, Solu-Medrol®, Deltasone®, Delta-Cortef®, Medrol®, Decadron® or Acthar®.

[00374] In another embodiment, the additional therapeutic agent is one or more compounds useful for treating symptoms of the disease such as bladder problems (e.g., Botox®, DDAVP Nasal Spray®, Detrol®, Ditropan®, Ditropan XL®,

Enablex®, Flomax®, Hytrin®, Minipress®, Oxytrol®, Pro-Banthine®, Sanctura®, Tofranil®, Vesicare®); infections (Bactrim®, Septra®, Cipro®, Macrodantin®, Hiprex®, Pyridium®); bowel dysfunction (Colace®, Dulcolax®, Enemeez®, Fleet enema, Mineral oil, Metamucil®, Milk of Magnesia®, glycerin suppositories);

depression (Cymbalta®, Effexor®, Paxil®, Prozac®, Wellbutrin®, Zoloft®);

dizziness and vertigo (Antivert®); emotional changes (Nuedexta®), Fatigue

(Amantadine®, Provigil®, Prozac®), itching (Atarax®); pain (Dilantin®, Elavil®, Klonipin®, Neurontin®, Pamelor®, Aventyl®, Tegetrol®); sexual problems

(Cialis®, Levitra®, Papaverine®, MUSE®, Prostin VR®, Viagra®); spasticity (Dantrium®, Gablofen®, Klonipin®, Lioresal®, Valium®, Zanaflex®); tremors (Laniazid®, Nydrazid®, Klonopin®, Rivotril®); or walking or gait difficulties (Ampyra®). [00375] In another embodiment, the kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in separate containers.

[00376] In another embodiment, the kits of the present invention are drawn to kits wherein the compounds or the pharmaceutical compositions of the present invention and the one or more additional therapeutic agent(s) are in the same container.

[00377] In another embodiment, the container is a bottle, vial, or blister pack, or combination thereof.

SCHEMES AND EXAMPLES

The compounds of the invention may be readily prepared by known methods and by using the following methods, schemes and examples. Aminotriazole compounds disclosed herein may be prepared using a Buchwald reaction as generally indicated by the two reactions in Scheme A. In the PI variation, a triazole bearing a primary amino group may be coupled with a suitable reaction partner J- A', where J is a leaving group (e.g., a halide) and A is A, as defined herein, or a derivative of A that may be further processed to arrive at a substitution present in A. In the P2 variation, a triazole bearing a leaving group (e.g., a halide) may be coupled with a suitable reaction partner H2N-A, where A is as described above.

Scheme A

Buchwald

Reaction conditions for effecting a Buchwald reaction are generally known to those skilled in the art and/or can be found in the literature, including the following source: http://www.organic-eheim^

Substituents on the A' moiety indicated above may be transformed to other substituents following the Buchwald reaction PI or P2. For example, substituents may be transformed through standard organic chemical reactions including, but not limited to, deprotection, oxidation, reduction, hydrolysis, amide bond formation, alkylation, reductive alkylation, Suzuki couplings, a further Buchwald reaction, and the like. The examples below illustrate various post-Buchwald transformations corresponding to substituents on A'.

The triazole compounds that participate in the Buchwald reaction of Scheme A may be prepared using Chan-Lam chemistry, as shown in Scheme B, to form the bond between the triazole moiety and R ⁸ . See e.g., Lam et al., Tetrahedron Letters (1998), 39, 2941-44. In Scheme B, the moiety Z represents a halide (e.g., bromo) or a nitro group. The nitro group can be converted to the corresponding amine shown in PI using standard conditions for reducing a nitro group.

Scheme B

Various procedures are illustrated below for the preparation of the reactants J-A'and H2N-A. The person skilled in the art will recognize that the specific procedures may be adapted to the synthesis of additional structural variations of compound within formula (Γ) and its subformulas without undue experimentation.

Compounds were named using either IUPAC nomenclature or the nomenclature used in ChemBioDraw Ultra (Version 12.0.2.1076, CambridgeSoft®). EXAMPLES

General methods. ¾ MR (obtained on a Bruker 400MHz Advance III Q P probe 1H/13C/19F or a Bruker 300MHz Advance I QNP probe 1H/13C/19F) spectra were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide- de (DMSO-D6 or DMSO-d6). Mass spectra (MS) were obtained using a Waters 3100 mass detector and one of the following UPLC (Ultra Performance Liquid

Chromatography) or HPLC (High Performance Liquid Chromatography) methods. UPLC method A: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH CI 8, 2.1 x 50 mm, 1.7 μιη particle size. Flow rate = 0.6 mL/min, injection volume = 2 μΐ _^ , and column temperature = 25 °C. Gradient 5%-95% phase B over 1.4 minutes.

UPLC method B: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH CI 8, 2.1 x 50 mm, 1.7 μιη particle size. Flow rate = 0.6 mL/min, injection volume = 2 μΐ _^ , and column temperature = 25 °C. Gradient 10-60% phase B over 1.4 minutes.

UPLC method C: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column 4.6 x 100mm Sunfire CI 8 column. Flow rate = 1.5 mL/min. Gradient 2-98% phase B over 3.8 minutes.

UPLC method D: Mobile Phase A: 95% water [50 mM ammonium formate pH 9]: 5% acetonitrile. Mobile Phase B: acetonitrile. Column: Waters Acquity BEH C8, 2.1 x 50 mm, 1.7 μιη particle size. Flow rate=0.6ml/min; Injection Volume: 2 μΕ.

Gradient 5-95% phase B over 1.4 minutes.

UPLC method E: Mobile Phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Acquity CSH Fluorophenyl, 2.1 x 50 mm, 1.7 μιη particle size. Flow rate=0.6ml/min; Injection Volume: 2 μί; Gradient 5-95% phase B over 1.4 minutes.

UPLC method F: Mobile Phase A: 95% water [50 mM ammonium formate pH 9] : 5% acetonitrile. Mobile Phase B : acetonitrile. Column: Waters Acquity BEH C8, 2.1 x 50 mm, 1.7 μιη particle size. Flow rate 0.6mL/min, Injection Volume: 2 μΕ.

Gradient 60-95% phase B over 1.4 minutes.

HPLC method G: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Xselect CI 8, 4.6 x 50 mm, 5 μιη particle size. Flow rate = 1.5 mL/min, injection volume = 10 μΕ. Gradient 5-95% phase B over 3 minutes.

HPLC method H: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: Waters Xbridge C8, 4.6 x 50 mm, 5 μιη particle size. Injection Volume: 10 μΕ. Gradient 60-95%) phase B over 3 minutes.

HPLC method I: Mobile phase A: water. Mobile phase B: acetonitrile. Mobile

Phase C 5% trifluoroacetic acid in water). Column: YMC-Pak C18, 4.6 x 50 mm, 5 μιη particle size, Injection Volume: 10 μί. Flow rate: 1.5 mL/min, Constant 2%> phase C. Gradient 10-90%> phase B over 4.5 minutes. HPLC method J: Mobile phase A: water. Mobile phase B: acetonitrile. Mobile Phase C 10% trifluoroacetic acid in water). Column: Waters Sunfire CI 8, 4.6 x 50 mm, 5 μπι particle size. Injection Volume: 10 μΐ. . Constant 2% phase C, Gradient 10- 90% phase B over 4.5 minutes.

HPLC method K: Mobile phase A: water. Mobile phase B: acetonitrile. Mobile Phase C 5% trifluoroacetic acid in water). YMC-Pak CI 8, 4.6 x 50 mm, 5 μιη particle size. Injection Volume: 10 μΐ.. Flow rate: 1.5 mL/min, Constant 1% phase C. Gradient 10-99% phase B over 4.5 minutes

UPLC Method L: Mobile phase A: water (0.1% formic acid). Mobile phase B: acetonitrile (0.1% formic acid). Column BEH C8, 2.1 x 50 mm, 1.7 μιη particle size, Injection volume 0.5 Flow rate 0.8 mL/min. Gradient Time (min): % of phase B: 0 min:3% , 0.2 min:3 %, 1.5min: 98%, 3 min:98%, 3.1min:3% ,4min 3%.

HPLC method M: Mobile phase A: water. Mobile phase B: acetonitrile Mobile Phase C 5% trifluoroacetic acid in water). Column: YMC-Pak C18, 4.6 x 50 mm, 5 μπι particle size, Injection Volume: 10 μί. Flow rate: 1.5 mL/min, Constant 2% phase C, Gradient 10-45% phase B over 4.5 minutes.

UPLC method N: Mobile phase A: water (10 mmol ammonium hydroxide, pH -10). Mobile phase B: acetonitrile (10 mmol ammonium hydroxide). Column: Waters XBridge C8 column, 4.6 x 100 mm. Flow rate = 1.5 mL/min. Gradient 2-98% phase B over 3.8 minutes.

UPLC method O: Mobile phase A: water (0.1 % trifluoroacetic acid). Mobile phase B: acetonitrile (0.1 % trifluoroacetic acid). Column: 4.6 x 100 mm Waters

XSelect PFP (pentafluorophenyl) column. Flow rate = 1.5 mL/min. Gradient 2-98% phase B over 3.8 minutes.

Normal phase silica gel flash chromatography was performed using pre-packed Isco RediSepRf regular or high performance (Isco Gold) columns as well as specialty capped silica gel columns such as Isco Gold Amine, Isco Gold Diol, and Isco Gold Cyano as specified in the Examples. Reverse phase chromatography was performed using pre-packed Isco RediSepRf reverse phase columns such as Isco C18 and Isco Gold C18Aq. Pyridine, dichloromethane (CH2CI2 or DCM), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and 1,4-dioxane were from Baker or Aldrich and in some cases the reagents were Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred magnetically unless otherwise noted.

[00378] The following definitions describe terms and abbreviations used herein:

DCM dichloromethane

DMA diemethylacetamide

EtOAc/EA ethyl acetate

Hex hexanes

HEP heptanes

HPLC high-performance liquid chromatography

LCMS liquid chromatography-mass spectrometry

ESI-MS electrospray ionization mass spectrometry

TLC thin layer chromatography

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

THF tetrahydrofuran

Et ₃ N tri ethyl amine

MP N-methylpyrrolidone

HOAc acetic acid

TFA trifluoroacetic acid

ACN acetonitrile

DCM dichloromethane

DCE dichloroethane

DMA dimethylacetamide

N2 nitrogen

R.T./RT/rt room temperature

AT ambient temperature

Aq or aq aqueous

Rac or rac racemic mixture

Rel relative stereochemistry

MeOH methanol

EtOH ethanol

t-BuOH t-butanol

t-BuONa sodium t-butoxide Pd/C palladium on carbon

SnAr nucleophilic aromatic substitution mechanism

t-BuXPhos Palladacycle chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, biphenyl) [2-(2-aminoethyl)phenyl]palladium(II) Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium

ISCO flash chromatography system

Si0 ₂ silica gel

MP-TMT macroporous polystyrene-bound tnmecaptotriazine

PL-HCO3 MP SPE polymer supported bicarbonate resin

RBF round-bottom flask

Cmpd Compound

EXAMPLE 1

Preparation of N-(2-fluoro-3 -isopropoxy-5-methylphenyl)- 1 -phenyl- IH- 1 ,2,4-triazol- 3 -amine Compound 598)

RG-1a RG-1 b

[00379] (a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH ₂ C1 ₂ , RT; (b) Palladium on carbon, H ₂ ; (c) DIAD, PPh ₃ , tetrahydrofuran, RT; (d) t-BuXPhos Palladacycle, tert-butanol, sodium tert-butoxide, 60 °C

Preparation of 3 -nitro-1 -phenyl- 1,2,4-triazole (RG-la)

[00380] A mixture of 3-nitro-lH-l,2,4-triazole (25 g, 219.2 mmol), copper(II) acetate (60 g, 330 mmol), 4 A molecular sieves (9.2 g, 45.51 mmol), pyridine (18 mL, 220 mmol) and phenylboronic acid (approximately 53.80 g, 441.2 mmol) was stirred at room temperature open to air for 7 days. The crude reaction mixture was filtered through Celite, washed with dichloromethane and ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. The crude was a cyan colored solid. The crude material was slurried with 1L of ethyl acetate and filtered through a silica plug. The silica plug was then washed with 2L of ethyl acetate. The filtrate was concentrated to dryness under reduced pressure and the residue was triturated with -150 mL of diethyl ether to yield 3 -nitro-1 -phenyl- 1,2,4-triazole (27 g, 65%). ¾ NMR (300 MHz, CDCh) δ 8.64 (d, J = 1.6 Hz, 1H), 7.88 - 7.66 (m, 2H), 7.59 (dtd, J = 14.7, 8.0, 7.4, 4.1 Hz, 3H) ppm. ESI-MS m/z calc. 190.04907, found 191.07 (M+l) ⁺ ; Retention time: 0.72 minutes.

Preparation of 1 -phenyl- L2,4-triazol-3 -amine (RG-lb)

[00381] A 1L round bottom flask was charged with 10% palladium on carbon (wet, Degussa type) (250 mg) and the flask evacuated and purged three times with nitrogen. Cannulated ethanol (100 mL) into the flask, followed by cannulation of 3-nitro-l- phenyl- 1,2,4-triazole (3.1 g, 16.30 mmol) in ethanol (150 mL). Evacuated flask under vacuum then added a balloon of hydrogen and stirred at room temperature for 18 hours. Filtered the crude reaction mixture through a pad of Celite, washed the pad with ethanol, then evaporated and azeotroped with dichloromethane to afford 1- phenyl-l,2,4-triazol-3 -amine (13.3 grams, 89%). ¾ NMR (300 MHz, OMSO-d ₆ ) δ 8.81 (s, 1H), 7.81 - 7.63 (m, 2H), 7.55 - 7.40 (m, 2H), 7.4-7.2 (m, 1H), 5.76 (s, 2H) ppm. ESI-MS m/z calc. 160.07489, found 160.95 (M+l) ⁺ ; Retention time: 0.55 minutes.

Preparation of l-bromo-2-fluoro-3-isopropoxy-5-methyl-benzene (RG-lc)

[00382] To a solution of 3-bromo-2-fluoro-5-methyl-phenol (1.9 g, 9.267 mmol), 2-propanol (1.1 mL, 14.37 mmol), and triphenylphosphine (3.9 g, 14.87 mmol) in tetrahydrofuran (60 mL) was added isopropyl N-isopropoxycarbonyliminocarbamate (DIAD) (2.7 mL, 13.94 mmol) and the mixture was allowed to stir overnight at room temperature under nitrogen. Celite was added to the crude reaction mixture and the mixture was concentrated to dryness under reduced pressure. Purified by silica gel chromatography (80 g column; 0-10% dichloromethane/heptane). Concentrated desired fractions to dryness under reduced pressure to afford l-bromo-2-fluoro-3- isopropoxy-5-methyl-benzene (2.04 g, 84%). ¾ NMR (400 MHz, CDCh) δ 6.98 - 6.88 (m, 1H), 6.77 - 6.67 (m, 1H), 4.57 - 4.40 (m, 1H), 2.27 (s, 3H), 1.35 (d, J = 6.1 Hz, 6H) ppm. Compound does not ionize well under standard LC/MS method.

Retention time: 0.99 minutes. Preparation of N-(2-fluoro-3 -isopropoxy-5-methylphenyl)- 1 -phenyl- IH- 1 ,2,4-triazol- 3 -amine (Compound 598)

[00383] 1 -phenyl- l,2,4-triazol-3 -amine (41 mg, 0.2560 mmol), l-bromo-2-fluoro- 3-isopropoxy-5-methyl-benzene (60 mg, 0.2428 mmol), chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (7.0 mg, 0.01019 mmol) and sodium tert-butoxide (73 mg, 0.7596 mmol) were mixed in tert-butanol (2 mL) and the reaction was degassed with nitrogen for 30 seconds. The reaction was heated at 60 °C for 3 hours. The reaction was cooled to room temperature and water was added to quench the reaction. Brine was added and the reaction was extracted with dichloromethane and the organic layer was concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (4 gram column; 10-90% ethyl acetate in hexanes). Concentrated the desired fractions to dryness under reduced pressure to yield N-(2-fluoro-3-isopropoxy-5-methylphenyl)-l- phenyl- lH-l,2,4-triazol-3 -amine (25.5 mg, 31%). ¾ NMR (300 MHz, DMSO-^e) δ 9.06 (d, J = 1.4 Hz, 1H), 8.74 (s, 1H), 7.99 - 7.68 (m, 2H), 7.68 - 7.46 (m, 2H), 7.44 - 7.18 (m, 1H), 6.54 (d, J = 6.8 Hz, 1H), 4.56 (p, J = 6.2 Hz, 1H), 2.27 (s, 3H), 1.28 (dd, J = 6.1, 1.7 Hz, 6H) ppm. ESI-MS m/z calc. 326.1543, found 327.01 (M+l) ⁺ ;

Retention time: 0.98 minutes.

[00384] Using the general synthetic schemes outlined in Schemes A and B, and using procedures analogous to those described in Example 1, the following

compounds can be synthesized from the appropriate intermediates; 112, 113, 597, 599 and 603. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 2

Preparation of of l-(3,4-difluorophenyl)-N-(2-fluoro-3-isopropoxy-5-methyl-phe nyl)-

L2,4-triazol-3 -amine (Compound 524)

[00385] (a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Pearlman's catalyst, H ₂ ; (c) K2CO3, DMF, 50 °C; (d) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 60 °C.

Preparation of of l-(3,4-difluorophenyl)-3-nitro-L2,4-triazole (RG-2a)

[00386] A 12 L 3 -neck flask equipped with a mechanical stirrer was charged with dichloromethane (4.5 L), 3-nitro-4H-l,2,4-triazole (100 g, 876.7 mmol), (3,4- difluorophenyl)boronic acid (200 g, 1.267 mol), 3 A molecular sieves (pellets, 200 g), diacetoxycopper (230 g, 1.266 mol) and pyridine (150 mL, 1.855 mol). The mixture was stirred at room temperature open to the atmosphere. After 1 day, the reaction mixture had dried up to the extent that stirring had ceased. The mixture was re- diluted with dichloromethane (4.5 L) and stirred for a further 3 days at room temperature open to the atmosphere. Extra dichloromethane was added daily to replace what was lost to evaporation. The reaction mixture was treated with Celite (200 g), then filtered through a pad of Celite. The plug was eluted with

approximately 6 L of dichloromethane. The combined filtrate was worked-up in batches as follows: ~2 L of dichloromethane solution was washed with ammonium hydroxide (10 vol% in water, 2 X 1.5 L) then 2 N (aq) hydrochloric acid (1 L). This was repeated until all dichloromethane filtrate had been treated. The combined organics were then dried with magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was triturated with methyl tert- butyl ether (250 mL) and filtered. The collected solid was washed with methyl tert- butyl ether (2 X 200 mL) then dried under suction to yield l-(3,4-difluorophenyl)-3- nitro-l,2,4-triazole (89.7 g, 45%). ¾ NMR (300 MHz, CDCh) δ 8.64 (s, 1H), 7.71 (ddd, J = 9.7, 6.6, 2.7 Hz, 1H), 7.55 (ddd, J = 8.1, 3.9, 2.0 Hz, 1H), 7.50 - 7.37 (m, 1H) ppm. ESI-MS m/z 227.07, Retention time: 2.69 minutes. Preparation of l-(3,4-difluorophenyl)-L2,4-triazol-3-amine (RG-2b)

[00387] A Parr vessel was charged with l-(3,4-difluorophenyl)-3-nitro-l,2,4- triazole (32.6 g, 144.2 mmol), Pearlman's Catalyst (10 wt% on C, wet) (7.6 g, 5.412 mmol) and acetic acid (300 mL). The mixture was hydrogenated on a Parr shaker for 2 hours. The reaction mixture was filtered through a pad of Celite, eluted with ethanol (400 mL), and concentrated to dryness under reduced pressure. The residue was dissolved in hot ethyl acetate (200 mL) and treated with heptane (400 mL). The mixture stood at room temperature for 3 days and was then filtered. The collected solid was dried under suction. A second crop of crystals was collected from the mother liquor in the same manner. Combined both crops to give l-(3,4- difluorophenyl)-l,2,4-triazol-3 -amine (28 g, 99%) as an off-white solid. ¾ MR (300 MHz, CDCh) δ 8.17 (s, 1H), 7.58 - 7.41 (m, 1H), 7.40 - 7.19 (m, 2H), 4.42 (s, 2H) ppm. ESI-MS m/z calc. 196.05605, found 197.12 (M+l) ⁺ ; Retention time: 0.6 minutes. Preparation of l-bromo-2-fluoro-3-isopropoxy-5-methyl-benzene (RG-2c)

[00388] 3-bromo-2-fluoro-5-methyl-phenol (500 mg, 2.44 mmol), 2-iodopropane (-487 uL, 830 mg, 4.88 mmol), and potassium carbonate (1.01 g, 7.32 mmol) were suspended in 5 mL of dry dimethylformamide and the reaction was sealed and heated at 50°C for 1.5 hours with stirring. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was washed with brine, dried with sodium sulfate and solvent was removed under reduced pressure to yield l-bromo-2-fluoro-3-isopropoxy-5-methyl-benzene (570 mg, 85%). ¾ NMR (400 MHz, CDCh) δ 6.95 - 6.87 (m, 1H), 6.71 (dd, J = 7.2, 2.0 Hz, 1H), 4.50 (dt, J = 12.2, 6.1 Hz, 1H), 2.34 - 2.13 (m, 3H), 1.35 (d, J = 6.1 Hz, 6H). 19F NMR (377 MHz, CDCh) -130.98, -131.00, -131.01 ppm.

Preparation of l-(3,4-difluorophenyl)-N-(2-fluoro-3-isopropoxy-5-methyl-phe nyl)- l,2,4-triazol-3 -amine (Compound 524)

[00389] l-(3,4-difluorophenyl)-l,2,4-triazol-3-amine; (163 mg, 0.83 mmol) and l-bromo-2-fluoro-3-isopropoxy-5-methyl-benzene; (250 mg, 0.91 mmol) were dissolved into a mixture of anhydrous 1,4-dioxane (2 mL) and tert-butanol (8 mL) and purged with nitrogen for several minutes. During the purge was added sequentially, chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (50 mg, 0.083 mmol) followed by sodium tert-butoxide (120 mg, 1.24 mmol). The vial was sealed and the reaction was heated to 50°C for ~2 hours with stirring. The reaction was diluted with methanol (approximately 2 mL) and all solvents were removed under reduced pressure. The residue was partitioned between water and dichloromethane. The organic phase was washed with brine, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (0-10% ethyl acetate/dichloromethane). The desired fractions were concentrated to dryness under reduced pressure to yield l-(3,4- difluorophenyl)-N-(2-fluoro-3-isopropoxy-5-methyl-phenyl)-l, 2,4-triazol-3-amine (113 mg, 33 % yield). ¾ MR (400 MHz, CDCh) δ 8.30 (s, 1H), 7.69 (dd, J = 7.1, 1.3 Hz, 1H), 7.58 (ddd, J = 10.8, 6.8, 2.6 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.36 - 7.20 (m, 3H), 6.43 (dd, J = 7.3, 1.7 Hz, 1H), 4.54 (dt, J = 12.2, 6.1 Hz, 1H), 2.36 (s, 3H), 1.37 (d, J = 6.1 Hz, 6H) ppm. ESI-MS m/z calc. 362.13544, found 364.0 (M+l) ⁺ ;

Retention time: 1.0 minutes.

[00390] Using the general synthetic schemes outlined in Schemes A and B, and using procedures analogous to those described in Example 2, the following compounds can be synthesized from the appropriate intermediates; 57, 94, 99, 110, 111, 115, 139, 171, 172, 177-179, 194-197, 205, 206, 277, 368, 495, 523, 625, 634, 635, 637 and 638. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 3

Preparation of N-r3-(2,2-difluoroethoxy)-5-methyl-phenyl1-l-(3,5-difluoroph enyl)- L2,4-triazol-3 -amine (Compound 505)

(a) Cu(OAc) ₂ , pyridine, CH2CI2, 3 A molecular sieves, RT; (b) Palladium on Carbon, H2; (c) Copper iodide, 1,10-phenanthroline, CS2CO3, 4 A molecular sieves, toluene, 120°C; (d) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 60 °C. Preparation of l-(3,5-difluorophenyl)-3-nitro-L2,4-triazole (RG-3a)

[00391] A 12 L 3-neck flask equipped with a mechanical stirrer was charged with dichloromethane (4.5 L), 3-nitro-4H-l,2,4-triazole (100 g, 876.7 mmol), (3,5- difluorophenyl)boronic acid (200 g, 1.267 mol), 3 A molecular sieves (pellets, 200 g), pyridine (150 mL, 1.855 mol) and copper(II)acetate (225 g, 1.239 mol). The mixture was stirred at room temperature open to the atmosphere for 4 days. Extra

dichloromethane was added daily to replace what was lost to evaporation. The reaction mixture was treated with Celite (200 g), then filtered through a pad of Celite. The plug was eluted with approximately 6 L of dichloromethane. The combined filtrate was worked-up in batches as follows: ~2 L of dichloromethane solution was washed with ammonium hydroxide (10 vol% in water, 2 X 1.5 L) then 2 N (aq) hydrochloric acid (1 L). This was repeated until all dichloromethane eluent had been treated. The organics were combined and dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was treated with methyl tert-butyl ether (400 mL). The resulting suspension stood at room temperature for 15 minutes, then filtered through a plastic frit. The collected solid was washed with methyl tert-butyl ether (2 X 100 mL) then dried under suction to yield l-(3,5- difluorophenyl)-3-nitro-l,2,4-triazole (119 g, 60%). ¾ NMR (400 MHz, DMSO- d ₆ ) δ 9.66 (s, 1H), 7.79 (dd, J = 8.0, 2.2 Hz, 2H), 7.52 (tt, J = 9.2, 2.3 Hz, 1H) ppm. ESI- MS m/z calc. 226.03023, found 227.22 (M+l) ⁺ ; Retention time: 0.74 minutes. Preparation of l-(3,5-difluorophenyl)-L2,4-triazol-3-amine (RG-3b)

[00392] A toluene (20 mL) mixture of l-bromo-3-iodo-5-methyl-benzene (1.442 g, 4.856 mmol), 2,2-difluoroethanol (approximately 1.195 g, 14.57 mmol), copper(I)iodide (92.5 mg, 0.4857 mmol), 1, 10-phenanthroline (approximately 175.0 mg, 0.9712 mmol), cesium carbonate (approximately 3.164 g, 9.712 mmol) and 0.43 g 4 A molecular sieves was stirred at 120 °C overnight. The reaction mixture was filtered through a plug of Florisil, concentrated to dryness under reduced pressure and purified by silica gel chromatography (80 g column; 20% ethyl acetate/heptane). The desired fractions were concentrated to dryness under reduced pressure to yield 1- bromo-3-(2,2-difluoroethoxy)-5-methyl-benzene (600 mg, 49%). ¾ NMR (400 MHz, CDCh) δ 7.02 (d, J = 1.8 Hz, 1H), 6.91 (t, J = 2.1 Hz, 1H), 6.70 (t, J = 1.7 Hz, 1H), 6.25 - 5.93 (m, 1H), 4.16 (tt, J = 13.0, 4.2 Hz, 2H), 2.32 (d, J = 9.5 Hz, 3H) ppm.

Preparation of N-r3-(2,2-difluoroethoxy)-5-methyl-phenyl1-l-(3,5-difluoroph enyl)- L2,4-triazol-3 -amine (Compound 505)

[00393] To a fert-butanol (6.907 mL) solution of l-(3,5-difluorophenyl)-l,2,4- triazol-3 -amine (98.08 mg, 0.5 mmol) and l-bromo-3-(2,2-difluoroethoxy)-5-methyl- benzene (163.2 mg, 0.65 mmol) was added chloro(2-di-t-butylphosphino-2',4',6'-tri-i- propyl-l, -biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos

Palladacycle) (approximately 16.28 mg, 0.025 mmol) and potassium tert-butoxide (approximately 112.2 mg, 1.0 mmol). The reaction mixture was stirred at 90 °C for 20 minutes in a sealed vial. To the reaction mixture was added ethyl acetate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated to dryness under reduced pressure and purified by silicagel chromatography (40 g Gold column (ISCO); 50% ethyl acetate/heptane). The desired fractions were concentrated to dryness under reduced pressure to yield N-[3-(2,2-difluoroethoxy)-5-methyl- phenyl]-l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (104.3 mg, 55%). ¾ NMR (400 MHz, CDCh) δ 8.34 (s, 1H), 7.29 - 7.26 (m, 2H), 7.21 (t, J = 2.2 Hz, 1H), 6.85 (q, J = 1.6 Hz, 1H), 6.85 - 6.79 (m, 1H), 6.75 (s, 1H), 6.48 - 6.36 (m, 1H), 6.15 (tt, J = 55.3, 4.2 Hz, 1H), 4.25 (td, J = 13.1, 4.2 Hz, 2H), 2.37 (s, 3H) ppm. ESI-MS m/z calc. 366.11038, found 367.11 (M+l) ⁺ ; Retention time: 0.88 minutes.

[00394] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 3, the following compounds can be synthesized from the appropriate intermediates; 492-494, 506 and 507. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 4

Preparation of N-r3-methyl-5-r(l-phenyl-L2,4-triazol-3-yl)amino1phenyl1acet amide m ound 538)

RG-4c RG-lb Compound 538

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) ethyl acetate, RT; (d) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 125 °C. Preparation of N-(3-bromo-5-methyl-phenyl)acetamide (RG-4c)

[00395] To a solution of 3-bromo-5-methyl-aniline (860 mg, 4.622 mmol) in ethyl acetate (10 mL) was added acetic anhydride (approximately 1.416 g, 1.309 mL, 13.87 mmol). The reaction mixture was stirred for 1 hour at room temperature and then concentrated to dryness under reduced pressure. The solids were triturated with ethyl acetate :hexane (1 :2; 20 mL). After filtration, the solids were collected and dried under reduced pressure to give N-(3-bromo-5-methyl-phenyl)acetamide (889 mg, 80%). ¹ H MR (300 MHz, CDCh) δ 7.53 (s, 1H), 7.28 (s, 1H), 7.10 (s, 2H), 2.33 (s, 3H), 2.18 (s, 3H) ppm. ESI-MS m/z calc. 226.99458, found 227.92 (M+l) ⁺ ;

Retention time: 0.8 minutes.

Preparation of N-[3-methyl-5-[(l-phenyl-L2,4-triazol-3-yl)aminolphenyllacet amide (Compound 538)

[00396] 1 -Phenyl- l,2,4-triazol-3 -amine (105 mg, 0.6555 mmol), N-(3-bromo-5- methyl-phenyl)acetamide (100 mg, 0.4384 mmol) and sodium tert-butoxide (85 mg, 0.8845 mmol) were suspended in 1,4-dioxane (4 mL) and purged with nitrogen for several minutes before the addition of tert-ButylXphos Palladacyle (22 mg, 0.03378 mmol). The mixture was microwaved at 125 °C for 35 minutes. The reaction was quenched with methanol (2 mL) and diluted with dichloromethane (10 mL). After filtration through Florisil (5 g), the solvent was evaporated under reduced pressure.

The crude product was triturated with water, ether and methanol to yield N-[3-methyl- 5-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]acetamide (66 mg, 47%). ¹ H MR (300 MHz, Methanol-A+CDCh) δ 8.58 (s, 1H), 8.00 - 7.94 (m, 2H), 7.55 - 7.49 (m, 3H), 7.39 (s, 1H), 7.21 (d, J = 10.3 Hz, 1H), 6.71 (d, J = 10.6 Hz, 1H), 4.09 - 4.02 (m, 4H), 3.44 - 3.38 (m, 4H) ppm. ESI-MS m/z calc. 307.1433, found 307.98 (M ⁺ l)+; Retention time: 0.76 minutes.

[00397] Using the general synthetic scheme outlined in Schemes A and B and the procedures analogous to those described in Example 4, the following compounds can be synthesized from the appropriate intermediates; 543 and 555. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00398] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, using procedures analogous to those described in Example 4, except that for the third step the depicted amide formation is replaced with a reductive amination performed under typical reductive amination conditions (for example using sodium triacetoxyborohydride in

dichloromethane/acetic acid); 304, 295, 297, 98, 167, 166, 173 and 174. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with still further variations in the substitutions of R ⁸ and A.

EXAMPLE 5

Preparation of l-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)morpholin-2-yllp henyll- 1.2.4-triazol-3 -amine (Compound 349); l-(3.5-difluorophenylVN-r3-r(2SV4-(oxetan- 3-yl moφholin-2-yl1phenyl1-L2,4-triazol-3-amine (Compound 351); and 1 -(3,5- difluorophenyl)-N-r3-r(2R)-4-(oxetan-3-yl)morpholin-2-yl1phe nyl1-1.2.4-triazol-3- amine (Compound 350)

Compound 350

C d 351

(a) Cu(OAc) ₂ , Pyridine, CH2CI2, 3 A molecular sieves, rt; (b) Palladium on carbon, H ₂ ; (c) dichloromethane, NaBH(OAc) ₃ , RT; (d) t-BuXPhos Palladacycle, NaOtBu, tBuOH, 80 °C; (e) SFC.

Preparation of 2-(3-bromophenyl)-4-(oxetan-3-yl)morpholine (RG-5c)

[00399] 2-(3-bromophenyl)morpholine (2.5 g, 10.33 mmol) and oxetan-3-one (1500 μΐ _^ , 23.40 mmol) were combined in dichloromethane (50 mL). Sodium triacetoxyborohydride (4 g, 18.87 mmol) was added. The mixture was stirred for 2 hours at room temperature. Methanol was added and the reaction mixture was evaporated under reduced pressure. The crude product was purified by silica gel chromatogaphy (80 g column; 5% methanol/methylene chloride with 0.1%

triethylamine modifier). The desired fractions were concentrated to dryness under reduced pressure to yield 2-(3-bromophenyl)-4-(oxetan-3-yl)morpholine (2.01 g, 51%). ¹ H MR (400 MHz, CDCh) δ 7.54 (t, J = 1.8 Hz, 1H), 7.43 (ddd, J = 7.8, 2.1, 1.2 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.30 - 7.17 (m, 1H), 4.74 - 4.64 (m, 4H), 4.67 - 4.55 (m, 1H), 4.07 (ddd, J = 11.5, 3.4, 1.5 Hz, 1H), 3.87 (td, J = 11.5, 2.5 Hz, 1H), 3.61 - 3.50 (m, 1H), 2.82 (dt, J = 1 1.3, 2.2 Hz, 1H), 2.74 - 2.65 (m, 1H), 2.20 (td, J = 11.4, 3.4 Hz, 1H), 1.97 (dd, J = 11.4, 10.3 Hz, 1H) ppm. ESI-MS m/z calc. 297.03644, found 299.93 Retention time: 0.74 minutes.

Preparation of of l-(3,5-difluorophenyl)-N-[3-[4-(oxetan-3-yl)morpholin-2- yl1phenyl1-L2,4-triazol-3 -amine (Compound 349)

[00400] l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (250 mg, 1.274 mmol) and 2- (3-bromophenyl)-4-(oxetan-3-yl)morpholine (400 mg, 1.341 mmol) were combined in degassed dioxane (5 mL). Sodium tert-butoxide (2 mL of 2 M, 4.000 mmol) followed by chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, l'-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (50 mg, 0.06768 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80 °C for 5 hours in a sealed vial. To the reaction mixture was added heptane. The reaction mixture was stirred and filtered. The filter cake was purified by MPLC: 80 g column, eluted with 5% methanol in methylene chloride (contains 0.1% TEA). The desired fractions were concentrated to dryness under reduced pressure to yield l-(3,5- difluorophenyl)-N-[3-[4-(oxetan-3-yl)morpholin-2-yl]phenyl]- l,2,4-triazol-3-amine (350 mg, 61%). ¾ MR (400 MHz, Methanol-^) δ 8.90 (s, 1H), 7.73 (s, 1H), 7.62 - 7.46 (m, 3H), 7.27 (t, J = 7.9 Hz, 1H), 6.95 (ddd, J = 11.1, 8.9, 7.2 Hz, 2H), 4.67 (dq, J = 9.3, 6.4 Hz, 4H), 4.57 (dd, J = 10.3, 2.1 Hz, 1H), 4.05 (dd, J = 11.5, 2.0 Hz, 1H), 3.85 (td, J = 11.5, 2.3 Hz, 1H), 3.53 (dd, J = 14.6, 8.5 Hz, 1H), 2.88 (d, J = 11.4 Hz, 1H), 2.75 (d, J = 11.4 Hz, 1H), 2.16 (td, J = 11.5, 3.4 Hz, 1H), 2.07 - 1.96 (m, 1H) ppm. ESI-MS m/z calc. 413.16632, found 414.1 (M ⁺ l) ⁺ ; Retention time: 0.86 minutes. Preparation of rel- 1 -(3 , 5 -difluorophenyD-N- [3 -\(2 S)-4-(oxetan-3 -yl)morpholin-2- yl1phenyl1-L2,4-triazol-3 -amine (Compound 351) and l-(3,5-difluorophenyl)-N-r3- r(2R)-4-(oxetan-3-yl)morpholin-2-yl1phenyl1-L2,4-triazol-3 -amine (Compound 350)

[00401] 1 -(3 , 5 -difluorophenyl)-N- [3 - [4-(oxetan-3 -yl)morpholin-2-yl]phenyl] - l,2,4-triazol-3 -amine (320 mg, 0.7047 mmol) was diluted in methanol (31 mg/mL). 1 mL of 31 mg/mL solution was injected on an IC column (20-250 mm) and eluted with 40% ethanol (5 mM Ammonia), 60% CO2 at a rate of 80 mL/minute sequentially until all the material was resolved.

Peak A (retention time 1.408 min) was concentrated to dryness to yield re/- 1 -(3,5- difluorophenyl)-N-[3-[(2R)-4-(oxetan-3-yl)morpholin-2-yl]phe nyl]-l,2,4-triazol-3- amine, 350 (122.4 mg, 79%)(stereochemistry was arbitrarily assigned). ¾ ΝΜΚ (300 MHz, CDCh) δ 8.35 (s, 1H), 7.62 - 7.50 (m, 2H), 7.39 - 7.24 (m, 3H), 6.99 (d, J = 7.6 Hz, 1H), 6.80 (tt, J = 8.7, 2.1 Hz, 1H), 4.76 - 4.60 (m, 5H), 4.11 (dd, J = 11.4, 2.0 Hz, 1H), 3.92 (td, J = 11.4, 2.2 Hz, 1H), 3.56 (p, J = 6.4 Hz, 1H), 2.88 (d, J = 11.3 Hz, 1H), 2.71 (d, J = 11.1 Hz, 1H), 2.22 (td, J = 11.3, 3.3 Hz, 1H), 2.06 (t, J = 10.8 Hz, 1H) ppm. ESI-MS m/z calc. 413.16632, found 414.22 (M+l) ⁺ ; Retention time: 0.7 minutes.

Peak B (retention time 1.73 min) was concentrated to dryness to yield re/-l-(3,5- difluorophenyl)-N-[3-[(2S)-4-(oxetan-3-yl)morpholin-2-yl]phe nyl]-l,2,4-triazol-3- amine, 351 (120.1 mg, 80 %) (stereochemistry was arbitrarily assigned). ¾ MR (300 MHz, CDCh) δ 8.35 (s, 1H), 7.63 - 7.47 (m, 2H), 7.41 - 7.13 (m, 4H), 6.99 (d, J = 7.6 Hz, 1H), 6.80 (tt, J = 8.7, 2.2 Hz, 1H), 4.79 - 4.57 (m, 5H), 4.11 (dd, J = 11.4, 2.0 Hz, 1H), 3.92 (td, J = 11.4, 2.4 Hz, 1H), 3.56 (p, J = 6.4 Hz, 1H), 2.88 (d, J = 11.3 Hz, 1H), 2.71 (d, J = 11.2 Hz, 1H), 2.22 (td, J = 11.4, 3.4 Hz, 1H), 2.12 - 1.98 (m, 1H), 1.27 (dd, J = 28.0, 11.3 Hz, 2H) ppm. ESI-MS m/z calc. 413.16632, found 414.17 (M+l) ⁺ ; Retention time: 0.7 minutes.

[00402] Using the general synthetic scheme outlined in Schemes A and B and ssing procedures analogous to those described in Example 5, the following racemic compounds can be synthesized from the appropriate intermediates, omitting the final chiral separation step; 496-502. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. [00403] The following compounds can be synthesized from the appropriate intermediates according to General Schemes A and B, using procedures analogous to those described in Example 5, except that for the third step the depicted reductive amination is replaced with an amide formation performed under typical conditions (for example acetyl chloride and diisopropyl ethylamine in dichloromethane at room temperature); 510-515. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 6

Preparation of N-r(l S)-l-(5-fluoro-2-pyridyl)ethyl1-N4-(l-phenyl-1.2.4-triazol-3 - yl)pyridine-2,4-diamine (Compound 121)

RG-6c RG-lb Compound 121 (a) Cu(OAc) ₂ , pyridine, CH2CI2, 4 A molecular sieves, RT; (b) Palladium on carbon, H ₂ ; (c) NaOH, NMP, 160 °C; (d) Cul, N,N'-dimethylethane-l,2-diamine, K2CO3, DMF, 110 °C.

Preparation of N-[(l S)-l-(5-fluoro-2-pyridyl)ethyll-4-iodo-pyridin-2-amine (RG-6c)

[00404] 2-fluoro-4-iodo-pyridine (323 mg, 1.449 mmol), (l S)-l-(5-fluoro-2- pyridyl)ethanamine (Hydrochloride salt) (approximately 307.1 mg, 1.739 mmol) were dissolved in N-methylpyrrolidine (10 mL) and treated with 2N sodium hydroxide (2 mL). The mixture was heated in the microwave at 160 °C for 30 minutes. Water (5 mL) was added and the mixture was extracted with ethyl acetate (2 X 10 mL). The combined organic layers were concentrated and the residue was purified by reverse phase HPLC with the gradient 10-90 % acetonitrile/water with a trifluoroacetic acid modifier. Concentration under vacuum provided N-[(l S)-l-(5-fluoro-2- pyridyl)ethyl]-4-iodo-pyridin-2-amine (92 mg, 18.5%). ESI-MS m/z calc. 343.14, found 344.34, Retention time: 2.04 minutes.

Preparation of N-r(l S)-l-(5-fluoro-2-pyridyl)etfayl1-N4-(l-phenyl-1.2.4-triazol- 3- yl)pyridine-2,4-diamine (Compound 121)

[00405] 1 -Phenyl- l,2,4-triazol-3 -amine (approximately 19.61 mg, 0.1224 mmol), N-[(l S)-l-(5-fluoro-2-pyridyl)ethyl]-4-iodo-pyridin-2-amine (35 mg, 0.1020 mmol) and potassium carbonate (approximately 28.19 mg, 0.2040 mmol) were dissolved in dimethylformamide. The mixture was degassed for 5 minutes with nitrogen, then copper(I) iodide and N,N'-dimethylethane-l,2-diamine (approximately 2.697 mg,

3.257 μΐ _^ , 0.03060 mmol) were added. The tube was sealed and heated to 110 °C for a week. The crude reaction mixture was filtered through Celite. The reaction mixture was applied on reverse phase HPLC for separation to obtain N-[(l S)-l-(5-fluoro-2- pyridyl)ethyl]-N4-(l-phenyl-l,2,4-triazol-3-yl)pyridine-2,4- diamine (2.3 mgs, 6%). ¾-NMR (300 MHz, CD3OD) δ 8.92 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 2.4 Hz, 2H),

7.88 (dt, J = 8.4, 1.2 Hz, 2H), 7.71 - 7.40 (m, 8H), 5.10 - 4.93 (m, 1H), 1.67 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z calc. 375.16077, found 376.55 (M+l) ⁺ ; Retention time: 2.28 minutes.

[00406] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 6, the following compounds can be synthesized from the appropriate intermediates; 160, 258, 259, 261, 262, 359, 361, 376, 413, 414, 416 and 484-486. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 7

Preparation of N3-ri-(3.5-difluorophenvn-1.2.4-triazol-3-yll-Nl-r(l S)-2-methoxy-l- methyl-ethyl]-5-methyl-benzene-1.3-diamine (Compound 352)

RG-7c R - b Compound 352

(a) Cu(OAc) ₂ , pyridine, CH2CI2, 3 A molecular sieves, RT; (b) palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, NaOtBu, tBuOH, 90 °C; (d) BrettPhos Palladacycle, tBuOH, NaOtBu, 50 °C.

Preparation of N-(3-chloro-5-methyl -phenyl)-! -(3, 5-difluorophenyl)-l,2,4-triazol-3- amine (RG-7c)

[00407] l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (1.12 g, 5.710 mmol), 1- bromo-3-chloro-5-methyl-benzene (2.72 g, 13.24 mmol), sodium tert-butoxide (approximately 909.8 mg, 9.467 mmol) and chloro(2-di-t-butylphosphino-2',4',6'-tri-i- propyl-l, -biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos

Palladacycle) (approximately 227.4 mg, 0.3078 mmol) were slurried into dry t- butanol (15.86 mL) and dry 1,4-dioxane (5.288 mL) and purged with nitrogen for -10 minutes. The reaction was sealed and stirred at 90 °C for ~1 hour. The reaction mixture was cooled to room temperature and poured into water (150 mL). The precipitate was filtered. The filter cake was washed with additional water (-75 mL) and methanol (-25 mL). Dried the filter cake in the high vacuum oven at 50°C overnight to yield N-(3-chloro-5-methyl-phenyl)-l-(3,5-difluorophenyl)-l,2,4-tr iazol- 3-amine (1.587 g, 4.629 mmol, 81%). ¾ NMR (300 MHz, DMSO-^e) δ 9.78 (s, 1H), 9.20 (s, 1H), 7.68 - 7.58 (m, 2H), 7.55 (d, J = 1.9 Hz, 1H), 7.34 (s, 1H), 7.28 (tt, J = 9.4, 2.3 Hz, 1H), 6.76 (s, 1H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 320.06403, found 321.07 (M+l) ⁺ ; Retention time: 1.02 minutes. Preparation of N3-ri-(3.5-difluorophenvn-1.2.4-triazol-3-yll-Nl-r(l S)-2-methoxy-l- methyl-ethyll-5-methyl-benzene-l -diamine (Compound 352)

[00408] (2S)-l-methoxypropan-2-amine (approximately 273.8 mg, 3.072 mmol), N-(3-chloro-5-methyl-phenyl)-l-(3,5-difluorophenyl)-l,2,4-tr iazol-3-amine (657 mg, 2.048 mmol), sodium tert-butoxide (454 mg, 4.724 mmol), and BrettPhos

Palladacycle (80 mg, 0.1001 mmol) were weighed into a 40 mL vial. Dioxane (2.5 mL) and tert-butanol (7.5 mL) were added. The vial was sealed and stirred at 50 °C overnight. The reaction mixture was reduced in volume with a stream of nitrogen. Diluted with dichloromethane (20 mL) and washed with 50% saturated sodium bicarbonate (10 mL). Passed the organics through a phase separator containing a plug of Florisil, washed with additional 100 mL of 5% methanol in dichloromethane and concentrated the organics to dryness under reduced pressure. The crude was diluted with dichloromethane (5 mL) and purified by silica gel chromatography (80 g Gold column (ISCO); 0-100% (ethyl acetate (10%methanol)/heptane). The desired pure fractions were concentrated to dryness under reduced pressure. Further purification was required. Diluted with 5 mL of DMSO and purified by reverse phase

chromatrography (150 g C 18 Aq column (ISCO); 0-100%) acetonitrile/water with 0.1%) trifluoroacetic acid modifier). The desired pure fractions were concentrated to dryness under reduced pressure. Diluted with dichloromethane (10 mL) and a few drops of methanol and washed with 50%> saturated sodium bicarbonate (5 mL).

Passed the organics through a phase separator and concentrated to dryness under reduced pressure to yield N3-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-Nl-[(l S)-2- methoxy-l-methyl-ethyl]-5-methyl-benzene-l,3-diamine (304.9 mg, 38%). ¾ NMR (300 MHz, OMSO-de) δ 9.17 (s, 1H), 9.13 (s, 1H), 7.73 - 7.56 (m, 2H), 7.21 (tt, J = 9.3, 2.3 Hz, 1H), 6.97 (s, 1H), 6.48 (s, 1H), 5.97 (s, 1H), 5.22 (d, J = 7.9 Hz, 1H), 3.64 - 3.49 (m, 1H), 3.43 (dd, J = 9.2, 4.7 Hz, 1H), 3.28 (s, 3H), 3.21 (dd, J = 9.2, 6.8 Hz, 1H), 2.14 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H) ppm. ESI-MS m/z calc. 373.17142, found 374.3 (M+l) ⁺ ; Retention time: 0.68 minutes. [00409] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 7, the following compounds can be synthesized from the appropriate intermediates; 342-348, 353, 452-483, 487-489, 518-522, 539, 540, 546, 560, 561, 566, 604-613 and 615-620. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 8

Preparation of 4-[[l-(4-fluorophenyl)-L2,4-triazol-3-yllaminol-2-isopropoxy -N- xetan-3-vDbenzamide (Compound 148)

(a) Cu(OAc) ₂ , pyridine, CH2CI2, 4 A molecular sieves, RT; (b) Palladium on carbon, H2; (c) HATU, dichloromethane, triethylamine, RT; (d) BrettPhos Palladacycle, tBuOH, NaOtBu, 110 °C

Preparation of of l-(4-fluorophenyl)-3-nitro-L2,4-triazole (RG-8a)

[00410] (4-fluorophenyl)boronic acid (6.378 g, 45.58 mmol), 3-nitro-lH-l,2,4- triazole (2.6 g, 22.79 mmol), copper acetate (approximately 6.208 g, 34.18 mmol) and 4 A molecular sieves (250 mg/0.33 mmol) were mixed in dichloromethane, and treated with pyridine (approximately 3.605 g, 3.686 mL, 45.58 mmol). The mixture was stirred at room temperature under air for 2 days. The crude was filtered through a plug of Celite and washed with water and brine. The organic layer was concentrated and purified by silica gel chromatography (10-60% ethyl acetate/ hexanes) to afford l-(4-fluorophenyl)-3-nitro-l,2,4-triazole (1.6 g, 6.918 mmol, 30.4%). ESI-MS m/z calc. 208.03966, found 209.17 (M+l) ⁺ ;207.09 (M-l) ⁺ ; Retention time: 2.56 minutes.

Preparation of l-(4-fluorophenyl)-L2,4-triazol-3 -amine (RG-8b)

[00411] 10% Palladium on carbon (approximately 13.09 mg, 0.1230 mmol) was placed in a round bottom flask (250 mL) and ethanol (50 mL) was added to this flask under nitrogen. l-(4-Fluorophenyl)-3-nitro-l,2,4-triazole (256 mg, 1.230 mmol) was added and the reaction was stirred under a hydrogen balloon atmosphere overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford l-(4-fluorophenyl)-l,2,4-triazol-3 -amine (210 mg, 96%) ESI-MS m/z calc. 178.06548, found 179.11 (M+l) ⁺ ; Retention time: 1.73 minutes.

Preparation of 4-bromo-2-isopropoxy-N-(oxetan-3-yl)benzamide (RG-8c)

[00412] To a solution of 4-bromo-2-isopropoxy -benzoic acid (500 mg, 1.930 mmol), oxetan-3 -amine (approximately 141.1 mg, 1.930 mmol) and HATU

(approximately 1.101 g, 2.895 mmol) in dichloromethane (approximately 9.648 mL) was added triethylamine (approximately 651.0 mg, 896.7 μΐ _^ , 6.433 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was carefully diluted with saturated sodium bicarbonate (15 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic extracts were washed with IN (aq) hydrochloric acid (2 mL) and dried over sodium sulfate to afford 4-bromo-2- isopropoxy-N-(oxetan-3-yl)benzamide (606 mg, 99%). ESI-MS m/z calc. 313.03134, found 314.23 Retention time: 1.00 minutes.

Preparation of 4-[[l-(4-fluorophenyl)-L2,4-triazol-3-yllaminol-2-isopropoxy -N- (oxetan-3-vDbenzamide (Compound 148)

[00413] Combined l-(4-fluorophenyl)-l,2,4-triazol-3 -amine (100 mg, 0.5613 mmol), 4-bromo-2-isopropoxy-N-(oxetan-3-yl)benzamide (approximately 160.3 mg, 0.5103 mmol), sodium tert-butoxide (approximately 32.69 mg, 0.3402 mmol) in 1,4- dioxane (3.1 mL). The mixture was degassed with nitrogen for 15 minutes. A catalytic amount of Brettphos Palladacycle (approximately 0.05 mmol) was added. The mixture was heated in a sealed tube at 1 10 °C for 18 hours. The reaction mixture was filtered and purified twice by reverse phase chromatography. The pure fractions were concentrated and converted to the corresponding HC1 salt of 4-[[l-(4- fluorophenyl)-l,2,4-triazol-3-yl]amino]-2-isopropoxy-N-(oxet an-3-yl)benzamide (12.6 mg, 5.0%). ¹ H MR (300 MHz, OMSO-de) δ 10.65 (s, 1H), 9.29 (s, 1H), 7.79 (ddd, J = 15.5, 1 1.0, 5.8 Hz, 3H), 7.68 - 7.57 (m, 1H), 7.27 (dd, J = 1 1.8, 5.3 Hz, 2H), 7.01 (d, J = 51.1 Hz, 1H), 5.33 (s, 1H), 4.89 (ddd, J = 22.7, 17.5, 9.3 Hz, 2H), 4.59 (s, 1H), 3.69 (dd, J = 38.2, 1 1.4 Hz, 2H), 1.80 - 1.12 (m, 6H) ppm. ESI-MS m/z calc. 41 1.17065, found 412.18 (M+l) ⁺ ; Retention time: 0.82 minutes.

[00414] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 8, the following compounds can be synthesized from the appropriate intermediates; 104, 105, 1 19, 143 and 144. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 9

Preparation of l-[5-[(l -phenyl- L2,4-triazol-3-yl)amino]spiro| ^" indoline-3,4'- piperidinel-l-yllethanone (Compound 305) & l-|T-isopropyl-5-r(l -phenyl- 1,2,4- triazol-3-yl)amino1spirorindoline-3,4'-piperidine1-l-yl1etha none (Compound 306)

(a) Cu(OAc) ₂ , pyridine, CH2CI2, 4 A molecular sieves, RT; (b) Palladium on carbon, H ₂ ; (c) dichloromethane, NaBH(OAc) ₃ , AcOH, RT; (d) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 120 °C; (e) dichloromethane, TFA, RT; (f) Acetone,

dichloromethane, NaBH(OAc) ₃ , AcOH, RT.

Preparation of of fert-butyl l-acetyl-5-bromo-spirorindoline-3,4'-piperidine1- - carboxylate (RG-9c) [00415] A mixture of tert-butyl 5-bromospiro[indoline-3,4'-piperidine]- - carboxylate (317 mg, 0.8631 mmol), acetic anhydride (approximately 440.6 mg, 407.2 μΐ _^ , 4.316 mmol) and triethylamine (approximately 174.7 mg, 240.6 μΐ _^ , 1.726 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to a residue under reduced pressure. The residue was diluted with dichloromethane (approximately 20 mL) and washed with water

(approximately 10 mL). The organics were passed through a phase separator and concentrated to dryness under reduced pressure to give tert-butyl l-acetyl-5-bromo- spiro[indoline-3,4'-piperidine]-l'-carboxylate (350 mg, 0.8551 mmol, 99%). ¹ H MR (300 MHz, CDCh) δ 8.12 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 4.18 (d, J = 11.2 Hz, 2H), 3.93 (s, 2H), 2.88 (t, J = 12.7 Hz, 2H), 2.27 (s, 3H), 1.85 (td, J = 13.2, 4.5 Hz, 2H), 1.69 (d, J = 13.5 Hz, 2H), 1.51 (s, 9H) ppm. ESI-MS m/z calc. 408.10486, found 409.32 (M+l) ⁺ ; Retention time: 0.92 minutes. Preparation of of fert-butyl l-acetyl-5-r(l-phenyl-L2,4-triazol-3- yl)aminolspiro[indoline-3,4'-piperidinel- -carboxylate (RG-9d)

[00416] tert-Butyl l-acetyl-5-bromo-spiro[indoline-3,4'-piperidine]-l'-carboxyl ate (250 mg, 0.6108 mmol), 1 -phenyl- l,2,4-triazol-3 -amine (approximately 117.4 mg, 0.7330 mmol) and sodium tert-butoxide (approximately 176.1 mg, 1.832 mmol) were suspended in 1,4-dioxane (10 mL) and purged with nitrogen for several minutes before the addition of tert-ButylXPhos Palladacyle(approximately 20.47 mg, 0.03143 mmol). The mixture was microwaved at 120 °C for 35 minutes. The reaction was quenched with methanol (0.5 mL), IN hydrochloric acid (800 uL) and diluted with dichloromethane (approximately 20 mL). After filtration through Florisil (5 g), the excess solvent was concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (40 g column; 0 % to 10% methanol/dichloromethane) and then repurified by silica gel chromatography (12 g column; 10 % to 100% ethyl acetate/hexanes) to afford tert-butyl l-acetyl-5-[(l- phenyl-l,2,4-triazol-3-yl)amino]spiro[indoline-3,4'-piperidi ne]- -carboxylate (200 mg, 0.4093 mmol, 67.02%). ¾ NMR (300 MHz, CDCh) δ 8.33 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.52 (t, J = 7.9 Hz, 3H), 7.43 - 7.30 (m, 2H), 6.82 (s, 1H), 4.18 (s, 2H), 2.97 (t, J = 12.1 Hz, 2H), 2.27 (s, 2H), 1.91 (dt, J = 15.4, 10.1 Hz, 2H), 1.73 (d, J = 13.6 Hz, 2H), 1.52 (s, 9H) ppm. ESI-MS m/z calc. 488.2536, found 489.35 (M+l) ⁺ ; Retention time: 0.82 minutes.

Preparation of l-[5-[(l-phenyl-L2,4-triazol-3-yl)aminolspiro[indoline-3,4'- piperidinel-l-yllethanone (Compound 305)

[00417] To tert-butyl-l-acetyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]spiro[indoline-3,4'-piperidine]-l'-carboxylate (60 mg, 0.1228 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (500 μΐ _^ , 6.490 mmol). The reaction mixture was stirred at room temperature for 2 hours and was then

concentrated to dryness. The residue was dissolved in dichloromethane/methanol (9: 1), filtered through a PL-HCCb PM SPE and dried to give l-[5-[(l-phenyl-l,2,4- triazol-3-yl)amino]spiro[indoline-3,4'-piperidine]-l-yl]etha none. ¹ H MR (300 MHz, CDCh) δ 8.32 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.56 - 7.45 (m, 3H), 7.42 - 7.32 (m, 2H), 6.82 (s, 1H), 3.94 (s, 1H), 3.51 (s, 3H), 3.15 (t, J = 14.8 Hz, 2H), 2.91 - 2.69 (m, 2H), 2.28 (s, 2H), 1.94 (td, J = 13.2, 4.1 Hz, 2H), 1.72 (d, J = 13.9 Hz, 2H) ppm. ESI-MS m/z calc. 388.20117, found 389.34 (M+l) ⁺ ; Retention time: 0.85 minutes.

Preparation of of l-n'-isopropyl-5-r(l-phenyl-L2,4-triazol-3- yl)amino1spirorindoline-3,4'-piperidine1-l-yl1ethanone (Compound 306)

[00418] To a solution of l-[5-[(l-phenyl-l,2,4-triazol-3-yl)amino]spiro[indoline- 3,4'-piperidine]-l-yl]ethanone (100 mg, 0.2574 mmol), acetone (approximately 149.5 mg, 189.0 μΐ., 2.574 mmol) and acetic acid (approximately 92.72 mg, 87.80 μΐ., 1.544 mmol) in dichloromethane (5.0 mL) was carefully added sodium

triacetoxyborohydride (approximately 327.2 mg, 1.544 mmol). The mixture was stirred for 18 hours. The reaction mixture was diluted with dichloromethane

(approximately 30 mL) and slowly quenched with saturated sodium bicarbonate (30 mL). After separation, the organic layer was washed with water, saturated sodium chloride and dried with sodium sulfate. The organics were filtered and concentrated to dryness under reduced pressure. The compound was purified on by silicagel chromatography (4 g column; 5-30% methanol/dichloromethane) to give 80 mg of desired product with trace impurities. The product was further purified by reverse phase HPLC. Pure fractions were filtered through PL-HCCb PM SPE and concentrated to dryness under reduced pressure to yield l-[l'-isopropyl-5-[(l-phenyl- l,2,4-triazol-3-yl)amino]spiro[indoline-3,4'-piperidine]-l-y l]ethanone (20 mg, 0.04413 mmol, 17.15). ¾ MR (300 MHz, CDCb) δ 8.32 (d, J = 3.5 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.69 (dt, J = 8.8, 1.8 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.43 - 7.32 (m, 3H), 7.12 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 13.4 Hz, 1H), 3.94 (d, J = 43.6 Hz, 2H), 2.94 (dd, J = 16.1, 12.3 Hz, 2H), 2.79 (dt, J = 13.0, 6.5 Hz, 1H), 2.39 - 2.21 (m, 4H), 2.12 - 1.96 (m, 2H), 1.75 (d, J = 14.4 Hz, 3H), 1.12 (d, J = 6.5 Hz, 6H) ppm. ESI-MS m/z calc. 430.2481, found 431.22 (M+l) ⁺ ; Retention time: 2.53 minutes. [00419] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 9, the following compound can be synthesized from the appropriate intermediate; 298. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A..

[00420] The following compound can also be synthesized according to Schemes A and B from the appropriate intermediate using procedures analogous to those described in Example 9, steps 1-4, except that instead of an acylation in step three, a reductive amination under typical conditions (sodium triacetoxyborohydride, dichloromethane/acetic acid) is performed; 309. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 10

Preparation of l-(oxetan-3-yl)-N-(l -phenyl- L2,4-triazol-3-yl)indolin-6-amine (Compound 302)

RG-lb RG-lOc

Cmpd 302

(a) Cu(OAc) ₂ , pyridine, CH2CI2, 4 A molecular sieves, RT; (b) Palladium on carbon, H2; (c) t-BuXPhos Palladacycle, dioxane, NaOtBu, 120 °C; (d) dichlorom ethane, NaBH(OAc) ₃ , RT.

Preparation of N-(l -phenyl- L2,4-triazol-3-yl)indolin-6-amine (RG-lOc)

[00421] 6-bromoindoline (120 mg, 0.6059 mmol), 1 -phenyl- l,2,4-triazol-3 -amine (approximately 116.4 mg, 0.7265 mmol) and sodium tert-butoxide (approximately 116 mg, 1.21 mmol) were suspended in 1,4-dioxane (4.0 mL) and purged with nitrogen for several minutes. Chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, - biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle)

(approximately 20.61 mg, 0.03165 mmol) was added and the vial was capped and microwaved at 120 °C for 35 minutes. The reaction was quenched with methanol (0.5 mL), IN hydrochloric acid (800 uL) and diluted with dichloromethane (approximately 10 mL). After filtration through Florisil (5 g), the excess solvent was concentrated to dryness under reduced pressure. The crude residue was purified by silica gel chromatography (12 g column; 10 % to 100% ethyl acetate/hexane) to give an inseparable mixture of N-(l -phenyl- l,2,4-triazol-3-yl)indolin-6-amine and N-(l- phenyl-l,2,4-triazol-3-yl)-lH-indol-6-amine (140 mg, 0.5048 mmol, 83.33). ¾ NMR (300 MHz, CDCh) δ 8.30 (s, 1H), 8.22 (s, 1H), 7.73 - 7.66 (m, 1H), 7.64 - 7.57 (m, 2H), 7.54 - 7.43 (m, 3H), 7.39 - 7.31 (m, 2H), 7.09 - 7.03 (m, 1H), 6.77 (dd, J = 7.9, 2.1 Hz, 1H), 4.31 (s, 2H), 3.85 (s, 1H), 3.59 (t, J = 8.3 Hz, 1H), 3.01 (t, J = 8.3 Hz, 1H) ppm. ESI-MS m/z calc. 277.13275, found 278.36 (M+l) ⁺ ; Retention time: 0.55 minutes. This mixture was carried into the next step as is.

Preparation of l-(oxetan-3-yl)-N-(l -phenyl- L2,4-triazol-3-yl)indolin-6-amine (Compound 302)

[00422] To a solution of N-(l -phenyl- l,2,4-triazol-3-yl)indolin-6-amine (55 mg, 0.1983 mmol), oxetan-3-one (approximately 85.75 mg, 1.190 mmol) and acetic acid (approximately 71.46 mg, 67.67 μΐ _^ , 1.190 mmol) in dichloromethane (2.750 mL) was added sodium triacetoxyborohydride (approximately 168.1 mg, 0.7932 mmol). The mixture was stirred for 1 hour. The reaction mixture was diluted with

dichloromethane (approximately 10 mL) and slowly quenched with saturated sodium bicarbonate (5 mL). After separation, the organic layer was washed with water, saturated sodium chloride and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC. The pure fractions were filtered through PL-HCO3 PM SPE and concentrated to dryness under reduced pressure to yield l-(oxetan-3-yl)-N-(l -phenyl- l,2,4-triazol-3-yl)indolin-6-amine (20 mg, 0.05579 mmol, 28.13) 1H NMR (300 MHz, CDCh) δ 8.56 (s, 1H), 7.79 - 7.65 (m, 2H), 7.64 - 7.52 (m, 2H), 7.51 - 7.44 (m, 1H), 7.08 (dd, J = 7.6, 0.6 Hz, 1H), 6.90 - 6.78 (m, 2H), 4.97 (dt, J = 13.8, 6.7 Hz, 4H), 4.69 - 4.56 (m, 1H), 3.53 (dd, J = 9.9, 6.2 Hz, 2H), 3.01 (t, J = 7.9 Hz, 2H). ESI-MS m/z calc. 333.15897, found 334.12 (M+l) ⁺ ;

Retention time: 3.53 minutes.

[00423] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 10, the following compounds can be synthesized from the appropriate intermediates; 296, 300, 301, 303, 307 and 308. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00424] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 10, the following compound can also be synthesized from the appropriate intermediate except for changing the last step from a reductive amination step to an acylation step carried out under typical acylation conditions (for example acetic anhydride, dichloromethane, room temperature); 294. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 11

Preparation of N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-l-yllpheny ll-l- phenyl- L2,4-triazol-3 -amine (Compound 319)

a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) DCM, NaBH(OAc) ₃ , AcOH, RT, dichloromethane; (d) DCM, TFA, RT; (e) DCM, NaBH(OAc) ₃ , RT; (f). t-BuXPhos Palladacycle, tBuOH, NaOtBu, 120 °C.

Preparation of fert-butyl 5-bromo-l-isopropyl-spiro[indoline-3,4'-piperidinel- - carb oxyl ate (RG- 11c)

[00425] To a solution of tert-butyl 5-bromospiro[indoline-3,4'-piperidine]- - carboxylate (650 mg, 1.770 mmol), acetone (approximately 1.028 g, 1.300 mL, 17.70 mmol) and acetic acid (approximately 637.8 mg, 604.0 μΐ _^ , 10.62 mmol) in dichloromethane (10.50 mL) was carefully added sodium triacetoxyborohydride (approximately 2.251 g, 10.62 mmol). The mixture was stirred for 4 hours at room temperature in a sealed vial. The reaction mixture was diluted with dichloromethane (approximately 10 mL) and slowly quenched with methanol and saturated sodium bicarbonate (3 mL). After separation, the organic layer was washed with water and brine and dried with sodium sulfate. The organics were filtered and concentrated to dryness under reduced pressure and the crude product was purified by silica gel chromatography (40 g column; 5-100% ethyl acetate/heptanes). The desired fractions were combined and concentrated to dryness under reduced pressure to afford tert- butyl 5-bromo-l-isopropyl-spiro[indoline-3,4'-piperidine]-l'-carbo xylate (703 mg, 1.717 mmol, 97%). ESI-MS m/z calc. 408.14124, found 409.39 (M+l) ⁺ ; Retention time: 1.1 minutes. ¾ NMR (300 MHz, CDCh) δ 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 4.08 (d, J = 12.1 Hz, 2H), 3.88 - 3.74 (m, 1H), 3.28 (s, 2H), 2.92 (t, J = 11.4 Hz, 2H), 1.86 - 1.62 (m, 4H), 1.51 (s, 9H), 1.18 (d, J = 6.6 Hz, 6H) ppm.

Preparation of 5-bromo-l-isopropyl-spiro[indoline-3,4'-piperidinel (RG-lld)

[00426] To a solution of 5-bromo-l-isopropyl-spiro[indoline-3,4'-piperidine] (450 mg, 1.063 mmol) (trifluoroacetate salt) (450 mg, 1.063 mmol), oxetan-3-one

(approximately 766.0 mg, 10.63 mmol) and acetic acid (approximately 383.0 mg, 362.7 μΐ _^ , 6.378 mmol) in dichloromethane (15 mL) was added sodium

triacetoxyborohydride (approximately 1.352 g, 6.378 mmol) carefully. The mixture was stirred for 4 hours at room temperature under nitrogen. The reaction mixture was diluted with dichloromethane (approximately 10 mL) and slowly quenched with methanol (2 mL) and saturated sodium bicarbonate (3 mL). After separation, the organic layer was washed with water and brine and dried with sodium sulfate. The organics were filtered through a plug of Florisil (~5 g). The solvent was removed under reduced pressure and the crude product was purified by silica gel

chromatography (12 g column; 0 -10% methanol/dichloromethane). The desired fractions were concentrated to dryness under reduced pressure to yield 5-bromo-l- isopropyl-l'-(oxetan-3-yl)spiro[indoline-3,4'-piperidine] (260 mg, 67%). ¹ H MR (300 MHz, CDCh) δ 7.16 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.29 (d, J = 8.3 Hz, 1H), 4.69 (d, J = 6.5 Hz, 4H), 3.87 - 3.70 (m, 1H), 3.61 - 3.46 (m, 1H), 3.21 (s, 2H), 2.73 (d, J = 6.7 Hz, 2H), 2.08 - 1.85 (m, 4H), 1.74 (d, J = 8.7 Hz, 2H), 1.16 (d, J = 6.6 Hz, 6H) ppm. ESI-MS m/z calc. 364.11502, found 365.4 (M+l) ⁺ ;

Retention time: 0.67 minutes.

Preparation of N-[3-(difluoromethyl)-5-[4-(oxetan-3-yl)piperazin-l-yllpheny ll-l- phenyl-l,2,4-triazol-3 -amine (Compound 319)

[00427] 5-Bromo-l-isopropyl- -(oxetan-3-yl)spiro[indoline-3,4'-piperidine] (110 mg, 0.3011 mmol), l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (64.97 mg, 0.3312 mmol) and sodium tert-butoxide (approximately 71.96 mg, 0.7488 mmol) were suspended in 1,4-dioxane (4.4 mL) and purged with nitrogen for several minutes before the addition of chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, - biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle)

(approximately 19.61 mg, 0.03011 mmol). The mixture was microwaved at 120 °C for 35 minutes. The reaction mixture was quenched with methanol (0.5 mL), IN hydrochloric acid (800 uL) and diluted with dichloromethane (approximately 10 mL). After filtration through Florisil (5 g), solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (40 g column; 0-10% methanol/dichloromethane) and repurified by silica gel chromatography (12 g column; 5-100%> ethyl acetate/heptane). The pure desired fractions were combined and concentrated to dryness under reduced pressure to yield N-[l-(3,5- difluorophenyl)- 1 ,2,4-triazol-3 -yl]- 1 -isopropyl- 1 '-(oxetan-3 -yl)spiro[indoline-3 ,4'- piperidine]-5-amine (50 mg, 33%). ¹ H NMR (300 MHz, CDCh) δ 8.28 (s, 1H), 7.36 - 7.29 (m, 1H), 7.25 (dd, J = 8.0, 2.3 Hz, 2H), 7.20 (d, J = 2.2 Hz, 1H), 6.77 (tt, J = 8.7, 2.3 Hz, 1H), 6.56 - 6.39 (m, 2H), 4.70 (d, J = 6.5 Hz, 4H), 3.91 - 3.73 (m, 1H), 3.55 (dd, J = 13.1, 6.5 Hz, 1H), 3.20 (s, 2H), 2.82 - 2.68 (m, 2H), 2.11 - 1.91 (m, 4H), 1.80 (dd, J = 16.0, 8.4 Hz, 2H), 1.17 (d, J = 6.6 Hz, 6H) ppm. ESI-MS m/z calc. 480.2449, found 481.41 (M+l) ⁺ ; Retention time: 0.61 minutes.

[00428] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 11, the following compound can be synthesized from the appropriate intermediate; 323. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 12

Preparation of 1 -(3 , 5 -difluorophenyl)-N- r4-fluoro-3 - Γ3 -fluoro- 1 -(oxetan-3 - yl)pyiTolidin-3-vHphenvH-L2,4-triazol-3-amine (Compound 325)

(a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ;(c) iPrMgCl, LiCl, THF, -40 °C; (d) DCM, TFA, RT; (e) DCM, AcOH,

NaBH(OAc) ₃ , RT; (f) Deoxo-fluor, -78 °C; (g). t-BuXPhos Palladacycle, dioxane, NaOtBu, 70°C.

Preparation of fert-butyl 3-(5-bromo-2-fluoro-phenyl)-3-hvdroxy-pyrrolidine-l- carboxylate (RG-12c)

[00429] A solution of isopropyl magnesium chloride-lithium chloride in tetrahydrofuran (30 mL of 1.3 M, 39.00 mmol) was cooled to -78 °C a. At -40 °C, 4- bromo-l-fluoro-2-iodo-benzene (approximately 11.18 g, 37.14 mmol) was added. The temperature was maintained between -40 °C and -35 °C. After approximately 2 hours, tetrahydrofuran (20 mL) was added the mixture was maintained at -35°C. tert- Butyl 3-oxopyrrolidine-l-carboxylate (approximately 7.016 g, 37.88 mmol) was added over 10 minutes. The reaction mixture was removed from the cold bath after a further 5 minutes. Aqueous saturated ammonium chloride was carefully added with cooling (ice bath) and then the reaction mixture was extracted twice with ethyl acetate. The combined organics were washed with aqueous saturated ammonium chloride, brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give a liquid that solidified over time. The solid was sonicated in the presence of 7% ethyl acetate/heptane and then filtered The resulting white solid was air dried by suction on a frit for 20 minutes to yield tert-butyl 3-(5-bromo-2-fluoro- phenyl)-3 -hydroxy-pyrrolidine- 1-carboxylate (8.3 g, 62%). ¾ MR (400 MHz, OMSO-de) δ 7.69 (d, J = 7.0 Hz, 1H), 7.55 (ddd, J = 8.6, 4.2, 2.6 Hz, 1H), 7.19 (dd, J = 11.3, 9.1 Hz, 1H), 5.73 (d, J = 4.5 Hz, 1H), 3.61 - 3.38 (m, 4H), 2.29 (s, 1H), 2.12 - 2.02 (m, 1H), 1.41 (s, 9H) ppm.

Preparation of 3-(5-bromo-2-fluoro-phenyl)pyrrolidin-3-ol (RG-12d)

[00430] To a suspension of tert-butyl 3 -(5 -bromo-2-fluoro-phenyl)-3 -hydroxy- pyrrolidine- 1-carboxylate (3 g, 8.328 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL, 51.92 mmol) at room temperature. After 1 hour of stirring, the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was dissolved in methanol and passed through a SPE bicarbonate cartridge (Agilent Stratospheres 5 g/60 mL) and concentrated to dryness under reduced pressure. The sample was placed under high vacuum for 3 hours to yield 3-(5-bromo- 2-fluoro-phenyl)pyrrolidin-3-ol (2.166 g, 8.327 mmol, 100%). ESI-MS m/z calc. 259.0008, found 262.07 (M+l) ⁺ ; Retention time: 0.52 minutes Preparation of 3-(5-bromo-2-fluoro-phenyl)-l-(oxetan-3-yl)pyrrolidin-3-ol (RG-12e)

[00431] To 3-(5-bromo-2-fluoro-phenyl)pyrrolidin-3-ol (2.166 g, 8.327 mmol) in dichloromethane (20 mL) was added acetic acid (approximately 750.0 mg, 710.2 μΐ _^ , 12.49 mmol) then oxetan-3-one (approximately 900.1 mg, 750.1 μΐ _^ , 12.49 mmol). Sodium triacetoxyborohydride (approximately 2.295 g, 10.83 mmol) was added and the mixture was stirred overnight at room temperature. Solid and saturated sodium bicarbonate were added and the layers were separated. The aqueous layer was re- extracted with dichloromethane and the combined organics were passed through a phase separator and concentrated to dryness under reduced pressure. Purification was performed by silica gel chromatography (80 g column; 0-10%

methanol/dichloromethane). The desired fractions were combined and concentrated to dryness under reduced pressure to afford 3-(5-bromo-2-fluoro-phenyl)-l-(oxetan-3- yl)pyrrolidin-3-ol (2.1 g, 80%). ESI-MS m/z calc. 315.027, found 318.08 (M+l) ⁺ ; Retention time: 0.54 minutes. Preparation of 3-(5-bromo-2-fluoro-phenyl)-3-fluoro-l-(oxetan-3-yl)pyrrolid ine (RG- 121 )

[00432] A solution of 3-(5-bromo-2-fluoro-phenyl)-l-(oxetan-3-yl)pyrrolidin-3-ol (1.705 g, 5.393 mmol) in dichloromethane (25 mL) was cooled to -78 °C and treated with bis(2-methoxyethyl)aminosulfur trifluoride (approximately 1.790 g, 1.492 mL, 8.090 mmol) over 10 minutes. After lh, at -78 °C, added excess saturated sodium bicarbonate and removed the bath. The aqueous layer was extracted with

dichloromethane (approximately 25 mL) and the combined organics were passed through a phase separating cartridge and concentrated to dryness under reduced pressure. Purification was performed by column chromatography (Si-amine (ISCO) 150 g column; 10-50%> ethyl acetate/hexane). Enriched desired material and a side product were collected and concentrated to dryness under reduced pressure to yield 3- (5-bromo-2-fluoro-phenyl)-3-fluoro-l-(oxetan-3-yl)pyrrolidin e (893 mg, 52%). ESI- MS m/z calc. 317.02267, found 318.08 (M+l) ⁺ ; Retention time: 0.54 minutes. Preparation of 1 -(3 , 5 -difluorophenvD-N- r4-fluoro-3 - Γ3 -fluoro- 1 -(oxetan-3 - yl)pyrrolidin-3-yl1phenyl1-L2,4-triazol-3-amine (Compound 325)

[00433] A Schlenck tube was charged with 3-(5-bromo-2-fluoro-phenyl)-3-fluoro- 1 -(oxetan-3 -yl)pyrrolidine (500 mg, 1.572 mmol), l-(3,5-difluorophenyl)-l,2,4- triazol-3 -amine (approximately 325.4 mg, 1.493 mmol), chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (approximately 46.45 mg, 0.06288 mmol), and sodium tert-butoxide (approximately 302.1 mg, 3.144 mmol). 1,4-Dioxane (4 mL) was added and the mixture was vacuum/nitrogen cycled three times. The reaction mixture was immersed in a glass bead bath set to 70 °C for approximately 3 hours. Water and dichloromethane were added and a precipitate was formed. The precipitate was collected by filtration. The precipitate was purified by silica gel chromatography (80 g Gold (ISCO) column; 25-100% ethyl acetate/hexane). On concentration of the pure fractions a white solid precipitated and was air dried by suction on a frit for 3 hours to afford l-(3,5-difluorophenyl)-N-[4-fluoro-3-[3-fluoro- 1 -(oxetan-3 -yl)pyrrolidin-3-yl]phenyl]-l,2,4-triazol-3 -amine (140.1 mg, 20%). ¾ MR (300 MHz, OMSO-de) δ 9.71 (s, 1H), 9.19 (s, 1H), 7.86 (dd, J = 6.8, 2.8 Hz, 1H), 7.73 - 7.56 (m, 3H), 7.33 - 7.13 (m, 2H), 4.61 (td, J = 6.6, 2.2 Hz, 2H), 4.51 (dd, J = 1 1.7, 5.7 Hz, 2H), 3.82 - 3.72 (m, 1H), 3.22 (dd, J = 24.1, 12.2 Hz, 1H), 2.97 (ddd, J = 23.4, 14.7, 8.4 Hz, 2H), 2.67 (dd, J = 14.7, 7.3 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.37 (t, J = 6.6 Hz, 1H) ppm. ESI-MS m/z calc. 433.1526, found 434.29 (M+l) ⁺ ;

Retention time: 0.61 minutes

EXAMPLE 13

Preparation of 2-isopropoxy-4-[(l-phenyl-L2,4-triazol-3-yl)aminolbenzamide

(Compound 264)

K(^-13c Cmpd 264

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) XantPhos, Pd ₂ (dba) ₃ , 1,4-dioxane, NaOtBu, 100 °C; (d) DCM, DIPEA, HOBt, EDCI, DMF, RT.

Preparation 2-isopropoxy-4-r(l-phenyl-L2,4-triazol-3-yl)amino1benzoic acid (RG- 14c)

[00434] 1 -phenyl- l,2,4-triazol-3 -amine (290 mg, 1.811 mmol), 4-bromo-2- isopropoxy-benzoic acid (approximately 516.1 mg, 1.992 mmol), sodium tert- butoxide (approximately 348.1 mg, 3.622 mmol), dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphine (approximately 165.8 mg, 0.1811 mmol) were combined in a vial. 1,4-Dioxane (approximately 11.8 mL) was added and the mixture was stirred overnight in a sealed vial at 100 °C. The reaction mixture was concentrated to dryness under reduced pressure and purified by reverse phase chromatography to yield 2-isopropoxy-4-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzoic acid (456 mg, 1.348 mmol, 74.4%). ESI-MS m/z calc. 338.13788, found

339.03(M+1) ⁺ Retention time: 1.01 minutes. Preparation of of 2-isopropoxy-4-r(l-phenyl-L2,4-triazol-3-yl)amino1benzamide (Compound 264) [00435] 1-A mixture of 2-isopropoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzoic acid (75 mg, 0.2217 mmol), ammonia hydrochloride (24 mg, 0.4487 mmol), HOBt (60 mg, 0.4440 mmol), EDCI (85 mg, 0.4434 mmol) and diisopropylethylenediamine (57 mg, 0.4410 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 12 hours. Water (30 mL) was added and the aqueous phase was extracted with ethyl acetate (2 ^χ 30 mL). The combined organic phases were washed with water (3 x 30 mL) and brine (30 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude was material was purified by silica gel chromatography (40 g column 0-10%

methanol/dichloromethane) to yield 2-isopropoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzamide (34.4 mg, 45%). ¾ MR (300 MHz, OMSO-de) δ 9.87 (s, 1H), 9.16 (d, J = 10.0 Hz, 1H), 7.85 (dd, J = 8.1, 3.2 Hz, 3H), 7.68 (s, 1H), 7.57 (t, J = 7.9 Hz, 2H), 7.47 (s, 1H), 7.43 - 7.29 (m, 2H), 7.12 (dd, J = 8.6, 1.7 Hz, 1H), 4.73 (dd, J = 11.9, 6.1 Hz, 1H), 1.54 - 1.33 (m, 6H) ppm. ESI-MS m/z calc. 337.15387, found 338.09 (M+l) ⁺ ; Retention time: 0.9 minutes.

[00436] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 13, the following compound can be synthesized from the appropriate intermediate; 125. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 14

Preparation of N4-ri-(3.5-difluorophenvn-1.2.4-triazol-3-yl1-2-methyl-Nl-rr i- (oxetan-3-yl)-3-piperidvHmethvHbenzene-L4-diamine (Compound 531)

(a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H2; (c) t-BuXPhos Palladacycle, sodium tert-butoxide, tert-butanol, 90°C; (d)

BrettPhos Palladacycle, tert-butanol, sodium tert-butoxide, 50 °C; (e) trifluoroacetic acid, dichlorom ethane; (f) oxetan-3-one, dichlorom ethane, NaBH(OAc) ₃ , AcOH.

Preparation of N-(4-chloro-3-methyl-phenyl)-l-(3,5-difluorophenyl)-L2,4-tri azol-3- amine (RG-14c)

[00437] l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (2.95 g, 15.04 mmol), 4- bromo-l-chloro-2-methyl-benzene (4 mL, 30.17 mmol), sodium tert-butoxide (3.15 g, 32.78 mmol) and chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2- (2-aminoethyl)phenyl]palladium(II) (/-BuXPhos Palladacycle) (460 mg, 0.6227 mmol) were slurried into dry tert-butanol (40 mL) and dry 1,4-dioxane (12 mL) and purged with nitrogen for approximately 5 minutes. The slurry was stirred at 90°C for 3 hours in a parr bottle with a Qian cap. The reaction mixture was cooled to room temperature and poured into 500 mL of water. The precipitate was filtered and washed with additional water (approximately 250 mL) and methanol (200 mL), then dried under high vacuum at 50°C overnight to yield N-(4-chloro-3-methyl-phenyl)-l- (3,5-difluorophenyl)-l,2,4-triazol-3-amine (4.05 g, 75%). ¾ MR (300 MHz, OMSO-de) δ 9.69 (s, 1H), 9.19 (s, 1H), 7.73 - 7.60 (m, 2H), 7.60 - 7.50 (m, 2H), 7.35 - 7.19 (m, 2H), 2.31 (s, 3H) ppm. ESI-MS m/z calc. 320.06403, found 321.11 (M+l) ⁺ ; Retention time: 1.01 minutes.

Preparation of 3-rr4-rr i-(3,5-difluorophenyl)-L2,4-triazol-3-yl1amino1-2-methyl- anilinolmethyllpiperidine-l-carboxylate (RG-14d)

[00438] N-(4-chloro-3-methyl-phenyl)-l-(3,5-difluorophenyl)-l,2,4-tr iazol-3- amine (236 mg, 0.6553 mmol), sodium tert-butoxide (201 mg, 2.091 mmol), and tert- butylXphos Palladacycle (approximately 22 mg) were weighed into a 40 mL vial. tert-Butyl 3-(aminomethyl)piperidine-l-carboxylate (250 mg, 1.167 mmol) was then added followed by dioxane (2.1 mL) and tert-butanol (6.3 mL). The mixture was flushed with a stream of nitrogen and the vial sealed. The reaction mixture was stirred over the weekend at 90 °C then concentrated under a stream of nitrogen. The mixture was diluted with 20 mL of dichloromethane and washed with 50% saturated sodium bicarbonate (8 mL). The organics were passed through a plug of Florisil (5 g), and the plug was washed withlO mL of 10% methanol/dichloromethane. The filtrate was concentrated to dryness under reduced pressure. The crude material was diluted with dimethylsulfoxide (3 mL) and purified by reverse phase chromatography (50 g C18Aq (ISCO) column, 0-100%) acetonitrile/water with a trifluoroacetic acid modifier). The desired fractions were concentrated to dryness to yield 3-[[4-[[l-(3,5- difluorophenyl)-l,2,4-triazol-3-yl]amino]-2-methyl-anilino]m ethyl]piperidine-l- carboxylate (108 mg, 0.2156 mmol, 32.90). LCMS showed that some of the Boc group fell off during purification and the mixture was carried into the deprotection step. ESI-MS m/z calc. 498.26, found 499.38 (M+l) ⁺ ; Retention time: 0.95 minutes. Preparation of N4-ri-(3.5-difluorophenylV1.2.4-triazol-3-yl1-2-methyl-Nl-(3 - piperidylmethyl)benzene-L4-diamine (RG-14e)

[00439] 3-[[4-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-2-m ethyl- anilino]methyl]piperidine-l-carboxylate (108 mg, 0.2156 mmol) was diluted with dichloromethane (3 mL). Trifluoroacetic acid (2 mL, 25.96 mmol) was added and the mixture was stirred overnight in a sealed vial. The reaction mixture was concentrated to dryness under reduced pressure. The crude oil was then placed in a vacuum oven at 50°C overnight to give N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl- (3-piperidylmethyl)benzene-l,4-diamine (104.8 mg, 0.161 1 mmol, 74.69%). The crude material was carried directly to the next step without further manipulation. ESI- MS m/z calc. 398.26, found 399.34 (M+l) ⁺ ; Retention time: 0.71 minutes.

Preparation of N4-ri-(3.5-difluorophenvn-1.2.4-triazol-3-yl1-2-methyl-Nl-rr i- (oxetan-3-yl)-3-piperidvHmethvHbenzene-L4-diamine (Compound 531)

[00440] N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-( 3- piperidylmethyl)benzene-l,4-diamine (104.8 mg, 0.161 1 mmol) was dissolved in 1,2- dichloroethane (4 mL). Oxetan-3-one (12 μΐ _^ , 0.1872 mmol) and

diisopropylethylamine (57 μΐ _^ , 0.3272 mmol) were added and stirred for 5 minutes. Sodium triacetoxyborohydride (1 10 mg, 0.5190 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with

dichloromethane (4 mL) and saturated aqueous sodium bicarbonate (4 mL) and stirred for 3 hours. The organics were passed through a phase separator and concentrated to dryness on a V10 evaporator. The crude product was diluted with dimethylsulfoxide (2 mL). The sample was purified by reverse phase HPLC (Waters SunFire CI 8

30x150 5uM column; acetonitrile/water gradient with a trifluoroacetic acid modifier). The fractions that contained the desired compound were combined and concentrated to dryness under reduced pressure. The sample was diluted with dichloromethane (8 mL) and washed with saturated sodium bicarbonate (4 mL). The organics were passed through a phase separator and concentrated to dryness under reduced pressure to yield N4-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-2-methyl-Nl-[ [l-(oxetan-3- yl)-3-piperidyl]methyl]benzene-l,4-diamine (10.4 mg, 0.021 14 mmol, 13.1%). ¾ MR (300 MHz, OMSO-de) δ 9.08 (s, 1H), 8.92 (s, 1H), 7.62 - 7.53 (m, 2H), 7.40 (dd, J = 8.6, 2.6 Hz, 1H), 7.23 - 7.11 (m, 2H), 6.50 (d, J = 8.7 Hz, 1H), 4.52 (td, J = 6.4, 2.8 Hz, 2H), 4.47 - 4.37 (m, 3H), 3.41 - 3.32 (m, 1H), 2.93 (s, 2H), 2.71 (d, J = 10.5 Hz, 1H), 2.09 (s, 3H), 1.95 - 1.71 (m, 3H), 1.69 - 1.53 (m, 2H), 1.50 - 1.39 (m, 1H), 1.11 - 0.90 (m, 1H) ppm. ESI-MS m/z calc. 454.22928, found 455.17 (M+l) ⁺ ; Retention time: 2.29 minutes.

[00441] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 14, the following compounds can be synthesized from the appropriate intermediates; 508, 525, 526, 529, 530, 532, 536 and 537. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 15

Preparation of N-r3-r4-rri-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-2- methyl- phenoxylcyclobutvUacetamide (Compound 509)

(a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) TEA, DCM, 0 °C; (d) DMF, 90 °C, CS2CO3; (e) TFA, DCM; (f) i. Ac ₂ 0, DCM, RT, ii. l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine, t-BuXPhos Palladacycle, NaOtBu, tBuOH, 50 °C.

Preparation of (ls,3s)-3-((fert-butoxycarbonyl)amino)cvclobutyl methanesulfonate

(RG-15c) [00442] At 0 °C, a solution of tert-butyl ((ls,3s)-3 -hydroxy cyclobutyl)carbamate (936.2 mg, 5 mmol) and triethylamine (approximately 1.012 g, 1.394 mL, 10.00 mmol) in dichlorom ethane (10 mL) was treated with methanesulfonyl chloride (approximately 687.3 mg, 464.4 μL, 6.000 mmol) in dichloromethane (5 mL) dropwise over 10 minutes. After stirring overnight while warming up, ethyl acetate and aqueous ammonium chloride were added. The organic layer was collected and concentrated to yield (ls,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl

methanesulfonate (1.32 g, 4.975 mmol, 99.5%). ¹ H MR (300 MHz, CDCh) δ 4.73 (tt, J = 7.6, 6.9 Hz, 1H), 3.85 (s, 1H), 3.01 (s, 3H), 2.93 (dtt, J = 9.9, 7.1, 3.3 Hz, 1H), 2.28 - 2.08 (m, 2H), 1.45 (s, 9H) ppm.

Preparation of fert-butyl ((lr,3r)-3-(4-bromo-2-methylphenoxy)cyclobutyl)carbamate (RG-15d)

[00443] (ls,3s)-3-((tert-Butoxycarbonyl)amino)cyclobutyl methanesulfonate (500 mg, 1.884 mmol), cesium carbonate (1.32 g, 4.051 mmol) and 4-bromo-2-methyl- phenol (236 mg, 1.262 mmol) were combined in a 40 mL vial. Dimethylformamide

(6 mL) was added and the vial was sealed. The reaction mixture was stirred overnight at 90 °C. The reaction mixture was concentrated to dryness under reduced pressure.

Dimethylsulfoxide (5 mL) was added and a small amount of precipitate was filtered. The filtrate was purified by reverse phase chromatography (50 g C18Aq (ISCO) column; 10-100% acetonitrile/water with a trifluoroacetic acid modifier) to provide after concentration tert-butyl ((lr,3r)-3-(4-bromo-2- methylphenoxy)cyclobutyl)carbamate (175 mg, 39%). ¾ MR (300 MHz, DMSO- d ₆ ) δ 7.43 - 7.20 (m, 3H), 6.62 (d, J = 8.7 Hz, 1H), 4.85 - 4.68 (m, 1H), 4.17 - 3.99 (m, 1H), 2.40 - 2.26 (m, 4H), 2.14 (s, 3H), 1.38 (s, 9H) ppm. ESI-MS m/z calc. 355.0783, found 356.24, Retention time: 1.05 minutes.

Preparation of (lr,3r)-3-(4-bromo-2-methylphenoxy)cvclobutan-l-amine (RG-15e)

[00444] tert-Butyl ((lr,3r)-3-(4-bromo-2-methylphenoxy)cyclobutyl)carbamate (175 mg, 0.4912 mmol) was diluted with dichloromethane (6 mL). Trifluoroacetic acid (4 mL, 51.92 mmol) was added and the mixture was stirred at room temperature in a sealed vial for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was diluted with dichloromethane (8 mL) and washed with saturated sodium bicarbonate (4 mL). The organics were passed through a phase separator and concentrated to dryness on the VI 0 evaporator under reduced pressure to provide (lr,3r)-3-(4-bromo-2-methylphenoxy)cyclobutan-l-amine (127 mg, 99%). ¾ MR (300 MHz, OMSO-de) δ 7.32 (dd, J = 2.5, 0.9 Hz, 1H), 7.27 (dd, J = 8.6, 2.6 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 4.85 - 4.74 (m, 1H), 3.62 - 3.48 (m, 1H), 2.29 - 2.16 (m, 2H), 2.16 - 2.04 (m, 5H), 1.82 (s, 2H) ppm. ESI-MS m/z calc. 255.02588, found 256.12 (M+l) ⁺ ; Retention time: 0.65 minutes.

Preparation of N-((lr.3rV3-(4-((l-(3.5-difluorophenylVlH-1.2.4-triazol-3-vn aminoV 2-methylphenoxy)cvclobutyl)acetamide (Compound 509)

[00445] (lr,3r)-3-(4-Bromo-2-methylphenoxy)cyclobutan-l-amine (42 mg, 0.1606 mmol) was dissolved in dichloromethane (1 mL). To this mixture was added acetic anhydride (30 μΐ _^ , 0.3180 mmol) and the vial was sealed. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 50% saturated sodium bicarbonate (3 mL). The organics were passed through a phase separator and concentrated to dryness on the V10 evaporator under reduced pressure. The crude N-((lr,3r)-3-(4-bromo-2- methylphenoxy)cyclobutyl)acetamide was treated with sodium tert-butoxide (65 mg, 0.6764 mmol), tert-ButylXphos Palladacyle (5 mg, 0.007281 mmol), and l-(3,5- difluorophenyl)-l,2,4-triazol-3 -amine (32 mg, 0.1631 mmol). The solids were diluted with 1,4-dioxane (0.5 mL) and tert-butanol (1.5 mL) and flushed with nitrogen. The vial was sealed and heated to 50 °C overnight with stirring. The reaction mixture was diluted with 8 mL of dichloromethane (5% methanol) and washed with 50% saturated sodium bicarbonate (4 mL). The organics were passed through a phase separator that contained a plug of Florisil (1 g) and concentrated to dryness on the Genevac under reduced pressure. This crude was diluted with dimethylsulfoxide (2 mL) and purified by reverse phase chromatography (50 g C18Aq (ISCO) column; 0-100%) acetonitrile water with a trifluoroacetic acid modifier). The pure fractions were concentrated to dryness under reduced pressure and diluted with 5%> methanol/dichloromethane (5 mL), then were washed with 50%> saturated sodium bicarbonate (3 mL). The organics were collected through a phase separator, concentrated to dryness under reduced pressure and then dried in the high vacuum oven at 50 °C for 3 hours to yield N- ((lr,3r)-3-(4-((l-(3,5-difluorophenyl)-lH-l,2,4-triazol-3-yl )amino)-2- methylphenoxy)cyclobutyl)acetamide (18.4 mg, 26%). ¾ MR (400 MHz, DMSO- di δ 9.26 (s, 1H), 9.13 (s, 1H), 8.25 (d, J = 7.1 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.51 (dd, J = 8.8, 2.8 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.23 (tt, J = 9.3, 2.4 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.34 - 4.25 (m, 1H), 2.37 - 2.28 (m, 4H), 2.16 (s, 3H), 1.81 (s, 3H) ppm. ESI-MS m/z calc. 413.16632, found 414.1 1 (M+l) ⁺ ;

Retention time: 3.63 minutes.

EXAMPLE 16

Preparation of 2-methyl-N-(l -phenyl- L2,4-triazol-3-yl)-5-(2-tetrahy dropyran-4- ylethoxy)pyridin-3 -amine (Compound 225)

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, dioxane, NaOtBu, 140 °C; (d) DIAD, PPh ₃ , THF, 45 °C.

Preparation of 6-methyl-5-r(l-phenyl-L2,4-triazol-3-yl)aminolpyridin-3-ol (RG-16c)

[00446] Chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l,r-biphe nyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (approximately 452.0 mg, 0.61 18 mmol), 1 -phenyl- l,2,4-triazol-3 -amine (980 mg, 6.1 18 mmol), sodium tert- butoxide (approximately 1.763 g, 18.35 mmol) and 5-bromo-6-methyl-pyridin-3-ol (approximately 1.150 g, 6.1 18 mmol) were combined in 1,4-dioxane (19.6 mL) and the reaction was degassed with nitrogen for 10 seconds. The reaction was capped in a microwave tube and heated at 140 °C in a microwave for 30 minutes. The crude material was absorbed onto 5 grams of silica gel and purified by silica gel

chromatography (10-90% (1% methanol/ethyl acetate)/hexanes) to afford 6-methyl-5- [(l-phenyl-l,2,4-triazol-3-yl)amino]pyridin-3-ol (650 mg, 2.418 mmol, 40%). ¾ NMR (400 MHz, OMSO-de) δ 1 1.52 (s, 1H), 9.55 (s, 1H), 9.29 (d, J = 14.2 Hz, 1H), 8.78 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.77 (t, J = 6.2 Hz, 1H), 7.57 (dd, J = 18.4, 10.0 Hz, 2H), 7.38 (dd, J = 28.7, 21.3 Hz, 1H), 2.68 (s, 3H) ppm. ESI-MS m/z calc. 267.1 12, found 268.46 (M+l) ⁺ ; Retention time: 0.58 minutes.

Preparation of 2-methyl-N-(l -phenyl- L2,4-triazol-3-yl)-5-(2-tetrahy dropyran-4- ylethoxy)pyridin-3 -amine (Compound 225)

[00447] 6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]pyridin-3-ol (60 mg, 0.2245 mmol), 2-tetrahydropyran-4-ylethanol (43.83 mg, 0.3368 mmol), and triphenylphosphine (88.34 mg, 78.04 μΐ _^ , 0.3368 mmol) were dissolved in

tetrahydrofuran (2 mL) and the solution was stirred at room temperature for 10 minutes. Isopropyl N-isopropoxycarbonyliminocarbamate (68.08 mg, 0.3368 mmol) was added into the reaction via a syringe under nitrogen. The reaction was gently heated at 45 °C for 2 hours. The solvent was removed under reduced pressure and the crude material was purified by reverse phase chromatography using 10-90%) acetonitrile/water. The pure fractions were combined and neutralized using aqueous sodium bicarbonate. The free base was dissolved in dichloromethane and treated with 2 equivalents of hydrochloric acid in 1,4-dioxane (2.0 M) and the resulting mixture was concentrated to dryness under reduced pressure to give 2-methyl-N-(l-phenyl- l,2,4-triazol-3-yl)-5-(2-tetrahydropyran-4-ylethoxy)pyridin- 3-amine hydrochloride (68.9 mg, 0.1574 mmol, 70.10%). ¾ NMR (400 MHz, OMSO-de) δ 9.70 (s, 1H), 9.25 (d, J = 14.9 Hz, 1H), 8.87 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.90 - 7.78 (m, 2H), 7.58 (t, J = 8.0 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 4.77 (dt, J = 12.3, 6.1 Hz, 2H), 4.25 (t, J = 6.3 Hz, 2H), 3.83 (dd, J = 1 1.3, 2.5 Hz, 2H), 3.28 (td, J = 1 1.8, 1.9 Hz, 2H), 2.79 - 2.67 (m, 3H), 1.78 - 1.62 (m, 4H), 1.26 (dd, J = 19.6, 7.8 Hz, 2H) ppm. ESI-MS m/z calc. 379.20084, found 380.52 (M+l) ⁺ ; Retention time: 0.71 minutes.

[00448] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 16, the following compounds can be synthesized from the appropriate intermediates; 198-201, 204, 207-210, 221-224, 226, 232 and 238-240. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 17

Preparation of 1-Γ3-ΓΓΓ6-ηΐ6ί1 ν1-5-Γ 1 -phenyl- L2,4-triazol-3-yl)amino ^" |-3- pyridyllaminolmethyll-l-piperidyl ^" |ethanone (Compound 235) & 2-methyl-N3-(l- phenyl-L2,4-triazol-3-yl)-N5-(3-piperidylmethyl)pyridine-3,5 -diamine (Compound 229)

RG-17d Cmpd 229 Cmpd 235

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 50 °C; (d) NaBH(OAc) ₃ , DCM, RT; (e) TFA, DCM, RT; (f) Ac ₂ 0, THF, RT.

Preparation of 2-methyl-N3-(l-phenyl-L2,4-triazol-3-yl)pyridine-3,5-diamine (RG- 17c)

[00449] 1 -Phenyl- l,2,4-triazol-3 -amine (698.7 mg, 4.362 mmol) and 5-bromo-6- methyl-pyridin-3 -amine (1.02 g, 5.453 mmol) were dissolved into tert-butanol (15 mL) and this solution was purged with nitrogen. During the purge, sodium tert- butoxide (630 mg, 6.56 mmol) was added followed by chloro(2-di-t-butylphosphino- 2',4',6'-tri-i-propyl-l,r-biphenyl)[2-(2-aminoethyl)phenyl]p alladium(II) (t-BuXPhos Palladacycle) (300 mg, 0.436 mmol). The reaction was sealed, heated, and stirred at 50 °C overnight. The reaction was diluted with methanol, pulled through a pad of diatomaceous earth and washed with methanol. The solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (0- 10%(methanol/0.1% Ammonium Hydroxide)/ dichloromethane). The pure fractions were concentrated to dryness to afford 2-methyl-N3-(l -phenyl- l,2,4-triazol-3 - yl)pyridine-3,5-diamine (110 mg, 0.3718 mmol, 8.520%). ¾ NMR (400 MHz, OMSO-de) δ 9.08 (s, 1H), δ 8.16 (s, 1H), 7.87 (d, J = 1.1 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.45 (d, J = 2.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 3.31 (s, 2H), 2.32 (s, 3H) ppm. ESI-MS m/z calc. 266.128, found 267.52, Retention time: 0.53 minutes. Preparation of fert-butyl 3-rrr6-methyl-5-r(l-phenyl-L2,4-triazol-3-yl)amino1-3- pyridyllaminolmethyllpiperidine-l-carboxylate (RG-17d)

[00450] 2-Methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)pyridine-3,5-diamin e (100 mg, 0.375 mmol) was dissolved in chloroform (5 mL) and treated with tert-butyl 3- formylpiperidine-l-carboxylate (90 mg, 0.41 mmol). The reaction was stirred vigorously during the addition of sodium triacetoxyborohydride (160 mg, 0.75 mmol). The vial was capped and stirred overnight at room temperature. The reaction was quenched with methanol (approximately 0.5 mL) and then treated with a saturated sodium carbonate solution. The organic layer was separated, washed with brine, dried with sodium sulfate and concentrated to dryness under reduced pressure to give tert- butyl 3-[[[6-methyl-5-[(l -phenyl- 1, 2,4-triazol-3-yl)amino]-3- pyridyl]amino]methyl]piperidine-l-carboxylate that was carried forward as is. ESI- MS m/z calc. 463.26956, found 464.58 Retention time: 0.68 minutes.

Preparation of 2-methyl-N3-(l-phenyl-1.2.4-triazol-3-ylVN5-(3- piperidylmethvDpyridine-3,5-diamine (Compound 229)

[00451] fert-Butyl 3-[[[6-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-3- pyridyl]amino]methyl]piperidine-l-carboxylate (390 mg, 0.8413 mmol) was dissolved into dichloromethane and treated with trifluoroacetic acid (2 mL). The solution was allowed to stand for 2 hours and deprotection was determined to be complete. Solvents were removed under reduced pressure and the residue was stirred with saturated sodium carbonate solution and water (1 : 1 volume) overnight. This mixture was extracted with ethyl acetate twice, the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The aqueous was extracted with dichloromethane 3 times; this was treated in the same fashion and combined with the ethyl acetate extracts. Material was dissolved in methanol and the solvent was removed under reduced pressure. The residue was further azeotroped with dichloromethane and hexanes to provide 2-methyl-N3-(l- phenyl-l,2,4-triazol-3-yl)-N5-(3-piperidylmethyl)pyridine-3, 5-diamine (270 mg, 0.6076 mmol, 65%). ¾ NMR (400 MHz, OMSO-de) δ 9.35 (s, 1H), 9.25 (s, 2H), 8.97 (s, 1H), 8.40 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.58 (t, J = 7.9 Hz, 2H), 7.52 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 3.29 (s, 1H), 3.15 (d, J = 15.6 Hz, 3H), 2.62 (s, 5H), 2.1 1 (s, 1H), 1.81 (d, J = 26.4 Hz, 2H), 1.67 (s, 1H), 1.24 (s, 1H) ppm. ESI-MS m/z calc. 363.21713, found 364.0 (M+l) ⁺ ; Retention time: 0.56 minutes.

Preparation of l-[3-[[[6-methyl-5-|Yl -phenyl- L2,4-triazol-3-yl)amino ^" |-3- pyridvHaminolmethvH-l-piperidvHethanone (Compound 235)

[00452] 2-Methyl-N3-(l-phenyl-l,2,4-triazol-3-yl)-N5-(3- piperidylmethyl)pyridine-3,5-diamine (100 mg, 0.2751 mmol) was dissolved in tetrahydrofuran (3 mL). Acetic anhydride (approximately 28.08 mg, 25.95 μΐ., 0.2751 mmol) was added. The mixture was stirred at room temperature for several hours. Solvents were removed under reduced pressure and crude materials were purified by silica gel chromatography (0-100%) (methanol/10%) dichloromethane/0.1%> Ammonium Hydroxide)/dichloromethane). The pure fractions were combined and concentrated under reduced pressure to give l-[3-[[[6-methyl-5-[(l-phenyl-l,2,4- triazol-3-yl)amino]-3-pyridyl]amino]methyl]-l-piperidyl]etha none (10 mg, 0.02220 mmol, 8.065). ¾ NMR (400 MHz, OMSO-de) δ 15.68 (s, 1H), 9.34 (d, J = 3.2 Hz, 1H), 9.24 (s, 1H), 8.39 (d, J = 2.9 Hz, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.63 - 7.45 (m, 3H), 7.40 (t, J = 7.4 Hz, 1H), 4.31 (d, J = 10.4 Hz, 1H), 4.04 (d, J = 12.4 Hz, 1H), 3.79 (d, J = 12.9 Hz, 1H), 3.68 (d, J = 13.5 Hz, 1H), 3.17 - 2.88 (m, 3H), 2.61 (d, J = 2.4 Hz, 3H), 1.97 (d, J = 6.3 Hz, 3H), 1.92 - 1.76 (m, 2H), 1.65 (d, J = 18.2 Hz, 2H), 1.47 - 1.17 (m, 3H) ppm. ESI-MS m/z calc. 405.22772, found 406.0 (M+l) ⁺ ; Retention time: 0.56 minutes.

[00453] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 17, steps 1-4, the following compounds can be synthesized from the appropriate intermediates; 230, 231 and 236. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00454] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 17, steps 1-5, the following compounds can be synthesized from the appropriate intermediates; 228 and 237.

Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 18

[00455] Preparation of 3-rri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1amino1-5- methyl-benzonitrile (Compound 600): fert-butyl N-rr3 ri-(3.5-difluorophenyl)-1.2.4- triazol-3-yllaminol-5-methyl-phenyllmethyllcarbamate (Compound 622); N-[3- (aminomethyl)-5-methyl-phenyl1-l-(3,5-difluorophenyl)-L2,4-t riazol-3-amine (dihvdrochloride salt) (Compound 624): and N-rr3-rri-(3.5-difluorophenyl)-1.2.4- triazol-3-yl1amino1-5-methyl-phenyl1methyl1methanesulfonamid e (Compound 646)

Cmpd 600 Cmpd 622

Cmpd 624

Cmpd 646

(a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, NaOtBu, tBuOH, 80 °C; (d) B0C2O, NiCh, MeOH, NaBH ₄ , 60-80 °C; (e) TFA, DCM, RT; (f) triethylamine, dioxane, reflux. Preparation of 3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-5-methyl - benzonitrile (Compound 600)

[00456] In a vial fitted with a stir bar was placed 3-bromo-5-methyl-benzonitrile (266 mg, 1.357 mmol), l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (205 mg, 1.045 mmol), sodium tert-butoxide (106 mg, 1.103 mmol), and chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (30 mg, 0.04607 mmol). tert-Butanol (5 mL) was added and the vial was sealed and purged with nitrogen. The mixture was heated to 80 °C overnight. The reaction was extracted with ethyl acetate and washed with water. The organics were treated with MP-TMT (ca 100 mg) and refluxed for 4 hours, to capture residual palladium. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 3-[[l- (3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-methyl-benz onitrile (0.35 g of 90% purity, 97%). A small sample of crude material was crystalized from acetonitrile to give analytically pure 3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-methy l- benzonitrile. ¾ MR (300 MHz, OMSO-de) δ 9.94 (s, 1H), 9.21 (s, 1H), 7.84 (s, 1H), 7.76 - 7.52 (m, 3H), 7.38 - 7.20 (m, 1H), 7.15 (s, 1H), 2.35 (s, 3H) ppm. ESI- MS m/z calc. 31 1.09827, found 312.15 (M+l) ⁺ ; Retention time: 0.95 minutes. Preparation of fert-butyl N-rr3-rri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1amino1-5- methyl-phenyllmethyl ^" |carbamate (Compound 622)

[00457] In a 50 mL round bottom flask fitted with a stir bar was placed 3-[[l-(3,5- difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-methyl-benzonitr ile (146 mg, 0.4217 mmol). To this was added methanol (25 mL), tert-butoxycarbonyl tert-butyl carbonate (368 mg, 1.686 mmol), dichloronickel;hexahydrate (123 mg, 0.5175 mmol) (dissolved with mild heating), and finally sodium borohydride (135 mg, 3.568 mmol). The reaction was warmed to 80°C because the starting material was not fully soluble, and more sodium borohydride (80 mg) was added. The reaction was aged at 60-80°C overnight and then quenched with N'-(2-aminoethyl)ethane-l,2-diamine

(approximately 197.5 mg, 206.8 μΐ _^ , 1.914 mmol) for 2 hours. The solution was concentrated to dryness and extracted with ethyl acetate and washed with saturated sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 20-100% ethyl acetate/heptane). The pure fractions were concentrated to dryness under reduced pressure to give tert-butyl N- [[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-met hyl- phenyl]methyl]carbamate (86 mg, 42%). ¾ NMR (300 MHz, OMSO-d ₆ ) δ 9.44 (s, 1H), 9.15 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.46 (s, 1H), 7.37 - 7.12 (m, 3H), 6.57 (s, 1H), 4.07 (d, J = 6.2 Hz, 2H), 2.26 (s, 3H), 1.38 (s, 9H) ppm. ESI-MS m/z calc. 415.18198, found 416.31 (M+l) ⁺ ; Retention time: 0.9 minutes.

Preparation of N-[3-(aminomethyl)-5-methyl-phenyll-l -(3,5-difluorophenyl)-L2,4- triazol-3 -amine (Dihydrochloride salt) (Compound 624)

[00458] tert-Butyl N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5- methyl-phenyl]methyl]carbamate (48 mg, 0.09880 mmol) was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (1 mL, 12.98 mmol). The reaction was aged 10 minutes at ambient temperature, concentrated to dryness and purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient, hydrochloric acid modifier). The pure fractions were concentrated to dryness under reduced pressure to give N-[3-(aminomethyl)-5- methyl-phenyl]-l-(3,5-difluorophenyl)-l,2,4-triazol-3-amine (dihydrochloride salt) (27.3 mg, 63%). ¾ NMR (300 MHz, OMSO-de) δ 9.63 (s, 1H), 9.21 (s, 1H), 8.35 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.57 (s, 1H), 7.36 (s, 1H), 7.32 - 7.17 (m, 1H), 6.85 (s, 1H), 3.97 (d, J = 5.8 Hz, 2H), 3.78 (s, 3H), 2.31 (s, 3H) ppm. ESI-MS m/z calc. 315.12955, found 316.16 (M+l) ⁺ ; Retention time: 0.7 minutes.

Preparation of N-rr3-rri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1amino1-5-me thyl- phenyllmethyllmethanesulfonamide (Compound 646)

[00459] (N-[3-(aminomethyl)-5-methyl-phenyl]-l-(3,5-difluorophenyl)- l,2,4- triazol-3 -amine (Dihydrochloride salt) (10 mg, 0.02576 mmol)) was dissolved in 1,4- dioxane (2 mL) and to it was added excess triethylamine (50 μΐ _^ , 0.3587 mmol) and excess methanesulfonyl chloride (20 mg, 0.1746 mmol). The mixture was heated to reflux briefly. The reaction mixture was concentrated to dryness under a stream of nitrogen, dissolved in dimethylsulfoxide (2.0 mL), filtered through a 0.45μπι filter and purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient, hydrochloric acid modifier). The product was obtained as a white solid N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-m ethyl- phenyl]methyl]methanesulfonamide (Hydrochloride salt) (5 mg, 43%). ¾ MR (300 MHz, OMSO-de) δ 9.15 (s, 1H), 7.75 - 7.60 (m, 2H), 7.55 (s, 1H), 7.32 - 7.13 (m, 2H), 6.69 (s, 1H), 4.10 (s, 2H), 2.89 (s, 3H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 393.10712, found 394.02 (M+l) ⁺ ; Retention time: 0.83 minutes.

[00460] Using the general synthetic scheme outlined in Schemes A and B, and using procedures analogous to those described in Example 18, steps 1-3 and after the completion of step 3, a reductive amination of the ketone intermediate to the final secondary alcohol can be carried out using typical ketone reduction conditions (for example sodium borohydride in methanol), the following compounds can be synthesized from the appropriate intermediates; 594 and 643. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00461] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 18, the following compound can be synthesized from the appropriate intermediate; 627. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 19

Preparation of l-[3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-5-met hyl- phenyl ^" |ethanone (Compound 591) and 2-[3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3- vHamino1-5-methyl-phenvHpropan-2-ol (Compound 595)

(a) Cu(OAc) ₂ , pyridine, 3 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, NaOtBu, tBuOH, 60-90 °C; (d) THF, MeLi, 0 °C to RT.

Preparation l-r3-rri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1amino1-5-met hyl- phenyllethanone (Compound 591)

[00462] In a vial fitted with a stir bar was placed l-(3,5-difluorophenyl)-l,2,4- triazol-3 -amine (519 mg, 2.646 mmol). To this was added l-(3-bromo-5-methyl- phenyl)ethanone (500 mg, 2.347 mmol), sodium tert-butoxide (293 mg, 3.049 mmol), and chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (66 mg, 0.1013 mmol). The vial was sealed and purged with nitrogen. To the reaction was added tert-butanol (8 mL), and the reaction was stirred at 60-90 °C for 4 hours. l-(3-Bromo-5-methyl- phenyl)ethanone (150 mg) was added to the reaction in tert-butanol (lmL). The mixture was heated for 1 hour. The reaction was stored in the freezer over the weekend. The reaction was warmed to melt and then concentrated to dryness under reduced pressure. The crude was pre-absorbed onto silica (ca 10 g in methanol/ethyl acetate) and purified by silica gel chromatography (40 g column, 30-100% ethyl acetate/ heptane). The pure fractions were concentrated to dryness under reduced pressure and crystalized from hot acetonitrile. The crystalline material was filtered to yield l-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-me thyl- phenyl]ethanone (0.29 g, 34%). ¾ NMR (300 MHz, OMSO-de) δ 9.74 (s, 1H), 9.20 (s, 1H), 8.15 (s, 1H), 7.79 - 7.52 (m, 3H), 7.40 - 7.14 (m, 2H), 5.85 (s, OH), 2.57 (s, 3H), 2.38 (s, 4H) ppm. ESI-MS m/z calc. 328.1 1356, found 329.17 (M+l) ⁺ ;

Retention time: 0.92 minutes.

Preparation of 2-[3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-5-met hyl- phenyllpropan-2-ol (Compound 595)

[00463] In a 50 mL round bottom flask equipped with a stir bar was placed l-[3- [[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-5-methyl- phenyl]ethanone (50 mg, 0.1371 mmol). The flask was stoppered and to it was added tetrahydrofuran (3 mL), followed by methyllithium (200 μL· of 3 M, 0.6000 mmol) dropwise at 0 °C. An orange homogenous solution resulted. The reaction was aged at 0 °C for 30 minutes and then warmed to room temperature slowly overnight. The reaction was quenched with water and extracted twice with ethyl acetate. The organics were concentrated under a stream of nitrogen, dissolved in dimethylsulfoxide (2.0 mL) and purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient, hydrochloric acid modifier). The desired fractions were concentrated to dryness under reduced pressure to give 2-[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3- yl]amino]-5-methyl-phenyl]propan-2-ol (Hydrochloride salt) (9.0 mg, 16%). ¾ NMR (300 MHz, OMSO-de) δ 9.14 (s, 1H), 7.76 - 7.51 (m, 3H), 7.36 - 7.09 (m, 2H), 6.81 (s, 1H), 2.28 (s, 3H), 1.42 (s, 6H) ppm. ESI-MS m/z calc. 344.14487, found 345.21 (M+l) ⁺ ; Retention time: 0.86 minutes.

EXAMPLE 20

Preparation of 1 -(3 ,4-difluorophenyl)-N-(3 -(4-(oxetan-3 -yPpiperazin- 1 -yPphenyl)- lH-L2,4-triazol-3-amine (Compound 334)

Cmpd 334 (a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) NaBH(OAc) ₃ , DCE; (c) 10% Palladium on carbon, H ₂ , THF; (d) t-BuXPhos Palladacycle, NaOtBu, t- BuOH 50 °C. Preparation of 3-bromo-l-(3,4-difluorophenyl)-L2,4-triazole (RG-20a)

[00464] Copper(II) acetate (approximately 18.42 g, 101.4 mmol), 3-bromo-lH- 1,2,4-triazole (10 g, 67.59 mmol), and 4 A molecular sieves (250 mg/0.33 mmol) were combined in dichloromethane and treated with 3,4-difluorophenyl boronic acid (14.94 g, 94.63 mmol), and pyridine (approximately 10.69 g, 10.93 mL, 135.2 mmol). The mixture was stirred at room temperature under air for 3 days. The reaction was filtered and the solid was washed with additional dichloromethane (200 mL). The combined organic layers were concentrated with silica gel and dry-loaded to purify on silica gel to afford 3-bromo-l-(3,4-difluorophenyl)-l,2,4-triazole (10.5 g, 54%). ¾ MR (400 MHz, DMSO-^e) δ 9.30 (s, 1H), 8.08 - 7.96 (m, 1H), 7.77 - 7.62 (m, 2H) ppm. ESI-MS m/z calc. 258.95566, found 260.32 (M+l) ⁺ ; Retention time: 0.96 minutes.

Preparation of l-(3,4-dimethyl-5-nitro-phenyl)-4-(oxetan-3-yl)piperazine (RG-20b)

[00465] l-(3-Nitrophenyl)piperazine (2 g, 9.651 mmol) was dissolved in dichloroethane (10 mL) and oxetan-3-one (1000 μΕ, 15.60 mmol) was added to the reaction. The reaction was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (3 g, 14.15 mmol) was added and the reaction was stirred at room temperature under nitrogen overnight. The reaction was quenched with 1M sodium hydroxide and diluted with water, then extracted with dichloromethane (2 X 10 mL). The combined organic layers were dried and concentrated to afford l-(3- nitrophenyl)-4-(oxetan-3-yl)piperazine (421 mg, 51%). ESI-MS m/z calc. 263.13, found 264.10 (M+l) ⁺ ; Retention time: 0.55 minutes.

Preparation of 3-[4-(oxetan-3-yl)piperazin-l-yl ^" |aniline (RG-20c)

[00466] A solution of l-(3-nitrophenyl)-4-(oxetan-3-yl)piperazine (1700 mg, 6.457 mmol) in tetrahydrofuran was treated with 10% palladium on carbon (100 mg, 0.9397 mmol). The flask was evacuated under vacuum and filled with hydrogen, and the procedure was repeated three times. The mixture was stirred under a hydrogen balloon for 24 hours, then was filtered through Celite and concentrated to provide 3- [4-(oxetan-3-yl)piperazin-l-yl]aniline(1.3 g, 86%). ESI-MS m/z calc. 233.15, found 234.12 (M+l) ⁺ ; Retention time: 0.23 minutes. Preparation of 1 -(3 ,4-difluorophenyl)-N-(3 -(4-(oxetan-3 -yPpiperazin- 1 -yPphenyl)- lH-l,2,4-triazol-3-amine (Compound 334)

[00467] 3-[4-(Oxetan-3-yl)piperazin-l-yl]aniline (200 mg, 0.8572 mmol), 3- bromo-l-(3,4-difluorophenyl)-l,2,4-triazole (250 mg, 0.9614 mmol) and sodium tert- butoxide , (1.5 mL of 2 M, 3.000 mmol) were dissolved in tert-butanol (20 mL). The reaction mixture was purged with nitrogen for 15 minutes, then treated with chloro(2- di-t-butylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (50 mg, 0.07281 mmol) and stirred at 50 °C for 2 hours. The reaction mixture was treated with trifluoroacetic acid (500 μΐ _^ , 6.490 mmol) then Pd-scanvenger was added and the mixture was stirred overnight. The resulting mixture was filtered, concentrated, redissolved in

dimethylsulfoxide (6 mL) and purified by reverse phase HPLC (Waters SunFire CI 8 30x150 5μΜ column; acetonitrile/water gradient, ammonium hydroxide modifier) to provide after concentration l-(3,4-difluorophenyl)-N-(3-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)-lH-l,2,4-triazol-3-amine (76.2 mg, 19.35%). ESI-MS m/z calc. 412.18, found 413.45 (M+l) ⁺ ; Retention time: 2.71 minutes. ¾ MR (400 MHz, OMSO-d ₆ ) δ 9.53 (s, 1H), 9.21 (s, 1H), 9.06 (s, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 7.30 (s, 1H), 7.13 (d, J = 5.2 Hz, 2H), 6.51 (d, J = 3.6 Hz, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 3.51 - 3.40 (m, 1H), 3.17 (s, 4H), 2.42 (s, 4H) ppm.

[00468] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 20, the following compounds can be synthesized from the appropriate intermediates; 330, 332, 333 and 335. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 21

Preparation of l-[4-methyl-3-r(l -phenyl- L2,4-triazol-3-yl)amino1phenyl1ethanone (Compound 573) and 1 4-methyl-34(1 -phenyl- 1.2.4-triazol-3- yl)amino ^" |phenyl ^" |ethanol (Compound 584)

RG-21a

Cmpd 573

Cmpd 573 Cmpd 584

(a) Cu(OAc)2, pyridine, 4 A molecular sieves, CH2CI2, RT; (b) t-BuXPhos

Palladacycle, dioxane, NaOtBu, 60-90 °C; (c) NaBH ₄ , MeOH, 50 °C Preparation of 3 -bromo-1 -phenyl- 1,2,4-triazole (RG-21a)

[00469] 3-Bromo-lH-l,2,4-triazole (3 g, 20.28 mmol), copper (II) acetate (7.37 g, 40.56 mmol), phenylboronic acid (4.945 g, 40.56 mmol), pyridine (3.208 mL, 40.56 mmol), and crushed and activated 4 A molecular sieves (15 g) were combined in a 1000 mL round bottom flask. The mixture was diluted with dichloromethane (300 mL), and stirred over the weekend with the cap loose at room temperature. The reaction mixture was filtered through Celite and washed with methanol

(approximately 100 mL). Celite was added and the mixture was concentrated to dryness under reduced pressure and purified by silica gel chromatography (80 gram Gold column (ISCO); 0-100% ethyl acetate/hexane). Possible regioisomer observed in 1H NMR and in LC/MS (impurity runs faster). No separation on normal phase. Combined the desired fractions and concentrated to dryness under reduced pressure. The enriched material was diluted with dimethylsulfoxide and purified by reverse phase chromatography (275 gram Gold C-18 column (ISCO); 10-100%

acetonitrile/water with trifluoroacetic acid modifier). The pure fractions were concentrated to dryness under reduced pressure to give 3 -bromo-1 -phenyl- 1,2,4- triazole (1.72 g, 38%). ¹ H NMR (400 MHz, OMSO-de) δ 9.31 (s, 1H), 7.88 - 7.76 (m, 2H), 7.65 - 7.52 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H) ppm. ESI-MS m/z calc. 222.9745, found 223.97 (M+l) ⁺ ; Retention time: 2.66 minutes.

Preparation of l-[4-methyl-3-[(l -phenyl- L2,4-triazol-3-yl)amino]phenyllethanone (Compound 573)

[00470] In a vial equipped with a stir bar was placed l-(3-amino-4- methylphenyl)ethanone (100 mg, 0.66 mmol). 3 -Bromo-1 -phenyl- 1,2,4-triazole (150.2 mg, 0.6703 mmol), sodium tert-butoxide (150.2 mg, 1.005 mmol), and t- ButylXPhos Palladacycle (21.8 mg, 0.033 mmol) were added and the vial was sealed and purged with nitrogen. To the reaction was added tert-butanol (4.0 mL). The reaction was warmed to 60 °C with stirring, for 30 minutes and then heated to 90 °C for 30 minutes. The reaction was extracted with ethyl acetate and water. The organics were treated with MP-TMT (200 mg) to capture residual palladium. The organics were concentrated under reduced pressure and the residue was crystalized from hot acetonitrile to give l-[4-methyl-3-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]ethanone (60 mg, 0.1950 mmol, 29.08%). ESI-MS m/z calc.

292.13242, found 293.19 (M+l) ⁺ ; Retention time: 0.84 minutes. ¾ NMR (300 MHz, OMSO-de) δ 9.12 (d, J = 2.6 Hz, 1H), 8.71 - 8.57 (m, 1H), 8.49 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.67 - 7.44 (m, 3H), 7.41 - 7.22 (m, 2H), 2.66 - 2.55 (m, 3H), 2.37 (s, 8H) ppm.

Preparation of l-[4-methyl-3-r(l -phenyl- L2,4-triazol-3-yl)amino1phenyl1ethanol (Compound 584) [00471] l-[4-Methyl-3-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]eth anone (32 mg, 0.1040 mmol) was dissolved in methanol (15 mL) and treated with sodium borohydride (30 mg), at 40 °C. Gas evolution was observed. The reaction was aged at 50 °C for 60 minutes. The reaction concentrated under a stream of nitrogen and the residue was dissolved in DMSO (1.8 mL), treated with 2N hydrochloric acid (200 ul) and purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient, hydrochloric acid modifier). The desired fractions were combined and concentrated to dryness under reduced pressure to give l-[4-methyl-3- [(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]ethanol (26 mg, 0.07119 mmol, 68.46). ESI-MS m/z calc. 294.14807, found 295.26 (M+l) ⁺ ; Retention time: 0.78 minutes. ¹ H MR (300 MHz, Acetonitrile-*) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.88 - 7.71 (m, 2H), 7.65 -7.47 (m, 2H), 7.44 - 7.32 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.01 - 6.75 (m, 2H), 4.82 (q, J = 6.5 Hz, 1H), 3.13 (s, 1H), 2.32 (s, 3H), 2.28 - 2.06 (m, 2H), 1.43 (d, 3H) ppm.

[00472] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 21, the following compounds can be synthesized from the appropriate intermediates; 583, 585-587, 658 and 659. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00473] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 21 (Steps 1-2), the following compounds can be synthesized from the appropriate intermediate; 647 and 651. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 22

Preparation of l-(3,5-difluorophenyl)-N-[3,4-dimethyl-5-(3-mo holinoazetidin-l- yl)phenyl]-l,2,4-triazol-3 -amine (Compound 365)

RG-22a

(a) HMPA, K2CO3, 112 °C; (b) t-BuXPhos Palladacycle, dioxane, tBuOH, NaOtBu, RT; (c) 10% Palladium on carbon, DCM, MeOH, H ₂ ; (d) t-BuXPhos Palladacycle, dioxane, tBuOH, NaOtBu, 30 °C.

Preparation of 3-bromo-l-(3,5-difluorophenyl)-L2,4-triazole (RG-22a)

[00474] An HMPA (45.01 mL) solution of 3-bromo-lH-l,2,4-triazole (4.439 g, 30 mmol) was treated with 1,3,5-trifluorobenzene (approximately 39.62 g, 300.0 mmol) and potassium carbonate (approximately 4.146 g, 30.00 mmol). The reaction mixture was stirred in a Q-tube at 112 °C overnight. To the reaction mixture was added ethyl acetate and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude material was purified by silica gel chromatography (80 g column; 20% ethyl acetate/heptane). The desired fractions were concentrated to dryness under reduced pressure to yield 3-bromo-l- (3,5-difluorophenyl)-l,2,4-triazole (5.7 g, 21.92 mmol, 73%). ¹ H MR (400 MHz, OMSO-de) δ 9.39 (s, 1H), 7.77 - 7.57 (m, 2H), 7.39 (tt, J = 9.3, 2.3 Hz, 1H) ppm. ESI-MS m/z calc. 258.95566, found 260.05 (M+l) ⁺ ; Retention time: 0.8 minutes.

Preparation of 4-[l-(2,3-dimethyl-5-nitro-phenyl)azetidin-3-yllmorpholine (RG-22b)

[00475] l-Bromo-2,3-dimethyl-5-nitro-benzene (2.5 g, 10.87 mmol) and 4- (azetidin-3-yl)morpholine (2.573 g, 1 1.96 mmol) were dissolved /suspended in dry 1,4-dioxane (20 mL) and tert-butanol (60 mL) and purged with nitrogen for several minutes. During the purge, chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, - biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (750 mg, 1.087 mmol) followed by sodium tert-butoxide (3.66 g, 38.04 mmol) were added. The reaction was stirred at ambient temperature for 4 hours under nitrogen. The reaction was diluted with methanol and all solvents removed under reduced pressure. The crude residue was stirred in water overnight and isolated via suction filtration. The precipitate was dissolved in dichloromethane and washed with brine, dried with sodium sulfate and purified by silica gel chromatography (0-10% methanol/ethyl acetate). The purified material was concentrated to dryness under reduced pressure and triturated with diethyl ether, stirred until powdered and collected via suction filtration (air dried) to yield 4-[l-(2,3-dimethyl-5-nitro-phenyl)azetidin-3- yl]morpholine (1.85 g, 5.715 mmol, 52.6%). ¾ MR (300 MHz, CDCh) δ 7.57 (d, J = 2.1 Hz, 1H), 7.32 - 7.16 (insolvent peak included, 1H), 4.08 (t, J = 7.2 Hz, 2H), 3.83 - 3.67 (m, 6H), 3.37 - 3.14 (m, 1H), 2.53 - 2.36 (m, 4H), 2.32 (s, 3H), 2.17 (s, 3H) ppm. ESI-MS m/z calc. 291.1583, found 292.29, Retention time: 0.61 minutes.

Preparation of 3,4-dimethyl-5-(3-moφholinoazetidin-l-yl aniline (RG-22c)

[00476] 4-[l-(2,3-Dimethyl-5-nitro-phenyl)azetidin-3-yl]morpholine (1.85 g, 6.350 mmol) was dissolved in methanol/dichloromethane (100 mL/25 mL), and the solution was placed under an atmosphere of carbon dioxide before addition of 10% Palladium on carbon (50% water) (506 mg, 0.476 mmol). Hydrogen gas was bubbled through the reaction for approximately 2 minutes the reaction was allowed to stir overnight at ambient temperature under a balloon of hydrogen. The catalyst was removed via suction filtration, washed with methanol and the filtrate was concentrated under reduced pressure. The crude was dissolved in dichloromethane and reconcentrated under reduced pressure to yield 3,4-dimethyl-5-(3-morpholinoazetidin-l-yl)aniline (1.1 g, 3.788 mmol, 59.6%). ¾ NMR (300 MHz, CDCh) δ 6.11 (d, J = 2.1 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 3.95 (dd, J = 7.5, 6.8 Hz, 2H), 3.77 - 3.69 (m, 4H), 3.66 (dd, J = 7.3, 6.1 Hz, 2H), 3.45 (d, J = 11.1 Hz, 2H), 3.26 - 3.15 (m, 1H), 2.52 - 2.30 (m, 4H), 2.16 (s, 3H), 2.00 (s, 3H) ppm. ESI-MS m/z calc. 261.1841, found 262.0 (M+l) ⁺ ; Retention time: 0.48 minutes.

Preparation of l-(3,5-difluorophenyl -N-Γ3,4-dimethyl-5-(3-moφholinoazetidin-l- yl)phenyll-L2,4-triazol-3 -amine (Compound 365)

[00477] 3-Bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (150 mg, 0.5768 mmol) and 3,4-dimethyl-5-(3-morpholinoazetidin-l-yl)aniline (165.8 mg, 0.6345 mmol) were placed in a vial and dissolved in 1,4-dioxane (2 mL) and tert-butanol (8 mL). The vial was briefly purged with nitrogen before addition of chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (39.6 mg, 0.057 mmol) followed by sodium tert-butoxide (83.1 mg, 0.865 mmol). The reaction was stirred at 30 °C sealed for an hour. The reaction was diluted with methanol and solvents were removed under reduced pressure. The residue was suspended in water and a precipitate was isolated via suction filtration. The filter cake was washed with water, dissolved in dichloromethane and purified by silica gel chromatogaphy (0-10% methanol/ethyl acetate). The purified materials were stirred with MP-TMT resin (Biotage- 801471) in dichloromethane/tetrahydrofuran for several hours to eliminate traces of palladium metal. The material was isolated from the resin via suction filtration. The resin was washed with dichloromethane and solvents were removed under reduced pressure. The residue was triturated with diethyl ether and was collected via suction filtration (air dried) to yield l-(3,5-difluorophenyl)-N-[3,4- dimethyl-5-(3-morpholinoazetidin-l-yl)phenyl]-l,2,4-triazol- 3-amine (155 mg, 0.3343 mmol, 57.95). ¾ MR (300 MHz, CDCh) δ 8.28 (s, 1H), 7.35 - 7.17 (m, 3H), 6.94 (d, J = 2.1 Hz, 1H), 6.83 - 6.68 (m, 2H), 6.56 (s, 1H), 4.06 (t, J = 7.0 Hz, 2H), 3.75 (dd, J = 10.7, 5.7 Hz, 6H), 3.26 (p, J = 6.3 Hz, 1H), 2.53 - 2.36 (m, 4H), 2.26 (s, 3H), 2.08 (s, 3H) ppm. ESI-MS m/z calc. 440.21362, found 441.0 (M+l) ⁺ ; Retention time: 0.69 minutes.

[00478] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 22, the following compounds can be synthesized from the appropriate intermediates; 154, 155, 326,

329, 364, 366, 367, 417-422, 447-450 and 628. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 23

L2,4-triazol-3 -amine (Compound 445)

Cmpd

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) neat, 130 °C; (c) K2CO3, DMF, 50 °C; (d) 10% Palladium on carbon, EtOAc, MeOH, H ₂ ; (e) t- BuXPhos Palladacycle, tBuOH, 1,4-dioxane, NaOtBu, 50 °C.

Preparation of 2-morpholino-5-nitro-phenol (RG-23b)

[00479] A mixture of 2-bromo-5-nitro-phenol (2.12 g, 9.725 mmol) and morpholine (approximately 4.236 g, 4.240 mL, 48.62 mmol) was stirred at 130 °C a sealed vial for 20 hours. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organics were dried with sodium sulfate, filtered, absorbed onto Celite and concentrated to dryness under reduced pressure. Celite/compound mixture was purified by silica gel chromatography (80 gram Gold (ISCO) column; 10-100% ethyl acetate/ hexane). The pure fractions were concentrated to dryness under reduced pressure to give 2-morpholino-5-nitro-phenol (1.1 g, 41%). ¾ MR (300 MHz, OMSO-de) δ 10.41 (s, 1H), 7.69 (dd, J = 8.8, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 3.73 (dd, J = 5.9, 3.5 Hz, 4H), 3.24 - 3.14 (m, 4H) ppm. ESI-MS m/z calc. 224.07971, found 225.35 (M+l) ⁺ ; Retention time: 0.78 minutes.

Preparation of 4-(2-isopropoxy-4-nitro-phenyl)morpholine (RG-23c)

[00480] 2-Morpholino-5-nitro-phenol (1.1 g, 4.440 mmol), potassium carbonate (1.3 g, 9.406 mmol) and 2-iodopropane (666 μΐ _^ , 6.660 mmol) were heated to 55 °C in anhydrous dimethylformamide (17 mL) for 18 hours in a sealed vial. Water was added to the reaction mixture and extracted twice with ethyl acetate. The organics were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude was diluted with minimal dimethyl sulfoxide and purified by the reverse phase chromatography (150 g C 18 Aq (ISCO) column; 0- 100%) acetonitrile/water with a trifluoroacetic acid modifier). The desired fractions were combined and concentrated to dryness under reduced pressure, diluted with dichloromethane, washed with 50%> saturated sodium bicarbonate, and passed through a phase separator. The organics were concentrated to dryness under reduced pressure to give 4-(2-isopropoxy-4-nitro-phenyl)morpholine (1.09 g, 91%). ¾ MR (300 MHz, OMSO-de) δ 7.82 (dd, J = 8.9, 2.6 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 4.83 - 4.68 (m, 1H), 3.25 - 3.85-3.65 (m, 4H), 3.15 (m, 4H), 1.31 (d, J = 6.0 Hz, 6H) ppm. ESI-MS m/z calc. 266.12665, found 267.2 (M+l) ⁺ ; Retention time: 0.9 minutes.

Preparation of 3-isopropoxy-4-morpholino-aniline (RG-23d)

[00481] A solution of 4-(2-isopropoxy-4-nitro-phenyl)morpholine (1.09 g, 4.059 mmol) in ethyl acetate (12 mL) and methanol (4 mL) containing 10% Palladium on Carbon, wet Degussa type (150 mg) was exposed to an atmosphere of hydrogen gas with a hydrogen balloon and was stirred overnight. The reaction mixture was filtered through Celite, washed with additional methanol and concentrated to give a light brown oil. To the filtrate was added hydrochloric acid (approximately 4.059 mL of 1 M, 4.059 mmol) and methanol (5 mL). The mixture was concentrated to dryness under reduced pressure to give 3-isopropoxy-4-morpholino-aniline (Dihydrochloride salt) (1.2 g, 96%). ¾ NMR (300 MHz, OMSO-de) δ 7.20 (d, J = 8.5 Hz, 1H), 6.96 - 6.88 (m, 1H), 6.80 (d, J = 8.5 Hz, 1H), 4.69 - 4.54 (m, 1H), 3.83 (t, J = 4.6 Hz, 4H), 3.25 - 3.13 (m, 4H), 1.33 (d, J = 6.0 Hz, 6H) ppm. ESI-MS m/z calc. 236.15248, found 237.15, Retention time: 0.69 minutes. Preparation of l-(3,4-difluorophenyl -~(N|-(3-isopropoxy-4-moφholino-phenyl - L2,4-triazol-3 -amine (Compound 445)

[00482] 3-Bromo-l-(3,4-difluorophenyl)-l,2,4-triazole (30.2 mg, 0.1 161 mmol), sodium tert-butoxide (45 mg, 0.4682 mmol), 3-isopropoxy-4-morpholino-aniline (Dihydrochloride salt) (53 mg, 0.1714 mmol) and t-ButylXPhos Palladcycle (4 mg, 0.005825 mmol) were weighed into a 4 mL vial. t-Butanol (0.75 mL) and 1,4- dioxane (0.25 mL) were added, and the vial was sealed and stirred at 50 °C overnight. The reaction mixture was cooled to room temperature, treated with DMSO (1.5 mL) and filtered through a 25 μπι filter plate. The filtrate was purified by by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient using a trifluoroacetic acid modifier). The pure fractions were combined and concentrated to dryness under reduced pressure. The solid was diluted with methanol (5 mL) and treated with 6N hydrochloric acid (0.5 mL) to give the hydrochloric acid salt. This sample was concentrated to dryness under reduced pressure to give l-(3,4- difluorophenyl)-N-(3-isopropoxy-4-mo holino-phenyl)-l,2,4-triazol-3-amine hydrochloride (17.4 mg, 0.03754 mmol, 32%). ¾ NMR (300 MHz, OMSO-de) δ 9.14 (s, 1H), 8.06 - 7.88 (m, 1H), 7.78 - 7.52 (m, 4H), 7.22 (dd, J = 8.9, 2.3 Hz, 1H), 4.76 (p, J = 6.0 Hz, 1H), 4.01 (d, J = 4.8 Hz, 4H), 3.61 (s, 4H), 1.46 (d, J = 6.0 Hz, 6H) ppm. ESI-MS m/z calc. 415.18198, found 416.36 (M+l) ⁺ ; Retention time: 2.87 minutes.

[00483] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 23, the following compounds can be synthesized from the appropriate intermediates; 9, 10, 12 and 446. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 24

Preparation of methyl 2-methoxy-5-|Yl -phenyl- L2,4-triazol-3-yl)amino ^" |benzoate (Compound 88); 2-methoxy-N.N-dimethyl-5-r( ^" l-phenyl-1.2.4-triazol-3- vDaminolbenzamide (Compound 100); and 2-methoxy-5 (l-phenyl-L2,4-triazol-3- yl)amino ^" |benzoic acid (Compound 109)

RG-20a

Cmpd 88

Cmpd 109

Cmpd 100 (a) Cu(OAc)2, pyridine, 4 A molecular sieves, CH2CI2, RT; (b) BrettPhos

Palladacycle, 1,4-dioxane, NaOtBu, 110 °C; (c) Li OH (2M, aq.), THF; (d) DMF, TEA, HATU. Preparation of methyl 2-methoxy-5-|Yl -phenyl- L2,4-triazol-3-yl)amino ^" |benzoate (Compound 88)

[00484] A mixture of 3 -bromo-1 -phenyl- 1,2,4-triazole (500 mg, 2.232 mmol), methyl 5-amino-2-methoxy-benzoate (approximately 525.8 mg, 2.902 mmol) and sodium tert-butoxide (approximately 643.5 mg, 6.696 mmol) were mixed in 1,4- dioxane (approximately 15.8 mL) and the mixture was degassed with nitrogen for 15 minutes. A catalytic amount of Brettphos Palladacycle was added. The mixture was heated in a sealed tube at 110 °C for 8 hours, filtered through Celite, dried down under reduced pressure and purified by silica gel chromatography (40 g column; 0- 100% ethyl acetate/hexanes). The desired fractions were combined and concentrated to dryness to give methyl 2-methoxy-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzoate (484.4 mg, 1.464 mmol, 65.58). ¹ H MR (300 MHz, CDCh) δ 8.35 (s, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.84 (dd, J = 8.9, 3.0 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 6.68 (s, 1H), 3.93 (d, J = 5.9 Hz, 6H) ppm. ESI-MS m/z calc. 324.12225, found 325.23 (M+l) ⁺ ; Retention time: 0.8 minutes.

Preparation of 2-methoxy-5-[(l-phenyl-L2,4-triazol-3-yl)amino ^" |benzoic acid (Compound 109)

[00485] Lithium hydroxide (approximately 771.0 μΐ _^ of 2M aq. soln, 1.542 mmol) was added to a stirred solution of methyl 2-methoxy-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]benzoate (250 mg, 0.7708 mmol) in tetrahydrofuran (5.0 mL) and the reaction was stirred at ambient temperature for 1 hour. The reaction was quenched with 1M HCl and extracted thrice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The solid was purified by reverse phase chromatography (50 g C18 column (ISCO); 0-100% acetonitrile/water). The desired fractions were combined and concentrated to dryness under reduced pressure to give 2-methoxy-5-[(l-phenyl- l,2,4-triazol-3-yl)amino]benzoic acid (185.5 mg, 56.8%). ¾ MR (300 MHz, CDCh) δ 8.27 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 4.09 (s, 3H) ppm. ESI-MS m/z calc. 310.1066, found 311.23 (M+l) ⁺ ; Retention time: 0.75 minutes.

Preparation of 2-methoxy-N,N-dimethyl-5-r(l -phenyl- L2,4-triazol-3- vDaminolbenzamide (Compound 100)

[00486] To a solution of 2-methoxy-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzoic acid (30 mg, 0.08651 mmol), N-methylmethanamine (hydrochloride salt)

(approximately 10.58 mg, 11.28 jiL, 0.1298 mmol) and HATU (approximately 49.35 mg, 0.1298 mmol) in dimethylformamide (627.2 μΐ.) was added triethylamine (approximately 29.18 mg, 40.19 μΐ _^ , 0.2884 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was carefully diluted with saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate (3 X 2 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by reverse phase chromatography (CI 8 column (ISCO); 20-95% acetonitrile/water). The desired fractions were combined and concentrated to dryness under reduced pressure and the salt was removed by passage through a NaHCCb SPE cartridge to give 2-methoxy- N,N-dimethyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]benzamide (15.6 mg, 0.04531 mmol, 52%). ¾ MR (300 MHz, CDCh) δ 8.32 (s, 1H), 7.72 - 7.64 (m, 3H), 7.55 - 7.47 (m, 2H), 7.41 - 7.32 (m, 2H), 6.97 - 6.90 (m, 1H), 3.84 (s, 3H), 3.15 (s, 3H), 2.91 (s, 3H) ppm. ESI-MS m/z calc. 337.15387, found 338.06 (M+l) ⁺ ; Retention time: 0.74 minutes.

[00487] Using the general synthetic scheme outlined in Schemes A and B and using procedures analogous to those described in Example 24, the following compounds can be synthesized from the appropriate intermediates; 101-103 and 106- 108. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 25

Preparation of N-r4-(3-furyl)-3-methoxy-phenyl1-l-phenyl-L2,4-triazol-3-ami ne (Compound 117); N-(3-methoxy-4-tetrahydrofuran-3-yl-phenyl)-l -phenyl- 1,2,4- triazol-3 -amine (Compound 118); re/-N-[3-methoxy-4-[(3S)-tetrahydrofuran-3- vHphenyll-1 -phenyl- l,2,4-triazol-3 -amine (Compound 126) and rg/-N-[3-methoxy-4- r(3R)-tetrahvdrofuran-3-yl1phenyl1-l-phenyl-L2,4-triazol-3-a mine (Compound 127)

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Pd(PPh ₃ , K2CO3, 90 °C; (c) 50 psi, H ₂ , MeOH; (d) ZantPhos, Pd ₂ (dba) ₃ , dioxane, NaOtBu, 110°C; (e) SFC.

Preparation of 3-(2-methoxy-4-nitro-phenyl)furan (RG-25b)

[00488] l-Bromo-2-methoxy-4-nitro-benzene (20.47 g, 88.22 mmol) and 3- furylboronic acid (approximately 11.85 g, 105.9 mmol) were dissolved in 1,4-dioxane (100 mL) and treated with potassium carbonate (118 mL of 3 M, 354.0 mmol). The mixture was degassed for 10 minutes with nitrogen, then

tetrakis(triphenylphosphine)palladium(0) (approximately 3.364 g, 2.911 mmol) was added and the round bottom flask was placed under nitrogen and heated to 90 °C overnight. The product does not ionize in the LC/MS. The reaction mixture was diluted with dichloromethane and washed with water. The organics were dried with magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to yield 3-(2-methoxy-4-nitro-phenyl)furan (22 g, 97%). ¾ NMR (400 MHz, DMSO- d ₆ ) δ 8.36 (m, 1H), 7.94 - 7.76 (m, 4H), 7.16 - 7.09 (m, 1H), 4.03 (s, 3H) ppm. Preparation of 3-methoxy-4-tetrahydrofuran-3-yl-aniline (RG-25c)

[00489] 3-(2-Methoxy-4-nitro-phenyl)furan (15.2 g, 69.35 mmol) was dissolved in methanol (230 mL) and degassed with nitrogen. Added 10% palladium on carbon (wet) (14 g, 6.578 mmol) and degassed with nitrogen for another few minutes. The sample was placed on a Parr shaker under hydrogen (45 psi) of hydrogen. After 6 hours, full conversion to the aniline, but very little conversion to the tetrahydrofuran analogue (-5%) was observed. Another 0.1 equivalents of 10% Palladium on carbon was added to the reaction mixture and the reaction was maintained under hydrogen (50 psi) over the weekend. Complete conversion to the desired product was observed. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to dryness, diluted with dimethylsulfoxide (10 mL) and purified by reverse phase chromatography (275 g Aq CI 8 column (ISCO); 0-50% acetonitrile/water with a trifluoroacetic acid modifier). The desired fractions were combined and concentrated to dryness under reduced pressure to yield 3-methoxy-4- tetrahydrofuran-3-yl-aniline (8.1 g, 60%). ¾ NMR (400 MHz, DMSO-^e) δ 6.83 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 6.10 (dd, J = 8.1, 2.1 Hz, 1H), 4.95 (s, 2H), 3.95 - 3.87 (m, 1H), 3.84 (td, J = 8.1, 4.8 Hz, 1H), 3.73 (m, 1H), 3.68 (s, 3H), 3.48 - 3.35 (m, 2H), 2.08 (m, 1H), 1.94 - 1.73 (m, 1H) ppm. ESI-MS m/z calc. 193.11028, found 193.99 (M+l) ⁺ ; Retention time: 0.52 minutes. Preparation of N-[4-(3-furyl)-3-methoxy-phenyll-l-phenyl-L2,4-triazol-3-ami ne

(Compound 117) and N-(3-methoxy-4-tetrahvdrofuran-3-yl-phenyl)-l -phenyl- 1,2,4- triazol-3 -amine (Compound 118) [00490] A mixture of 3-methoxy-4-tetrahydrofuran-3-yl-aniline (127.7 mg, 0.6607 mmol), 4-(3-furyl)-3-methoxy-aniline (150 mg, 0.7928 mmol), 3-bromo-l-phenyl- 1,2,4-triazole (approximately 148.0 mg, 0.6607 mmol) and sodium tert-butoxide (approximately 127.0 mg, 1.321 mmol) were mixed in 1,4-dioxane. The mixture was degassed for 5 minutes with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (approximately 60 mg, 0.066 mmol) and dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphine (approximately 38 mg, 0.066 mmol) were added. The tube was sealed and heated at 1 10 °C overnight. The reaction mixture was cooled to room temperature and filtered through Celite, and the residue was purified by reverse phase chromatography to provide two compounds: N-[4-(3-furyl)- 3-methoxy-phenyl]-l-phenyl-l,2,4-triazol-3-amine (14.7 mg); ¾ MR (300 MHz, CDCh) δ 8.36 (s, 1H), 7.95 (dd, J = 1.6, 0.8 Hz, 1H), 7.77 - 7.64 (m, 2H), 7.59 - 7.30 (m, 6H), 7.06 (dd, J = 8.3, 2.2 Hz, 1H), 6.99 (s, 1H), 6.78 (dd, J = 1.9, 0.8 Hz, 1H), 3.99 (s, 3H) ppm. ESI-MS m/z calc. 332.12732, found 333.45 (M+l) ⁺ ; Retention time: 3.31 minutes; and N-(3-methoxy-4-tetrahydrofuran-3-yl-phenyl)-l -phenyl - l,2,4-triazol-3 -amine (38.6 mg). ¹ H MR (300 MHz, CDCh) δ 8.37 (s, 1H), 7.79 - 7.63 (m, 2H), 7.59 - 7.45 (m, 2H), 7.45 - 7.31 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.90 (s, 1H), 4.21 - 4.10 (m, 1H), 4.04 (td, J = 8.2, 5.1 Hz, 1H), 3.91 (s, 3H), 3.75 - 3.67 (m, 2H), 2.28 (dtd, J = 12.2, 7.2, 5.1 Hz, 1H), 2.12 - 1.98 (m, 1H), 1.97 - 1.81 (m, 1H) ppm. ESI-MS m/z calc. 336.15863, found 337.48 (M+l) ⁺ ; Retention time: 3.1 minutes.

Preparation of re/-N-r3-methoxy-4-IY3 S)-tetrahydrofuran-3-yl1phenyl1-l -phenyl- l,2,4-triazol-3 -amine (Compound 126) and re/-N-r3-methoxy-4-r(3R)- tetrahydrofuran-3-yl ^" |phenyl ^" |-l -phenyl- L2,4-triazol-3 -amine (Compound 127)

[00491] N-(3-Methoxy-4-tetrahydrofuran-3-yl-phenyl)-l -phenyl- l,2,4-triazol-3 - amine (23 mg, 0.06828 mmol) was resolved by SFC on an IA column using 40% ethanol in supercritical CO2 to obtain two enantiomers. Peak A was arbitrarily assigned as the S-isomer while peak B was arbitrarily assigned as the R-isomer. Peak A was concentrated to dryness to yield re/-N-[3-methoxy-4-[(3 S)-tetrahydrofuran-3- yl]phenyl]-l -phenyl- l,2,4-triazol-3 -amine (8.8 mg, 67%). ¾ NMR (400 MHz, OMSO-de) δ 9.42 (s, 1H), 9.09 (s, 1H), 7.91 - 7.80 (m, 2H), 7.55 (dd, J = 8.5, 7.4 Hz, 2H), 7.42 (d, J = 2.1 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 3.97 (t, J = 7.1 Hz, 1H), 3.89 (td, J = 8.2, 5.0 Hz, 1H), 3.84 - 3.70 (m, 4H), 3.51 (dt, J = 22.8, 7.6 Hz, 2H), 2.16 (dtd, J = 12.3, 7.4, 4.9 Hz, 1H), 1.92 (dq, J = 12.1, 7.8 Hz, 1H) ppm. ESI-MS m/z calc. 336.15863, found 337.36 (M+l) ⁺ ; Retention time: 0.83 minutes. Peak B was concentrated to dryness to yield re/-N-[3-methoxy-4-[(3R)-tetrahydrofuran-3-yl]phenyl]-l -phenyl- l,2,4-triazol-3- amine (8.7 mg, 69%). ¹ H MR (400 MHz, DMSO-^e) δ 9.42 (s, 1H), 9.08 (s, 1H),

7.88 - 7.80 (m, 2H), 7.59 - 7.51 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.97 (t, J = 7.0 Hz, 1H),

3.89 (td, J = 8.1, 4.9 Hz, 1H), 3.84 - 3.71 (m, 4H), 3.52 (dq, J = 22.8, 7.6 Hz, 2H), 2.16 (dtd, J = 12.2, 7.4, 4.9 Hz, 1H), 1.92 (dq, J = 12.1, 7.8 Hz, 1H) ppm. ESI-MS m/z calc. 336.15863, found 337.4 (M+l) ⁺ ; Retention time: 0.83 minutes.

[00492] Using the general synthetic scheme outlined in Schemes A and B and procedures analogous to those described in Example 25, the following compounds can be synthesized from the appropriate intermediates but without optional enantiomer sepraration by SFC; 58, 128, 132, 133, 150-152, 156, 157 and 162. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 26

Preparation of 2-methyl-N-(l -phenyl- L2,4-triazol-3-yl)-5-r(3R)-tetrahy drofuran-3- yllpyridin-3 -amine (Compound 256)

Cmpd 256

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b)Pd(PPri3)4, dioxane, Na ₂ C0 ₃ , 80 °C; (c) 250 psi, H ₂ , methanol, 10% Palladium on carbon, 10% Platinum on carbon; (d) SFC (e) tBuOH, t-ButylXPhos Palladacycle, NaOtBu, 50 °C.

Preparation of 5-(3-furyl)-2-methyl-3-nitro-pyridine (RG-26b)

[00493] 5-Bromo-2-methyl-3-nitro-pyridine (5 g, 23.0 mmol) and 3-furylboronic acid (2.85 g, 25.3 mmol) were dissolved in 1,4-dioxane (75 mL) and purged with nitrogen for several minutes. During the purge, a 2M sodium carbonate solution (20 mL) was added, followed by tetrakis(triphenylphosphine)palladium (0) (2.7 g, 2.34 mmol). The flask was sealed and the reaction was heated in a sand bath to 80 °C for 3.0 hours. The reaction was cooled and the solvent was removed under reduced pressure. The resulting residue was partitioned between water and dichloromethane and the organic phase was washed with brine, dried on sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-100% dichloromethane/(10% methanol/dichloromethane). The purification was repeated on the same support (0-100% dichloromethane/(5% methanol/dichloromethane) to yield 5-(3-furyl)-2-methyl-3-nitro-pyridine (1.8 g, 30%) (contains some impurities; was taken forward as is). ESI-MS m/e calc. 204.05, found 205.05 (M+l) ⁺ ; Retention time: 0.79 minutes.

Preparation of 2-methyl-5-tetrahydrofuran-3-yl-pyridin-3-amine (RG-26c)

[00494] 5-(3-Furyl)-2-methyl-3-nitro-pyridine (1.8 g, 8.82 mmol) was dissolved in methanol (100 mL) treated with 10% palladium on carbon (500 mg) and platinum oxide (500 mg). The mixture was placed in a steel bomb and subjected to 250 psi hydrogen for 12 hours. The pressure at the end of the reaction was reduced by -75-80 psi during the course of the reaction. The crude mixture of product and starting material was isolated, new portions of catalyst were added, and hydrogenation was continued at 250 psi of hydrogen. A 50 psi reduction in pressure was noted from the initial pressure. The reaction mixture was filtered through a pad of diatomaceous earth, the pad was washed with methanol and the filtrate was concentrated to an oil under reduced pressure. The crude material was azeotroped with chloroform to provide 2-methyl-5-tetrahydrofuran-3-yl-pyridin-3-amine (1.7 g, contains -10% chloroform, 86%). ¹ H MR (400 MHz, CDCh) δ 7.84 (d, J = 1.8 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.98 - 3.81 (m, 1H), 3.71 (dd, J = 8.5, 6.8 Hz, 1H), 3.40 - 3.25 (m, 1H), 2.48 - 2.28 (m, 1H), 2.41(s, 3H), 1.95 (dq, J = 12.4, 7.8 Hz, 1H) ppm. ESI-MS m/e calc. 178.11, found 179.10 (M+l) ⁺ ; Retention time: 0.39 minutes.

Preparation of rg/-2-methyl-5-[(3R)-tetrahydrofuran-3-yllpyridin-3-amine (RG-26d- a]

and re/-2-methyl-5-r(3 S)-tetrahydrofuran-3-vHpyridin-3 -amine (RG-26d-b)

[00495] Racemic product from above reaction was submitted for SFC separation into the two enantiomers. The separation was carried out on an AD (4.6 xlOO mm) column using 24% methanol /0.2% diethylamine/75%) carbon dioxide. The first peak, peak A (retention time 0.767 minutes) was arbitrarily assigned as the (R) enantiomer. The second peak, peak B (retention time 0.854 minutes) was arbitrarily assigned as the (S) enantiomer.

Preparation of rg/-2-methyl-N-(l-phenyl-L2,4-triazol-3-yl)-5-r(3R)-tetrahyd rofuran- 3-vHpyridin-3-amine (Compound 256)

[00496] 3 -Bromo-1 -phenyl- 1,2,4-triazole (94 mg, 0.42 mmol) and re/-3-amino-2- methyl-5-[(R)-tetrahydrofuran-3-yl)pyridine (75 mg, 0.42 mmol) were dissolved in dry tert-butanol (10 mL) and purged with nitrogen for several minutes. During the purge, chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (30 mg, 0.042 mmol) was added, followed by sodium tert-butoxide (60 mg, 0.63 mmol). The reaction was stirred at 50 °C under a nitrogen atmosphere for two hours, then diluted with methanol and the solvents were removed under reduced pressure. The crude residue was partitioned between dichloromethane and water, the organic phase was washed with brine, dried on anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography

(dichloromethane, then 2.5% methanol/dichloromethane (0.1% ammonium

hydroxide), then 2.5% methanol/dichloromethane (0.1% ammonium hydroxide)). The product was dissolved in dichloromethane and treated with 2M ethereal hydrochloric acid. The mixture was diluted with hexanes and the solvents were removed under reduced pressure. The resulting solid was triturated with hot hexanes, cooled and filtered to yield re/-2-methyl-N-(l-phenyl-l,2,4-triazol-3-yl)-5-[(3R)- tetrahydrofuran-3-yl]pyridin-3 -amine (48 mg white solid, 25.8%>) - relative enantiomeric structure arbitrarily assigned. ¾ MR (400 MHz, DMSO- de) δ 9.68 (s, 1H), 9.27 (s, 1H), 9.10 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.88 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 4.14 - 3.95 (m, 2H), 3.84 (dd, J = 15.3, 8.0 Hz, 1H), 3.76 - 3.59 (m, 3H), 2.77 (s, 3H), 2.48 - 2.34 (m, 1H), 1.97 (dt, J = 20.7, 6.7 Hz, 1H) ppm: - methylene peaks partially obscured by water peak. ESI-MS m/e calc. 321.16, found 322.22 (M+l) ⁺ ; Retention time: 0.56 minutes.

[00497] The following compound can be synthesized from the appropriate intermediates according to general Schemes A and B, using procedures analogous to those described in Example 26, where the final step was performed on the opposite enantiomer obtained from the SFC separation; 257. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00498] The following compounds can be synthesized from the appropriate intermediates according to general Schemes A and B, using procedures analogous to those described in Example 26, except no chiral separation of intermediates is performed; 181, 182 and 188-190.

[00499] The following compounds can be synthesized from appropriately substituted 4-nitro pyridines, according to general Schemes A and B, using procedures analogous to those described in Example 26. No chiral separation of intermediates is performed; 241-243. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 27

Preparation of N-(3-methoxy-4-pyrrolidin-3-yl -phenyl)-! -phenyl- 1,2,4-triazol -3- amine (Compound 129) H3-r2-methoxy-4-rn-phenyl-l,2,4-triazol-3- yl)amino1phenyl1pyrrolidin-l-vHethanone (Compound 130)

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Pd(PPh ₃ ) ₄ , 1,4- dioxane, Na ₂ C0 ₃ ; (c) 50 psi, H ₂ , MeOH; (d) 1,4-dioxane, Pd ₂ (dba) ₃ , Xantphos, NaOtBu, 110 °C; (e) 4N HC1 in 1,4-dioxane; (f) DCM, TEA, RT.

Preparation of fert-butyl 3-(2-methoxy-4-nitro-phenyl)-2,5-dihydropyrrole-l- carboxylate (RG-27b) [00500] In a microwave tube, l-bromo-2-methoxy-4-nitro-benzene (292 mg, 1.258 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5- dihydropyrrole-l-carboxylate (409 mg, 1.386 mmol) were mixed with dioxane (5 mL) and potassium carbonate (2 mL of 2 M, 4.000 mmol) was added. The mixture was degassed with nitrogen for 5 minutes and tetrakis(triphenylphosphine)palladium(0) (135 mg, 0.1168 mmol) was added. The mixture was sealed and heated at 110 °C overnight. The reaction was cooled to room temperature, filtered through Celite and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (40 g column; 0-60% ethyl acetate/hexane) to afford tert- butyl 3-(2-methoxy-4-nitro-phenyl)-2,5-dihydropyrrole-l-carboxylat e (38 0 mg, 94%). ESI-MS m/z calc. 320.1372, found 321.52 (M+l) ⁺ ; Retention time: 0.9 minutes.

Preparation of fert-butyl 3-(4-amino-2-methoxy-phenyl)pyrrolidine-l-carboxylate (RG-27c)

[00501] In a 25 mL round botton flask, tert-butyl 3-(2-methoxy-4-nitro-phenyl)- 2,5-dihydropyrrole-l-carboxylate (380 mg, 1.186 mmol) was dissolved in ethanol (4 mL), to which 10% Palladium on carbon (approximately 126.2 mg, 0.1186 mmol) was added. A three-way adapter was put on top of the flask connected to a hydrogen balloon and vacuum. The system was flushed with hydrogen three times by exhausting with vacuum pump and refilling with hydrogen through the 3 -way connector. This mixture was stirred at room temperature under a hydrogen balloon overnight. The mixture was filtered through pre-packed Celite (4 g, wet with methanol) and washed with methanol (10 mL). The combined filtrates were concentrated under reduced pressure to afford tert-butyl 3-(4-amino-2-methoxy- phenyl)pyrrolidine-l-carboxylate (328 mg, 95%) ESI-MS m/z calc. 292.17868, found 293.48 (M+l) ⁺ ; Retention time: 0.76 minutes.

Preparation of fert-butyl 3-[2-methoxy-4-|Yl-phenyl-L2,4-triazol-3- vDaminolphenvHpyrrolidine-l-carboxylate (Compound 128)

[00502] A mixture of 1,4-dioxane (5 mL), tert-butyl 3-(4-amino-2-methoxy- phenyl)pyrrolidine-l-carboxylate (314 mg, 1.074 mmol), 3 -bromo-1 -phenyl- 1,2,4- triazole (approximately 200.5 mg, 0.8950 mmol), and sodium tert-butoxide (approximately 172.0 mg, 1.790 mmol) was degassed for 5 minutes with nitrogen, then tris(dibenzylideneacetone)dipalladium (approximately 81 mg, 0.089 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (approximately 51 mg, 0.089 mmol) were added. The tube was sealed and the mixture was heated at 110 °C overnight. After the reaction was cooled to room temperature, the mixture was filtered through pre-packed Celite (10 g, wet with methanol). The Celite pad was washed with methanol (10 mL) and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column; 0-50 % ethyl acetate/hexane) to afford tert-butyl 3-[2-methoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]pyrrolidine-l-carboxylate (250 mg, 59%). ¾ MR (300 MHz,

CDCh) δ 8.35 (s, 1H), 7.79 - 7.61 (m, 2H), 7.60 - 7.44 (m, 2H), 7.46 - 7.32 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 7.00 (dd, J = 8.2, 2.2 Hz, 1H), 6.84 (s, 1H), 3.91 (s, 3H), 3.89 - 3.49 (s, 3H), 3.49 - 3.16 (m, 2H), 2.17 (s, 1H), 2.14 - 1.91 (m, 1 H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 435.22705, found 436.41 (M+l) ⁺ ; Retention time: 0.87 minutes.

Preparation of N-(3-m ethoxy-4-pyrrolidin-3-yl-phenyl)-l -phenyl- L2,4-triazol-3- amine (Compound 129)

[00503] To fert-butyl 3-[2-methoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]pyrrolidine-l-carboxylate (80 mg, 0.1837 mmol) in a 20 mL scintillation vial with stir bar, HC1 (3 mL of 4 M, 12.00 mmol) in dioxane was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC with the (10-90 % acetonitrile/water with a trifluoroacetic acid modifier). The desired fractions were concentrated to dryness, then the product was dissolved in methanol (1 mL) and passed through a sodium bicarbonate cartridge. The cartridge was washed with additional methanol (3 mL). The combined filtrates were concentrated under reduced pressure to afford N-(3-methoxy-4-pyrrolidin-3-yl-phenyl)-l -phenyl- 1,2,4- triazol-3 -amine (52 mg, 84%). ¹ H MR (300 MHz, Methanol-^) δ 8.81 (s, 1H), 7.87 - 7.74 (m, 2H), 7.62 - 7.44 (m, 3H), 7.45 - 7.30 (m, 1H), 7.22 - 7.07 (m, 2H), 3.92 (s, 3H), 3.78 - 3.47 (m, 3H), 3.28 - 3.11 (m, 2H), 2.43 - 2.13 (m, 2H) ppm. ESI-MS m/z calc. 335.17462, found 336.37 (M+l) ⁺ ; Retention time: 0.65 minutes. Preparation of l-[3-[2-methoxy-4-[(l-phenyl-L2,4-triazol-3- yl)amino1phenyl1pyrrolidin-l-yl1ethanone (Compound 130)

[00504] Dichloromethane (2 mL) was added to N-(3-methoxy-4-pyrrolidin-3-yl- phenyl)-l -phenyl- l,2,4-triazol-3 -amine (21 mg, 0.06225 mmol) followed by triethylamine (18 μΐ _^ , 0.1291 mmol) and acetyl chloride (5 μΐ _^ , 0.07032 mmol). The mixture was stirred at room temperature sealed for 2 hours. The solvent was removed under reduced pressure and the crude product was purified by reverse phase HPLC (10-90 % acetonitrile/water with a tnfluoroacetic acid modifier). The desired fractions were concentrated to dryness, then the product was dissolved in methanol (1 mL) and passed through a sodium bicarbonate cartridge. The cartridge was washed with additional methanol (3 mL). The combined filtrates were concentrated under reduced pressure to afford l-[3-[2-methoxy-4-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]pyrrolidin-l-yl] ethanone (5.5 mg, 22%). ¾ MR (300 MHz, Methanol-^) δ 8.83 (s, 1H), 7.94 - 7.75 (m, 2H), 7.63 - 7.47 (m, 2H), 7.48 - 7.28 (m, 2H), 7.21 - 7.02 (m, 2H), 3.90 (d, J = 2.9 Hz, 3H), 3.83 - 3.51 (m, 3H), 3.53 - 3.37 (m, 2H), 2.34 - 2.13 (m, 2H), 2. 0 8 (d, J = 3.3 Hz, 3H) ppm. ESI-MS m/z calc.

377.18518, found 378.4 (M+l) ⁺ ; Retention time: 0.81 minutes.

[00505] The following compounds can be synthesized from the appropriate intermediates according to general Schemes A and B, using procedures analogous to those described in Example 27; 141, 142 and 147. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00506] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, using procedures analogous to those described in Example 27, but with a 1,3 instead of a 1,4 relationship between the nitro and the halogen group; 153, 158, 180, 247-249 and 252-254. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 28

Preparation of N-(3,5-difluoro-4-tetrahvdrofuran-3-yl-phenyl)-l-phenyl-L2,4 -triazol- 3-amine (Compound 145) and N-r3,5-difluoro-4-(3-furyl)phenyl1-l-phenyl-L2,4- triazol-3 -amine (Compound 146)

RG-28b

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Pd ₂ (dba) ₃ , Xantphos, 1,4-dioxane, NaOtBu, 110 °C; (c) 1,4-dioxane, K2CO3, Pd(PPh ₃ ) ₄ , 160 °C; (d) Pt0 ₂ , AcOH, EtOH, H ₂ (50 psi). Preparation of N-(4-bromo-3,5-difluoro-phenyl)-l -phenyl- l,2,4-triazol-3 -amine (RG- 28b)

[00507] In a 20 mL microwave tube, 3 -bromo-1 -phenyl- 1,2,4-triazole (365 mg, 1.629 mmol), 4-bromo-3,5-difluoro-aniline (406 mg, 1.952 mmol) and sodium tert- butoxide (315 mg, 3.278 mmol) were mixed in 1,4-dioxane (10 mL). The mixture was degassed with nitrogen for 5 minutes then

tris(dibenzylideneacetone)dipalladium(0) (150 mg, 0.1638 mmol) and dicyclohexyl- [2-(2,4,6-triisopropylphenyl)phenyl]phosphine (95 mg, 0.1642 mmol) were added. The tube was sealed and the mixture was heated at 110 °C overnight. The reaction mixture was cooled to room temperature and filtered through pre-packed Celite (20 g, wet with methanol). The Celite plug was washed with methanol (15 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (40 g column; 0-60% ethyl acetate/hexane) to afford N-(4-bromo-3,5-difluoro-phenyl)-l-phenyl-l,2,4-triazol-3-ami ne (182 mg, 32%). ESI-MS m/z calc. 349.99786, found 353.15 (M+l) ⁺ ; Retention time: 0.87 minutes.

Preparation of N- [3 , 5 -difluoro-4-(3 -furyPphenyll - 1 -phenyl- 1 ,2,4-triazol-3 -amine (Compound 146)

[00508] In a 5 mL microwave tube, N-(4-bromo-3,5-difluoro-phenyl)-l-phenyl- l,2,4-triazol-3 -amine (67 mg, 0.1908 mmol), and 3-furylboronic acid (32 mg, 0.2860 mmol) were mixed in 1,4-dioxane (2 mL). An aqueous solution of potassium carbonate (1 mL of 2 M, 2.0 mmol) was added and the mixture was degassed with nitrogen for 5 minutes. Tetrakis (triphenylphosphine)palladium(O) (22 mg, 0.01904 mmol) was added and the tube was sealed and heated in the microwave at 160 °C for 10 minutes. After cooling to room temperature, the mixture was filtered through prepacked Celite (4 g, wet with methanol) and the Celite was washed with additional methanol (5 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column; 0-60% ethyl acetate/hexane) to afford N-[3,5-difluoro-4-(3-furyl)phenyl]-l-phenyl-l,2,4- triazol-3 -amine (50 mg, 77%). ¾ MR (300 MHz, CDCh) δ 8.39 (s, 1H), 7.90 (qd, J = 1.8, 0.8 Hz, 1H), 7.80 - 7.66 (m, 2H), 7.62 - 7.49 (m, 3H), 7.47 - 7.36 (m, 1H), 7.30 (d, J = 3.1 Hz, 2H), 7.27 - 7.19 (m, 1H), 6.91 (qd, J = 1.9, 0.8 Hz, 1H) ppm.

Preparation of N-(3,5-difluoro-4-tetrahvdrofuran-3-yl-phenyl)-l-phenyl-L2,4 -triazol- 3 -amine (Compound 145)

[00509] In a 100 mL hydrogenation flask, N-[3,5-difluoro-4-(3-furyl)phenyl]-l- phenyl-l,2,4-triazol-3 -amine (50 mg, 0.1478 mmol) was dissolved in ethanol (10 mL) and the system was flushed with nitrogen and treated with platinum oxide (5 mg, 0.02202 mmol), followed by a drop of acetic acid. The mixture was put on a Parr shaker for hydrogenation at 50 psi for three days. The mixture was filtered through pre-packed Celite (5 g, wet with methanol) and the Celite pad was washed with additional methanol (5 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (10-90%

acetonitrile/water with a trifluoroacetic acid modifier). The desired fractions were dried down under reduced pressure. The product was dissolved in methanol (1 mL) and passed through a sodium bicarbonate cartridge. The cartridge was washed with additional methanol (3 mL) and the combined filtrate was concentrated to dryness under reduced pressure to afford N-(3,5-difluoro-4-tetrahydrofuran-3-yl-phenyl)-l- phenyl-l,2,4-triazol-3 -amine (3.2 mg, 12%). ¾ NMR (300 MHz, CDCh) δ 8.56 (s, 1H), 8.49 (s, 1H), 7.80 - 7.65 (m, 2H), 7.58 (ddd, J = 8.1, 7.0, 1.3 Hz, 2H), 7.53 - 7.38 (m, 1H), 7.27 - 7.08 (m, 2H), 4.16 - 4.05 (m, 2H), 3.98 (q, J = 7.6 Hz, 1H), 3.88 - 3.57 (m, 2H), 2.43 - 2.11 (m, 2H) ppm. ESI-MS m/z calc. 342.1292, found 343.3 (M+l) ⁺ ; Retention time: 0.85 minutes.

[00510] The following compound can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 28; 138. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 29 Preparation of l-(3,5-difluorophenyl)-N-(5-isopropoxy-2-methyl-phenyl)-L2,4 - triazol-3 -amine (Com ound 375)

(a) HMPA, K2CO3, 112 °C; (b) t-BuXPhos Palladacycle, 1,4-dioxane, tBuOH, NaOtBu, 50 °C.

Preparation of l-(3,5-difluorophenyl)-N-(5-isopropoxy-2-methyl-phenyl)-L2,4 - triazol-3 -amine (Compound 375)

[00511] 5-Isopropoxy-2-methyl-aniline (Hydrochloride salt) (22 mg, 0.1091 mmol), 3-bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (25 mg, 0.09614 mmol), sodium tert-butoxide (28 mg, 0.2914 mmol), and tert-butylXphos Palladcycle (4 mg, 0.005825 mmol) were weighed into a 4 mL vial. tert-Butanol (400.0 iL) and 1,4- dioxane (100.0 iL) were added. The vial was sealed and stirred at 50 °C for 2 hours. The mixture was cooled to room temperature, dimethyl sulfoxide (1.5 mL) was added and the suspension was filtered through a 25 μπι filter plate. The sample was purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient with a trifluoroacetic acid modifier). The pure fractions were concentrated to dryness under reduced pressure on a Genevac EZ2 elite. The sample was diluted with DCM and washed with 50% saturated sodium bicarbonate. The organics were passed through a phase separator and concentrated to dryness under reduced pressure to yield 1 -(3 , 5 -difluorophenyl)-N-(5 -i sopropoxy-2-methyl-phenyl)- 1 ,2,4-triazol-3 -amine (10.0 mg, 30%). ¾ MR (300 MHz, OMSO-de) δ 9.18 (s, 1H), 8.37 (s, 1H), 7.64 - 7.52 (m, 3H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.01 (dd, J = 8.3, 0.8 Hz, 1H), 6.44 (dd, J = 8.2, 2.6 Hz, 1H), 4.53 (hept, J = 6.1 Hz, 1H), 2.20 (s, 3H), 1.29 (d, J = 6.0 Hz, 6H) ppm. ESI-MS m/z calc. 344.14487, found 345.29 (M+l) ⁺ ; Retention time: 4.76 minutes.

[00512] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 29; 13-18, 22-30, 34, 35, 49, 50, 52, 53, 59-61, 72, 83, 107, 120, 122, 123, 134, 185, 187, 251, 270, 274, 292, 310, 31 1, 316-318, 327, 357, 373, 374, 377-412, 423-444, 567-570, 572, 574-576, 590, 592, 593 and 629-633. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00513] The following compound can be synthesized from 2,3-dimethyl-5-nitro- aniline using procedures analogous to those described in Example 29, followed by a nitro reduction step performed under typical conditions (for example palladium on carbon (10% w/w), hydrogen (50 psi), methanol/ethyl acetate); 328. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 30

Preparation of 1 -(3 , 5 -difluorophenyl)-N-(3 -i sopropoxy-4-tetrahydrofuran-3 -yl- phenyl)-l ,2,4-triazol-3 -amine (Compound 284)

RG-22a

(a) HMPA, K2CO3, 112 °C; (b) K2CO3, acetonitrile, reflux; (c) Pd(dppf)Cl ₂ CH2CI2, 1,4-dioxane, Na ₂ C0 ₃ , 130 °C; (d) Pearlman's Catalyst, EtOH, AcOH, H ₂ ; (e) t- BuXPhos Palladacycle, 1,4-dioxane, NaOtBu, 80 °C. Preparation of l-bromo-2-isopropoxy-4-nitro-benzene (RG-30b)

[00514] To a solution of 2-bromo-5-nitro-phenol (2 g, 9.174 mmol) in acetonitrile (10.0 mL) was added 2-iodopropane (approximately 2.495 g, 14.68 mmol), and potassium carbonate (approximately 2.536 g, 18.35 mmol). The resulting mixture was heated to reflux for approximately 2 hours. The reaction mixture was diluted with dichloromethane. After filtration, the filtrate was concentrated under reduced pressure to afford l-bromo-2-isopropoxy-4-nitro-benzene (2.35 g, 93%). ¹ H MR (300 MHz, CDCh) δ 7.75 (d, J = 2.6 Hz, 1H), 7.73 - 7.69 (m, 2H), 4.72 (dt, J = 12.1, 6.1 Hz, 1H), 1.46 (d, J = 6.1 Hz, 6H) ppm. ESI-MS m/z calc. 258.9844, found 260.23 (M+l) ⁺ ; Retention time: 0.98 minutes.

Preparation of 3-(2-isopropoxy-4-nitro-phenyl)-2,5-dihvdrofuran (RG-30c)

[00515] A mixture of l-bromo-2-isopropoxy-4-nitro-benzene (300 mg, 1.084 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxabor olane

(approximately 318.8 mg, 1.626 mmol), [Ι, -

Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with

dichloromethane (approximately 43.82 mg, 0.05420 mmol) and aqueous solution of sodium carbonate (approximately 1.084 mL of 2 M, 2.168 mmol) in 1,4-dioxane (3 mL) was purged with nitrogen for 1 minute and then microwaved at 130 °C for 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water. The organics were separated and concentrated to dryness under reduced pressure. This crude material was purified by silica gel chromatography (12 g column; 5-50% ethyl acetate/hexane). The desired fractions were concentrated to dryness under reduced pressure to give 3-(2-isopropoxy-4-nitro-phenyl)-2,5- dihydrofuran (260 mg, 1.043 mmol, 96.23). ¾ NMR (300 MHz, CDCh) δ 7.79 (dt, J = 5.1, 2.2 Hz, 2H), 7.28 (d, J = 2.1 Hz, 1H), 6.81 - 6.74 (m, 1H), 5.06 (td, J = 4.8, 2.1 Hz, 2H), 4.89 (td, J = 4.8, 2.0 Hz, 2H), 4.79 (dt, J = 12.1, 6.1 Hz, 1H), 1.47 (d, J = 6.0 Hz, 6H) ppm. ESI-MS m/z calc. 249.10011, found 250.33 (M+l) ⁺ ; Retention time: 0.9 minutes. Preparation of 3-isopropoxy-4-tetrahydrofuran-3-yl-aniline (RG-30d)

[00516] A suspension of 3-(2-isopropoxy-4-nitro-phenyl)-2,5-dihydrofuran (260 mg, 1.043 mmol) and 10% palladium on carbon (approximately 222.0 mg, 0.2086 mmol) in methanol (50 mL) was shaken under hydrogen (50psi) for 18 hours.

Concentration of the reaction mixture provided 3-isopropoxy-4-tetrahydrofuran-3-yl- aniline (240 mg, 97%). ESI-MS m/z calc. 221.14159, found 222.38 (M+l) ⁺ ;

Retention time: 0.59 minutes. The material was used directly in the next reaction without further purification. Preparation of 1 -(3 , 5 -difluorophenyl)-N-(3 -i sopropoxy-4-tetrahydrofuran-3 -yl- phenyl)-L2,4-triazol-3 -amine (Compound 284)

[00517] A mixture of 3-isopropoxy-4-tetrahydrofuran-3-yl-aniline (80 mg, 0.3615 mmol) and 3-bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (approximately 112.8 mg, 0.4338 mmol) in 1,4-dioxane (3.0 mL) was purged with nitrogen for several minutes. To this mixture was added chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, - biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle)

(approximately 23.54 mg, 0.03615 mmol), and then sodium tert-butoxide

(approximately 52.11 mg, 0.5422 mmol). The reaction mixture was microwaved at 80 °C for 35 minutes. The reaction was quenched with IN hydrochloric acid (300 uL), diluted with dichlorom ethane (15 mL) and washed with water (2 X 3 mL). The organic layer was filtered through Florisil (5 g) and concentrated to dryness under reduced pressure. The crude material was purified on by silica gel chromatography (12 g column; 10-100%) ethyl acetate/hexane) to give 50 mg of desired product with trace of impurity. The above solid was collected and carefully triturated with methanol (0.5 mL+0.5 mL) to afford l-(3,5-difluorophenyl)-N-(3-isopropoxy-4- tetrahydrofuran-3-yl-phenyl)-l,2,4-triazol-3 -amine (40 mg, 26%). ¾ NMR (400 MHz, CDCb) 6 8.23 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.81 (dd, J = 8.3, 2.2 Hz, 1H), 6.71 (tt, J = 8.7, 2.3 Hz, 1H), 6.60 (s, 1H), 4.63 - 4.51 (m, 1H), 4.14 - 4.03 (m, 1H), 3.94 (qd, J = 7.9, 4.1 Hz, 1H), 3.90 - 3.79 (m, 1H), 3.68 - 3.56 (m, 2H), 2.26 - 2.12 (m, 1H), 1.97 (ddd, J = 15.6, 12.2, 7.9 Hz, 1H), 1.35 (dd, J = 6.0, 2.3 Hz, 6H) ppm. ESI-MS m/z calc. 400.17108, found 401.35 (M+l) ⁺ ; Retention time: 0.98 minutes. [00518] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 30; 276, 278-280, 282, 283, 288 and 289. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 31

Preparation of of N-[3,4-bis(3,6-dihydro-2H-pyran-4-yl)phenyll-l -phenyl- 1,2,4- triazol-3 -amine (Compound 287) and N-[3,4-di(tetrahydropyran-4-yl)phenyl ^" |-l- phenyl- l,2,4-triazol-3 -amine (Compound 291)

Cmpd 291 a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH ₂ C1 ₂ , RT; (b) Pd(dppf)Cl ₂ CH ₂ C1 ₂ , 1,4-dioxane, Na ₂ C0 ₃ , 130 °C; (c) t-BuXPhos Palladacycle, dioxane, NaOtBu, 90 °C; (d) Palladium on carbon, H ₂ , 50 psi, MeOH Preparation of 3,4-bis(3,6-dihydro-2H-pyran-4-yl)aniline (RG-31b)

[00519] A mixture of 3,4-dibromoaniline (220 mg, 0.8768 mmol), 2-(3,6-dihydro- 2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (approximately 405.2 mg, 1.929 mmol), [l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (approximately 35.45 mg, 0.04384 mmol) and an aqueous solution of sodium carbonate (approximately 1.315 mL of 2 M, 2.630 mmol) in 1,4- dioxane (3 mL) was purged with nitrogen for 1 minute and then microwaved at 130 °C for 30 minutes. The reaction mixture was diluted with dichloromethane, methanol and filtered through Florisil (5 g). The filtrate was concentrated to dryness under reduced pressure. The crude was purified by silica gel chromatography (12 g column; 10-100% ethyl acetate/hexane) to give 3,4-bis(3,6-dihydro-2H-pyran-4-yl)aniline (210 mg, 0.8161 mmol, 93.09). ¾ NMR (300 MHz, CDC1 ₃ ) δ 6.99 (d, J = 8.1 Hz, 1H), 6.60 (dd, J = 8.1, 2.5 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 5.75 (tt, J = 2.8, 1.6 Hz, 1H), 5.70 (tt, J = 2.8, 1.6 Hz, 1H), 4.32 - 4.24 (m, 4H), 3.87 (t, J = 5.4 Hz, 4H), 3.68 (s, 2H), 2.37 (qt, J = 5.4, 2.8 Hz, 4H) ppm. ESI-MS m/z calc. 257.14157, found 258.38 (M+l) ⁺ ; Retention time: 0.55 minutes.

Preparation of N-[3,4-bis(3,6-dihydro-2H-pyran-4-yl)phenyll-l-phenyl-L2,4-t riazol- 3 -amine (Compound 287)

[00520] A mixture of 3,4-bis(3,6-dihydro-2H-pyran-4-yl)aniline (205 mg, 0.7966 mmol) and 3 -bromo-1 -phenyl- 1,2,4-triazole (approximately 214.2 mg, 0.9559 mmol) in 1,4-dioxane (12 mL) was purged with nitrogen for several minutes. To the above mixture was added tert-ButylXPhos Palladacyle (approximately 51.88 mg, 0.07966 mmol), and then sodium tert-butoxide (approximately 114.8 mg, 1.195 mmol). The reaction mixture was microwaved at 90 °C for 35 minutes. The reaction was quenched with IN hydrochloric acid (300 uL), diluted with dichloromethane (15 mL) and washed with water (2 X 10 mL). The organic layer was concentrated to dryness under reduce pressure and purified by silica gel chromatography (12 g column; 0-10% methanol/dichloromethane). The desired fractions were combined and concentrated to dryness under reduced pressure to give 75 mg of desired product with trace of impurity. The above solid was collected and carefully triturated with

dichloromethane (2 X 1 mL) then methanol (2 X 1 mL) to afford N-[3,4-bis(3,6- dihydro-2H-pyran-4-yl)phenyl]-l -phenyl- l,2,4-triazol-3 -amine (125 mg, 0.2965 mmol, 37%). ¾ NMR (300 MHz, DMSO- d ₆ ) δ 9.49 (s, 1H), 9.08 (s, 1H), 7.83 (dd, J = 8.6, 1.1 Hz, 2H), 7.64 - 7.50 (m, 3H), 7.36 (dd, J = 13.1, 4.9 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H), 5.83 - 5.63 (m, 2H), 4.29 - 4.05 (m, 4H), 3.77 (q, J = 5.4 Hz, 4H), 2.29 (s, 4H) ppm. ESI-MS m/z calc. 400.1899, found 401.31 (M+l) ⁺ ; Retention time: 0.86 minutes.

Preparation of N-r3,4-di(tetrahvdropyran-4-yl)phenyl1-l-phenyl-L2,4-triazol -3-amine (Compound 291)

[00521] A suspension of N-[3,4-bis(3,6-dihydro-2H-pyran-4-yl)phenyl]-l-phenyl- l,2,4-triazol-3 -amine (87 mg, 0.2064 mmol) and 10% palladium on carbon

(approximately 43.93 mg, 0.04128 mmol) in methanol (50 mL) was shaken under hydrogen (50 psi) for 48hours. The solvent was removed under reduced pressure to give N-[3,4-di(tetrahydropyran-4-yl)phenyl]-l-phenyl-l,2,4-triazo l-3-amine (55 mg, 0.1292 mmol, 62.58). ¾ NMR (300 MHz, CDCh) δ 8.24 (s, 1H), 7.66 - 7.58 (m, 2H), 7.49 - 7.33 (m, 4H), 7.27 (ddd, J = 7.4, 3.9, 1.1 Hz, 1H), 7.16 (s, 1H), 6.58 (s, 1H), 4.13 - 3.93 (m, 4H), 3.61 - 3.42 (m, 4H), 3.08 - 2.87 (m, 2H), 1.96 - 1.73 (m,

4H), 1.57 (dd, J = 28.8, 15.8 Hz, 4H) ppm. ESI-MS m/z calc. 404.22122, found 405.4 (M+l) ⁺ ; Retention time: 0.85 minutes.

[00522] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 31; 281, 285, 285 and 290. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 32

N ⁵ -isopropyl-2-methyl-N ³ -(l -phenyl- L2,4-triazol-3-yl)pyridine-3,5-diamine

(Compound 211)

Cmpd 211

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Pd2(dba) ₃ , Xantphos, THF, NaHMDS, 110 °C; (c) Pd ₂ (dba) ₃ , Xantphos, 1,4-dioxane, NaOtBu, 100 °C. Preparation of N ⁵ -isopropyl-2-methyl-pyridine-3,5-diamine (RG-32b)

[00523] In a 5 mL microwave tube were added 5-bromo-2-methyl-pyridin-3-amine (130 mg, 0.6950 mmol), propan-2-amine (240 μΐ _^ , 2.793 mmol) and tetrahydrofuran (2 mL). The reaction mixture was degassed with nitrogen for 5 minutes.

Tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.07644 mmol) and dicyclohexyl- [2-(2,4,6-triisopropylphenyl)phenyl]phosphine (36 mg, 0.07552 mmol) were added to the mixture, followed by (bis(trimethylsilyl)amino)sodium (3 mL of 1 M, 3.0 mmol). The tube was sealed and the mixture was heated at 110 °C overnight. The reaction mixture was cooled to room temperature and poured into water (5 mL). The reaction mixture was extracted with ethyl acetate (5 X 3 mL) and dichloromethane (2 X 3 mL). The combined organic extracts were concentrated under reduced pressure and the crude product was purified by reverse phase HPLC with (10-90 % acetonitrile/water with a trifluoroacetic acid modifier). The purified fractions were concentrated under vacuum to afford N ⁵ -isopropyl-2-methyl-pyridine-3,5-diamine (43 mg, 37 %). ESI- MS m/z calc. 165.1266, found 166.1 (M+l) ⁺ ; Retention time: 0.51 minutes.

Preparation of N ⁵ -isopropyl-2-methyl-N ³ -(l -phenyl- L2,4-triazol-3-yl)pyridine-3, 5- diamine (Compound 211)

[00524] In a 5 mL microwave tube, 3 -bromo-1 -phenyl- 1,2,4-triazole (29 mg, 0.1294 mmol), N ⁵ -isopropyl-2-methyl-pyridine-3,5-diamine (21 mg, 0.1271 mmol) and sodium tert-butoxide (25 mg, 0.2601 mmol) were mixed in dioxane (2 mL). The mixture was degassed with nitrogen for 5 minutes, then

tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.01201 mmol) and dicyclohexyl- [2-(2,4,6-triisopropylphenyl)phenyl]phosphine (8 mg, 0.01383 mmol) were added. The tube was sealed and the mixture was heated at 100 °C overnight. After cooling to room temperature, the mixture was filtered through pre-packed Celite (4 g, wet with MeOH) and the pad was washed with methanol (5 mL). The combined filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (10-90% acetonitrile/water with a trifluoroacetic acid modifier). The pure fractions were concentrated under vacuum and the resulting product was re- dissolved in methanol (1 mL), passed through a bicarbonate cartridge, then the cartridge was washed with additional methanol (3 mL). The filtrate was concentrated under reduced pressure to afford N ⁵ -isopropyl-2-methyl-N ³ -(l-phenyl-l,2,4-triazol-3- yl)pyridine-3,5-diamine (12 mg, 29%). ¾ MR (300 MHz, Methanol -ί¾) δ 8.90 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.95 - 7.79 (m, 2H), 7.63 - 7.47 (m, 2H), 7.48 - 7.33 (m, 2H), 3.66 (hept, J = 6.4 Hz, 1H), 2.58 (s, 3H), 1.28 (d, J = 6.3 Hz, 6H) ppm. ESI-MS m/z calc. 308.17496, found 309.17 (M+l) ⁺ ; Retention time: 0.64 minutes.

[00525] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 32; 161, 163-165, 169, 170, 175, 186, 212, 213, 244 and 263. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 33

Preparation of 3-[2-[6-methyl-5-[(l-phenyl-L2,4-triazol-3-yl)aminol-3- pyridyllethvHoxetan-3-ol (Compound 217)

Cmpd 217

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Et ₂ H, Cul, PdCl ₂ (PPh ₃ ) ₂ , RT; (c) 10% Pd/C, EtOH, H ₂ ; (d) Pd ₂ (dba) ₃ , Xantphos, 1,4-dioxane, NaOtBu, 110 °C.

Preparation of 3-r2-(6-methyl-5-nitro-3-pyridyl)ethvnyl1oxetan-3-ol (RG-33b) [00526] In a 5 mL microwave tube equipped with a stirring bar was charged diethylamine (3 mL), 5-bromo-2-methyl-3-nitro-pyridine (120 mg, 0.5529 mmol), copper iodide (10 mg, 0.05251 mmol) and dichloropalladium; triphenylphosphine (39 mg, 0.05556 mmol), followed by 3-ethynyloxetan-3-ol (65 mg, 0.6626 mmol). The vial was wrapped with aluminum foil and stirred at room temperature overnight. This mixture was partitioned between ethyl acetate (3 mL) and saturated aqueous sodium carbonate (2 mL). The aqueous was separated and was extracted with ethyl acetate (2 X 4 mL). The combined organic phases were washed with water (1 X 3 mL) and brine (1 X 2 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (4 g column; 0-80 % ethyl acetate/hexane) to afford 3-[2-(6-methyl-5-nitro-3-pyridyl)ethynyl]oxetan-3-ol (52 mg, 40%). ESI-MS m/z calc. 234.06406, found 2 35.1 (M+l) ⁺ ; Retention time: 0.66 minutes.

Preparation of 3-r2-(5-amino-6-methyl-3-pyridyl)ethyl1oxetan-3-ol (RG-33c)

[00527] A 50 mL round bottom flask was charged with 3-[2-(6-methyl-5-nitro-3- pyridyl)ethynyl]oxetan-3-ol (52 mg, 0.2220 mmol) and 10% palladium on carbon (approximately 23 mg, 0.02220 mmol). Ethanol (5 mL) was added, then a three-way adapter was fitted on top of the flask and connected to a hydrogen balloon. The system was flushed with hydrogen three times by exhausting with a vacuum pump and refilling with hydrogen through the 3 -way connector. The mixture was stirred at room temperature under the hydrogen balloon for 2 hours. The mixture was filtered through pre-packed Celite (4 g, wet with methanol) and washed with methanol (10 mL). The solvent was removed under reduced pressure to afford 3-[2-(5-amino-6- methyl-3-pyridyl)ethyl]oxetan-3-ol (19 mg, 41%). ESI-MS m/z ca 1 c. 208.12119, found 209.12 (M+l) ⁺ ; Retention time: 0.27 minutes.

Preparation of 3-r2-r6-methyl-5-r(l-phenyl-L2,4-triazol-3-yl)amino1-3- pyridyllethvHoxetan-3-ol (Compound 217)

[00528] A 5 mL microwave tube fitted with a stirring bar was charged with dioxane (2 mL), 3-[2-(5-amino-6-methyl-3-pyridyl)ethyl]oxetan-3-ol (19 mg, 0.09123 mmol), 3 -bromo-1 -phenyl- 1,2,4-triazole (22 mg, 0.09819 mmol) and sodium tert- butoxide (18 mg, 0.1873 mmol). The mixture was degassed with nitrogen for 5 minutes, then dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (6 mg, 0.01037 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009828 mmol) were added. The tube was sealed and the mixture was heated at 110 °C overnight. After cooling to room temperature, the mixture was filtered through pre-packed Celite (4 g, wet with methanol), and washed with methanol (5 mL). The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (10-90% acetonitrile/water with a trifluoroacetic acid modifier). The pure fractions were concentrated under vacuum and the product was dissolved in methanol (1 mL), passed through a bicarbonate cartridge, then the cartridge was washed with methanol (3 mL). The solvent was removed under reduced pressure to afford 3 -[2- [6- methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]-3-pyridyl]ethy l]oxetan-3-ol (19 mg, 55%). ¹ H MR (300 MHz, Methanol-^) δ 9.21 (d, J = 1.7 Hz, 1H), 8.94 (s, 1H),

8.14 (d, J = 1.7 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.65 - 7.51 (m, 2H), 7.50 - 7.32 (m, 1H), 4.60 (d, J = 6.7 Hz, 2H), 4.57 - 4.40 (m, 2H), 3.03 - 2.86 (m, 2H), 2.76 (s, 3H), 2.3 4 -

2.15 (m, 2H) ppm. ESI-MS m/z calc. 351.169 53, found 352.16 (M+l) ⁺ ; Retention time: 0.57 minutes.

[00529] The following compound can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 33; 218. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00530] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, using procedures analogous to those described in Example 33, except that the reduction of the nitro group is performed under selective conditions that left the alkyne triple bond unchanged (for example iron and ammonium chloride in ethanol/water); 362 and 363. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 34

Preparation of N-ri-(3.5-difluorophenvn-1.2.4-triazol-3-yl1-2-methyl-5-r(l- methyl-4- piperidyl)methyl1pyridin-3 -amine (Compound 233)

(a) HMPA, K2CO3, 112 °C; (b) DMF, PPh ₃ , Pd(OAc) ₂ , KOAc, 100 °C; (c) 4M HC1 in 1,4-dioxane, RT; (d) Formaldehyde, CH3CN, NaBftCN, RT; (e) Palladium on carbon, EtOH, H ₂ ; (f) Pd ₂ (dba) ₃ , Xantphos, 1,4-dioxane, NaOtBu, 110 °C.

Preparation of fert-butyl 4-[(6-methyl-5-nitro-3-pyridyl)methylenelpiperidine-l- carboxylate (RG-34b)

[00531] To a solution of 5-bromo-2-methyl-3-nitro-pyridine (500 mg, 2.304 mmol) in dimethylformamide (10 mL) in a 20 mL microwave tube were added

tiphenylphosphine (121 mg, 0.4613 mmol), palladium acetate (II) (52 mg, 0.2316 mmol), potassium acetate (455 mg, 4.636 mmol), and tert-butyl 4- methylenepiperidine-l-carboxylate (460 mg, 2.332 mmol). The mixture was degassed with nitrogen for 5 minutes. The tube was sealed and heated at 100 °C overnight. The mixture was cooled to room temperature and water (10 mL) was added to the reaction mixture followed by extraction with ethyl acetate (3 X 20 mL). The combined organic fractions were washed with water (1 X 20 mL), brine (1 X 20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography (4 g column; 0-50 % ethyl acetate/hexane) to afford tert-butyl 4-[(6-methyl-5-nitro-3- pyridyl)methylene]piperidine-l-carboxylate (320 mg, 42%). ESI-MS m/z calc.

333.16885, found 334.15 (M+l) ⁺ ; Retention time: 0.8 minutes.

Preparation of 2-methyl-3-nitro-5-(4-piperidylidenemethyl)pyridine (RG-34c)

[00532] tert-Butyl 4-[(6-methyl-5-nitro-3-pyridyl)methylene]piperidine-l- carboxylate (320 mg, 0.9599 mmol) in a scintillation vial with stir bar was treated with HC1 in dioxane (8 mL of 4 M, 32.00 mmol). The mixture was stirred at room temperature for lhour. The solvent was removed under reduced pressure to afford 2- methyl-3-nitro-5-(4-piperidylidenemethyl)pyridine (Hydrochloride salt) (220 mg, 85%). ESI-MS m/z calc. 233.11642, found 23 4.11 (M+l) ⁺ ; Retention time: 0.55 minutes.

Preparation of 2-methyl-5-[(l-methyl-4-piperidylidene)methyll-3-nitro-pyrid ine (RG- 34d)

[00533] 2-Methyl-3-nitro-5-(4-piperidylidenemethyl)pyridine (220 mg, 0.9431 mmol) and formaldehyde (0.6 mL, 21.78 mmol) (37 % in water) were dissolved in acetonitrile (5 mL). Sodium cyanoborohydride (295 mg, 4.694 mmol) was added, followed by a drop of acetic acid. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (10-90% acetonitrile/water with a trifiuoroacetic acid modifier). The solvent was removed under reduced pressure on the Genevac to afford 2-methyl-5-[(l-methyl-4-piperidylidene)methyl]-3-nitro-pyrid ine (trifluoroacetate salt) (131 mg, 13%). ESI-M S m/z calc. 247.13208, found 248.16 (M+l) ⁺ ; Retention time: 0.55 minutes. Preparation of 2-methyl-5-r(l-methyl-4-piperidyl)methyl1pyridin-3-amine (RG-34e)

[00534] In a 50 mL round bottom flask with stir bar, 2-methyl-5-[(l-methyl-4- piperidylidene)methyl]-3-nitro-pyridine (131 mg, 0.5297 mmol) was dissolved in ethanol (10 mL) and treated with 10% palladium on carbon (57 mg, 0.05356 mmol). A three way valve was used to exhaust the system via removing air with a vacuum pump and refilling with hydrogen three times. The mixture was stirred under a hydrogen balloon for 2 hours. The mixture was filtered through pre-packed Celite (4 g, wet with methanol) and washed with methanol (10 mL). The combined solvents were removed under reduced pressure to afford 2-methyl-5-[(l -methyl -4- piped dyl)methyl]pyridin-3 -amine (98 mg, 84%). ESI-MS m /z calc. 219.17355, found 220.15 (M+l) ⁺ ; Retention time: 0.27 minutes.

Preparation of N-ri-(3.5-difluorophenvn-1.2.4-triazol-3-yl1-2-methyl-5-r(l- methyl-4- piperidyl)methyl1pyridin-3 -amine (Compound 233)

[00535] In a 5 mL microwave tube equipped with a stirring bar dioxane (2 mL), 2- methyl-5-[(l-methyl-4-piperidyl)methyl]pyridin-3-amine (25 mg, 0.1 140 mmol) and 3-bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (33 mg, 0.1 142 mmol) were added, followed by NaOtBu (33 mg, 0.3434 mmol). The mixture was degassed for 5 minutes with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (1 1 mg, 0.01201 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (7 mg, 0.01210 mmol) were added. The tube was sealed and the mixture was heated at 1 10 °C overnight. After cooling to room temperature, the mixture was filtered through prepacked Celite (4 g, wet with methanol) and washed with methanol (5 mL). The combined filtrates were concentrated under reduced pressure. The crude product was purified by reverse phase HPLC with the (10-90 % acetonitrile/water with a trifluoroacetic acid modifier). After concentration under reduced pressure, the product was dissolved in methanol (1 mL), passed through a sodium bicarbonate cartridge, then the cartridge was washed with additional methanol (3 mL). The solvent was removed under reduced pressure to afford N-[l-(3,5-difluorophenyl)- l,2,4-triazol-3-yl]-2-methyl-5-[(l-methyl-4-piperidyl)methyl ]pyridin-3-amine (1 1 mg, 23%). ¾ MR (300 MHz, Methanol-^) δ 9.04 (d, J = 2.8 Hz, 2H), 8.15 (d, J = 1.7 Hz, 1H), 7.67 - 7.51 (m, 2H), 7.04 (tt, J = 9.0, 2.3 Hz, 1H), 3.63 - 3.43 (m, 2H), 3.07 - 2.89 (m, 3H), 2.85 (d, J = 3.8 Hz, 4H), 2.76 (s, 3H), 2.12 - 1.91 (m, 3H), 1.61 (dd, J = 14.8, 11.2 Hz, 2H) ppm. ESI-MS m/z calc. 398.20306, found 399.2 (M+l) ⁺ ; Retention time: 0.56 minutes.

[00536] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 34; 215, 216, 219, 220 and 234. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 35

Preparation of N-ri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1-5-methyl-2-(oxe tan-3-yl)- 3,4-dihydro-lH-isoquinolin-7-amine (Compound 336)

RG-35c

RG-35e

Cmpd 336

(a) HMPA, K2CO3, 112 °C; (b) Trifluoromethanesulfonic acid, 0 °C-RT, 1- iodopyrrolidine-2,5-dione; (c) DCM, DCE, NaBH(OAc) ₃ , RT; (d) dioxane, H2O, CS2CO3, Pd(dppf)Cl ₂ CH ₂ Cl2,130°C; (e) THF, 10% Palladium on carbon, H ₂ ; (f) t- BuXPhos Palladacycle, tBuOH, NaOtBu, 90 °C.

Preparation of 5-iodo-7-nitro-L2,3,4-tetrahydroisoquinoline (RG-35b)

[00537] 7-Nitro-l,2,3,4-tetrahydroisoquinoline (1600 mg, 8.979 mmol) was treated with trifluoromethanesulfonic acid (5 mL). The mixture was cooled to 0 °C. To the mixture was added l-iodopyrrolidine-2,5-dione (2.3 g, 10.22 mmol) portionwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was added to ice and stirred for 10 minutes. To this mixture was added sodium hydroxide (20 mL of 6 M, 120.0 mmol) until a yellow precipitate was formed. The precipitate was filtered, washed with water, and dried to yield crude 5- iodo-7-nitro-l,2,3,4-tetrahydroisoquinoline (2.2 g, 80.95%). ESI-MS m/z calc.

303.97, found 304.89 (M+l) ⁺ ; Retention time: 0.59 minutes. The product was utilized in the next step without further purification.

Preparation of 5-iodo-7-nitro-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinoline (RG-35c)

[00538] A mixture of 5-iodo-7-nitro-l,2,3,4-tetrahydroisoquinoline (2.22 g, 7.301 mmol) and oxetan-3-one (1000 μΐ _^ , 15.60 mmol) was dissolved in dichloroethane (50 mL) and dichloromethane (50 mL). To this mixture was added sodium

triacetoxyborohydride (2.4 g, 11.32 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The organics were separated, dried with sodium sulfate, filtered and concentrated to dryness under reduced pressure to yield 5-iodo-7-nitro-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinoline as a yellow solid (2.15 g, 81.78%), ESI-MS m/z calc. 360.00, found 360.94 (M+l) ⁺ ; Retention time: 0.60 minutes. The product was utilized in the next step without further purification.

Preparation of 5-methyl-7-nitro-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinoline (RG- 35d]

[00539] 5-Iodo-7-nitro-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinoline (1.5 g, 4.165 mmol), methylboronic acid (0.4 g, 6.682 mmol) and cesium carbonate (5 g, 15.35 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) in a microwave vial. The mixture was degassed with nitrogen for 15 minutes. To the mixture was added [l,l '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (300 mg, 0.3674 mmol). The microwave vial was sealed and heated to 130 °C in the microwave for 45 minutes. Water was added to the reaction mixture followed by extraction with ethyl acetate (3 X 150 mL). The combined organic fractions were washed with brine (1 X 50 mL) and water (2 X 50 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (80 g column; 10% methanol/dichloromethane) to provide 5-methyl-7-nitro-2-(oxetan-3-yl)-3,4-dihydro- lH-isoquinoline (0.85 g, 82%). ESI-MS m/z calc. 248.12, found 249.11 (M+l) ⁺ ; Retention time: 0.52 minutes. Preparation of 5-methyl-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinolin-7-amine (RG- 35e)

[00540] A solution of 5-methyl-7-nitro-2-(oxetan-3-yl)-3,4-dihydro-lH- isoquinoline (1.6 g, 6.444 mmol) in tetrahydrofuran (100 mL) was treated with 10% palladium on carbon (100 mg, 0.09397 mmol). The reaction mixture was placed under vacuum and then filled with hydrogen. This procedure was repeated 3 times. The reaction mixture was stirred under a hydrogen balloon for 4 days. The reaction mixture was filtered through Celite and the filtrate was dried to provide crude 5- methyl-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinolin-7-amine (1.2 g, 85%). ESI-MS m/z calc. 218.14, found 219.12 (M+l) ⁺ ; Retention time: 0.24 minutes. The product was utilized in the next step without further purification.

Preparation of N-[l-(3,5-difluorophenyl)-L2,4-triazol-3-yll-5-methyl-2-(oxe tan-3-yl)- 3,4-dihvdro-lH-isoquinolin-7-amine (Compound 336)

[00541] 5-Methyl-2-(oxetan-3-yl)-3,4-dihydro-lH-isoquinolin-7-amine (200 mg, 0.9162 mmol), 3-bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (300 mg, 1.154 mmol) and sodium tert-butoxide (2 mL of 2 M, 4.000 mmol) were dissolved in tert-butanol (5 mL). The reaction mixture was purged with nitrogen for 15 minutes and treated with chloro (2-di-t-butylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)[2-(2- aminoethyl)phenyl] palladium(II) (t-BuXPhos Palladacycle) (50 mg, 0.07281 mmol). The reaction mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (300 μΐ _^ , 3.894 mmol) was added to the reaction mixture followed by a palladium scanvenger resin. The mixture was stirred overnight. The resin was filtered and the filtrate dried under reduced pressure. The crude material was dissolved in dimethylsulfoxide (4 mL) and purified by reverse phase chromatography (150 g C18 (ISCO) column, 10-100%) acetonitrile/water with a formic acid modifier) to provide N-[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]-5-methyl-2-(ox etan-3-yl)-3,4- dihydro-lH-isoquinolin-7-amine (14.1 mg, 3.5%). ¾ MR (400 MHz, DMSO- d ₆ ) δ 9.35 (s, 1H), 9.15 (s, 1H), 8.16 (s, 1H, residual formic acid), 7.63 (d, J = 6.5 Hz, 2H), 7.39 - 7.13 (m, 3H), 4.63 (t, J = 6.4 Hz, 2H), 4.53 (t, J = 6.0 Hz, 2H), 3.62 - 3.53 (m, 1H), 3.41 (s, 2H), 2.57 (dd, J = 24.3, 5.1 Hz, 4H), 2.16 (s, 3H) ppm. ESI-MS m/z calc. 397.17, found 398.12 (M+l) ⁺ ; Retention time: 0.71 minutes.

[00542] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 35; 337-341. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 36

Preparation of l-(3,5-difluorophenyl)-N-(3-isopropoxy-2,5-dimethylphi

l 2,4-triazol-3 -amine (Compound 516)

RG-22a (a) HMPA, K2CO3, 112 °C; (b) DMF, K2CO3, 50°C; (c) 10% Palladium on carbon, DCM, MeOH, H ₂ ; (d) t-BuXPhos Palladacycle, dioxane, tBuOH, NaOtBu, 30 °C.

Preparation of l-isopropoxy-2,5-dimethyl-3-nitro-benzene (RG-36b) [00543] 3-Nitro-2,5-dimethyl-phenol (300 mg, 1.8 mol), 2-iodopropane (600uL, 1.03 mg, 6.0 mmol) and potassium carbonate (1.2g, 9.0 mmol) were dissolved in dry dimethylformamide (6 mL) and stirred sealed at 50°C for 1.5 hours. The solvent was removed under reduced pressure and the residue was partitioned between

water/saturated brine 1 : 1 and dichlorom ethane. The layers were separated and the aqueous was extracted again. The combined organic layers were dried and concentrated under reduced pressure to provide l-isopropoxy-2,5-dimethyl-3-nitro- benzene (350 mg, 83%). ¾ NMR (400 MHz, CDC13) δ 7.20 (s, 1H), 6.86 (s, 1H), 4.63 - 4.43 (m, 1H), 2.36 (d, J = 0.5 Hz, 3H), 2.29 (s, 3H), 1.35 (d, J = 6.1 Hz, 6H) ppm.

Preparation of 3-isopropoxy-2,5-dimethyl-aniline (RG-36c)

[00544] l-Isopropoxy-2,5-dimethyl-3-nitro-benzene (350 mg , 1.5 mmol) was dissolved in methanol (20 mL) and dichloromethane (10 mL) and placed under a carbon dioxide atmosphere before adding 10% palladium on carbon (50% water)

(approximately 50 mg) Hydrogen gas was bubbled into the solution for ~1 minute and the reaction was allowed to stir under a hydrogen balloon for 4 hours. The catalyst was removed via suction filtration and the filtrate was concentrated under reduced pressure to provide 3-isopropoxy-2,5-dimethyl-aniline (250 mg, 83%). ¾ NMR (400 MHz, CDCh) δ 6.18 (d, J = 6.1 Hz, 2H), 4.45 (dt, J = 12.1, 6.0 Hz, 1H), 3.55 (s, 2H), 2.22 (d, J = 0.4 Hz, 3H), 2.00 (s, 3H), 1.31 (d, J = 6.1 Hz, 6H) ppm.

Preparation of l-(3,5-difluorophenyl)-N-(3-isopropoxy-2,5-dimethylphenyl)-l H- L2,4-triazol-3 -amine (Compound 516)

3-Bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (approximately 220 mg, 0.84 mmol) and 3-isopropoxy-2,5-dimethyl-aniline (150 mg, 0.84 mmol) were dissolved in dry 1,4-dioxane (2 mL) and dry tert-butanol (8 mL) and purged with nitrogen for several minutes. During the purge, chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, - biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) (t-BuXPhos Palladacycle)

(approximately 50 mg, 0.084 mmol) was added, followed by sodium tert-butoxide (160 mg, 1.67 mmol). The reaction was capped and stirred at 30 °C for 3 hours. The reaction mixture was diluted with methanol and the solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried on sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-100% ethyl acetate/dichloromethane) and repurified on silica gel (10% ethyl

acetate/dichloromethane) to provide l-(3,5-difluorophenyl)-N-(3-isopropoxy-2,5- dimethylphenyl)-lH-l,2,4-triazol-3-amine (20 mg, 84%). ¾ NMR (400 MHz, CDCh) δ 8.30 (s, 1H), 7.59 (s, 1H), 7.31 - 7.17 (m, 2H), 6.77 (ddd, J = 8.7, 5.5, 2.2 Hz, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 4.50 (dt, J = 12.1, 6.0 Hz, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H) ppm. ¹⁹ F NMR (377 MHz, CDC13) -106.76, -106.78, -106.80 ppm. ESI-MS m/z calc. 358.16052, found 359.0 (M+l) ⁺ ; Retention time: 1.03 minutes.

[00545] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 36; 68, 116 and 517. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 37

Preparation of l-(3,5-difluorophenyl)-N-(5-isopropoxy-2,3-dimethyl-phenyl)- L2,4- triazol-3 -amine (Compound 601)

RG-37c RG-22a

Cmpd 601 (a) HMPA, K2CO3, 112 °C; (b) TBSC1, DMAP, DCM, DIPEA, RT; (c) 10%

Palladium on carbon, heptane, H2; (d) t-BuXPhos Palladacycle, dioxane, tBuOH, NaOtBu, 50-60 °C; (e) MP, NaH, 50 °C Preparation of fert-butyl-(3,4-dimethyl-5-nitro-phenoxy)-dimethyl-silane (RG-37b)

[00546] 3,4-dimethyl-5-nitro-phenol (2.00 g, 1 1.96 mmol), fert-butyl-chloro- dimethyl-silane (2.82 g, 18.71 mmol), and 4-dimethylaminopyridine (0.16 g, 1.31 mmol were dissolved in dichloromethane (18 mL) and N-ethyl-N-isopropyl-propan-2- amine (3.09 g, 4.17 mL, 23.92 mmol) was added, resulting in an orange solution. The reaction was aged at room temperature for two hours. The solution was diluted with dichloromethane and washed with IN hydrochloric acid (50 mL). The organics were separated, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude material. The crude was purified by silica gel chromatography (12 g column; 0-100% ethyl acetate/heptane). Product fractions were concentrated to dryness under reduced pressure to give tert-butyl-(3,4-dimethyl- 5-nitro-phenoxy)-dimethyl-silane (3.16 g, 11.23 mmol, 94%). ¾ NMR (300 MHz, Acetonitrile-*) δ 6.85 (d, J= 2.6 Hz, 1H), 6.77 (d, J= 2.7 Hz, 1H), 2.10 (s, 3H), 2.03 (s, 3H), 0.77 (s, 9H), 0.00 (s, 6H) ppm. Preparation of 5-rfert-butyl(dimethyl)silyl1oxy-2,3-dimethyl-aniline (RG-37c)

[00547] In a Parr shaker flask was placed tert-butyl-(3,4-dimethyl-5-nitro- phenoxy)-dimethyl-silane (3.16 g, 11.23 mmol) in heptane with 10% palladium on carbon (351 mg, 1.65 mmol, 50% water). The flask was evacuated and purged with hydrogen three times. The flask was charged to 1 atmosphere with hydrogen and shaken over the weekend, recharged to 1 atmosphere hydrogen and allowed to shake 2 more days. The bottle was evacuated, charged with nitrogen, and filtered through Celite. The solvent was removed on a rotary evaporator to give 5-[tert- butyl(dimethyl)silyl]oxy-2,3-dimethyl-aniline (2.46 g, 9.80 mmol, 87%). ¾ NMR (300 MHz, Acetonitrile-*) δ 5.90 (s, 2H), 3.75 (s, 2H), 1.99 (s, 3H), 1.77 (s, 3H), 0.81(s, 9H), 0.00 (s, 6H) ppm. ESI-MS m/z calc. 251.17055, found 252.24 (M+l) ⁺ Retention time: 0.76 minutes. Preparation of 3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl1amino1-4,5-dim ethyl- phenol (RG-37d)

[00548] In a flask with stir bar was placed 5-[tert-butyl(dimethyl)silyl]oxy-2,3- dimethyl-aniline (1.35 g, 5.38 mmol). To this was added tert-butanol (18.0 mL), previously deoxygenated with nitrogen gas. To the mixture was added 3-bromo-l- (3,5-difluorophenyl)-l,2,4-triazole (1.24 g, 4.77 mmol) and sodium tert-butoxide (917 mg, 9.54 mmol), chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl] palladium(II) (t-BuXPhos Palladacycle) (144 mg, 0.221 mmol, 0.046 eq.) and more tert-butanol (12 mL). The flask was purged with nitrogen and stirred at about 50-60 °C overnight. The reaction was concentrated to dryness and extracted with ethyl acetate and water. The aqueous was neutralized with IN hydrochloric acid (4.8 mL, pH 6) and extracted with ethyl acetate. The organics were separated, dried over sodium sulfate, filtered and concentrated to crude. The crude was dissolved in hot ethyl acetate (ca 30 mL) and treated with MP-TMT (1.99 g of 0.64 mmol/g, 1.274 mmol) and refluxed for 1 hour, to remove traces of palladium. The mixture was filtered hot, cooled to room temperature, and pre-adsorbed onto silica gel (ca 15 g). This material was purified by silica gel chromatography (40 g column; 30-100% ethyl acetate /heptane), to give 3-[[l-(3,5-difluorophenyl)-l,2,4- triazol-3-yl]amino]-4,5-dimethyl-phenol (0.58 g, 1.29 mmol, 27%). ¾ NMR (300 MHz, OMSO-de) δ 8.86 (s, 1H), 8.74 (s, 1H), 7.67 - 7.45 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 6.98 (m, 1H), 6.32 (d, J = 2.5 Hz, 1H), 2.93 (m, 3H), 2.21 (s, 3H), 2.09 (s, 3H) ppm. ESI-MS m/z calc. 316.1 1356, found 317.19 (M+l) ⁺ : Retention time: 0.85 minutes. Preparation of l-(3,5-difluorophenyl)-N-(5-isopropoxy-2,3-dimethyl-phenyl)- L2,4- triazol-3 -amine (Compound 601)

[00549] In a vial equipped with a stir bar was placed sodium hydride (4.6 mg, 0.192 mmol) and 3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3-yl]amino]-4,5-dim ethyl- phenol (20.6 mg, 0.046 mmol). To this was added N-methyl-2-pyrrolidone (1.8 mL), and 2-bromopropane (20 μΐ _^ , 0.213 mmol), and the vial was sealed. The reaction was stirred at 50 °C overnight. The reaction was quenched with IN hydrochloric acid (200 ul) and purified by reverse phase HPLC (Waters SunFire C 18 30x150 5uM column; acetonitrile/water gradient using a hydrochloric acid modifier) to give l-(3,5- difluorophenyl)-N-(5-isopropoxy-2,3-dimethyl-phenyl)-l,2,4-t riazol-3-amine

(hydrochloride salt) (10.3 mg, 0.024 mmol, 52%). ¾ MR (300 MHz, OMSO-de) δ 9.14 (s, 1H), 8.3 1 (s, 1H), 7.73 - 7.45 (m, 2H), 7.38 - 7.10 (m, 2H), 6.42 (s, 1H), 4.65 - 4.35 (m, 1H), 2.21 (s, 3H), 2.08 (s, 3H), 1.27 (d, J = 6.1 Hz, 6H) ppm. ESI-MS m/z calc. 358.16052, found 359.47 (M+l) ⁺ : Retention time: 4.66 minutes.

[00550] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 37; 19, 565, 571, 577-580, 621 and 639. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 38

Preparation of fert-Butyl N-[[3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-2- fluoro- 5 -methyl -phenyl 1 methyl 1 carbamate (Compound 623); N-r3-(aminomethyl)-2- fluoro-5-methyl-phenyl1-l-(3,5-difluorophenyl)-L2,4-triazol- 3-amine (Compound

626); and N-rr3-rri-(3.5-difluorophenylV1.2.4-triazol-3-yl1amino1-2-fl uoro-5-methyl- phenyll methyl lacetamide (Compound 636)

(a) HMPA, K2CO3, 112 °C; (b) 10% Palladium on carbon, EtOH, H ₂ ; (c) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 60-110 °C; (d) B0C2O, NiCh 6H2O, NaBH ₄ , MeOH; (e) 1.4-dioxane, 4N HC1, 105 °C; (f) 1.4-dioxane, TEA 110 °C. Preparation of 3-amino-2-fluoro-5-methyl-benzonitrile (RG-38b)

[00551] In a Parr flask was placed 2-fluoro-5-methyl-3-nitro-benzonitrile (1.00 g, 5.55 mmol) in ethanol (75 mL). This was purged with nitrogen and to it was added 10% palladium on carbon (0.22 g, 0.207 mmol). The flask was evacuated, purged with hydrogen, and charged to 1 atmosphere with shaking, for 15 minutes. The reaction was evacuated and purged with nitrogen, and the solution was filtered through Celite and concentrated to dryness with a stream of nitrogen gas, to give 3- amino-2-fluoro-5-methyl-benzonitrile (833 mg, 5.27 mmol, 95%), as a greenish brown solid. ¹ H MR (300 MHz, OMSO-de) δ 6.87 (dd, J = 8.6, 2.2 Hz, 1H), 6.72 (dd, J = 4.9, 2.3 Hz, 1H), 5.59 (s, 2H), 2.18 (s, 3H) ppm. ESI-MS m/z calc.

150.05933, found 151.05 (M+l) ⁺ : Retention time: 0.8 minutes.

Preparation of 3-rri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1amino1-2-fluoro -5- methyl-benzonitrile (RG-38c)

[00552] In a microwave vial equipped with a stir bar was placed 3-amino-2-fluoro- 5-methyl-benzonitrile (276 mg, 1.75 mmol), 3-bromo-l-(3,5-difluorophenyl)-l,2,4- triazole (544 mg, 1.88 mmol), sodium tert-butoxide (263 mg, 2.74 mmol), and chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (55 mg, 0.08 mmol).

This was sealed and purged with nitrogen. To it was added tert-butanol (10 mL) and the reaction was heated to 60 °C in the microwave for 1 hour, and then 1 10 °C in the microwave for 1 hour. The reaction was extracted with ethyl acetate and water twice. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to crude (0.72 g). This was purified by reverse phase chromatography (150 g C18 column (ISCO); 20-100% acetonitrile/water with 0.1% v/v trifluoroacetic acid, in two injections). Fractions containing product were concentrated and then extracted with ethyl acetate and saturated sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrated to give 3-[[l-(3,5- difluorophenyl)-l,2,4-triazol-3-yl]amino]-2-fluoro-5-methyl- benzonitrile (0.28 g, 0.77 mmol, 48%), as a tan solid. ¾ MR (300 MHz, OMSO-de) δ 9.58 (s, 1H), 9.22 (s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 7.78 -7.55 (m, 2H), 7.36 - 7.15 (m, 2H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 329.08884, found 330.21 (M+l) ⁺ : Retention time: 0.97 minutes.

Preparation of fert-Butyl N-[[3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-2- fluoro- 5 -methyl -phenyl 1 methyl 1 carbamate Compound 623)

[00553] In a flask equipped with a stir bar was placed 3-[[l-(3,5-difluorophenyl)- l,2,4-triazol-3-yl]amino]-2-fluoro-5-methyl-benzonitrile (50 mg, 0.137 mmol). To this was added methanol (10 mL), tert-butoxycarbonyl tert-butyl carbonate (114 mg, 0.522 mmol), dichloronickel;hexahydrate (10.3 mg, 0.0433 mmol), dissolved with mild heating, and finally sodium borohydride (45 mg, 1.189 mmol). The hot solution was aged several minutes and the black color discharged to give a clear, light yellow solution. This solution was treated with N'-(2-aminoethyl)ethane-l,2-diamine (64 mg, 0.620 mmol) for 10 minutes and then concentrated to dryness, to give a yellow solid, which was recrystallized from hot ethyl acetate/heptane. The resulting solid was purified by SFC (40% ethanol (5 mM Ammonia), 60% carbon dioxide on a AD-H, 20x250 mm column, at 80 mL/min flow), to give fert-butyl N-[[3-[[l-(3,5- difluorophenyl)-l,2,4-triazol-3-yl]amino]-2-fluoro-5-methyl- phenyl]methyl]carbamate (24.4 mg, 0.053 mmol, 39%). ¾ MR (300 MHz, DMSO- d ₆ ) δ 9.17 (s, 1H), 8.96 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.70 -7.54 (m, 2H), 7.39 - 7.17 (m, 2H), 6.74 - 6.57 (m, 1H), 4.14 (d, J = 5.6 Hz, 2H), 2.28 (s, 3H), 1.40 (s, 9H) ppm. ESI-MS m/z calc. 433.17255, found 434.02 (M+l) ⁺ : Retention time: 0.88 minutes.

Preparation of N-r3-(aminomethyl)-2-fluoro-5-methyl-phenyl1-l-(3,5- difluorophenyl)-L2,4-triazol-3 -amine (Compound 626)

[00554] In a vial was placed tert-butyl N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol- 3-yl]amino]-2-fluoro-5-methyl-phenyl]methyl]carbamate (17 mg, 0.037 mmol). To this was added 1,4-dioxane (3 mL), to give a homogenous solution. The vial was sealed and to it was added hydrochloric acid in dioxane (2 mL of 4 M, 8.000 mmol). The vial was heated to 105 °C for 1 hour, resulting in a white turbid mixture. The mixture was concentrated to dryness. The crude material was dissolved in

dimethylsulfoxide (2.0 mL) and purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient using a hydrochloric acid modifier). The pure fractions were combined and concentrated to dryness under reduced pressure to give N-[3-(aminomethyl)-2-fluoro-5-methyl-phenyl]-l-(3,5- difluorophenyl)-l,2,4-triazol-3 -amine (dihydrochloride salt) (11.1 mg, 73%). ¾

MR (300 MHz, OMSO-de) δ 9.22 (s, 2H), 8.40 (s, 3H), 7.98 (d, J = 7.5 Hz, 1H), 7.73-7.56 (m, 2H), 7.36 - 7.19 (m, 1H), 6.92 (d, J = 6.0 Hz, 1H), 4.03 (d, J = 5.8 Hz, 2H), 2.33 (s, 3H) ppm. ESI-MS m/z calc. 333.12012, found 334.20 (M+l) ⁺ :

Retention time: 2.36 minutes.

Preparation of N-[[3-[[l-(3,5-difluorophenyl)-L2,4-triazol-3-yllaminol-2-fl uoro-5- methyl-phenyllmethvHacetamide (Compound 636)

[00555] To a tube containing N-[3-(aminomethyl)-2-fluoro-5-methyl-phenyl]-l- (3,5-difluorophenyl)-l,2,4-triazol-3-amine (dihydrochloride salt) (14.2 mg, 0.035 mmol) was added 1,4-dioxane (4.0 mL) and triethylamine (24 mg, 0.237 mmol). The mixture was heated to 110 °C to dissolve the salt. To this was added acetyl chloride (3.5 mg, 0.0446 mmol) in 1,4-dioxane (285 ul). The reaction was heated to 110 °C for 10 minutes. The reaction was concentrated to dryness with a stream of nitrogen. The crude material was diluted in DMSO (2.0 mL) and purified by reverse phase HPLC (Waters SunFire C18 30x150 5μΜ column; acetonitrile/water gradient using a hydrochloric acid modifier) to give N-[[3-[[l-(3,5-difluorophenyl)-l,2,4-triazol-3- yl]amino]-2-fluoro-5-methyl-phenyl]methyl]acetamide (Hydrochloride salt) (9.6 mg, 0.022 mmol, 63%). ¹ H MR (300 MHz, OMSO-de) δ 9.18 (d, J= 1.4 Hz, 1H), 8.99 (s, 1H), 8.28 (t, J= 5.9 Hz, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.63 (d, J= 7.9 Hz, 2H), 7.35 - 7.18 (m, 1H), 6.68 (d, J= 5.9 Hz, 1H), 4.26 (d, J= 5.8 Hz, 2H), 2.29 (s, 3H), 1.87 (s, 3H) ppm. ESI-MS m/z calc. 375.1307, found 376.02 (M+l) ⁺ : Retention time: 0.82 minutes.

[00556] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 38; 642 and 644. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

[00557] The following compounds can be synthesized according to the Schemes A and B from the appropriate intermediates using procedures analogous to those described in Example 38, Steps 1-3; 640 and 602. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 39

Preparation of l-(3,4-difluorophenyl)-N-r3-methyl-4-r4-(oxetan-3-yl)piperaz in-l- yl1phenyl1-L2,4-triazol-3 -amine (Compound 370)

(a) Cu(OAc)2, pyridine, 4 A molecular sieves, CH2CI2, RT; (b) t-BuXPhos

Palladacycle, dioxane, tBuOH, NaOtBu, 30 °C; (c) 10% Palladium on carbon, DCM, MeOH, H ₂ (d) t-BuXPhos Palladacycle, dioxane, tBuOH, NaOtBu, 30 °C. Preparation of l-(2-methyl-4-nitro-phenyl)-4-(oxetan-3-yl)piperazine (RG-39b)

[00558] l-Bromo-2-methyl-4-nitro-benzene (2.5 g, 11.57 mmol) and l-(oxetan-3- yl)piperazine (1.810 g, 12.73 mmol) were suspended in dry 1,4-dioxane (20 mL) and t-butanol (60 mL). The reaction mixture was purged with nitrogen for several minutes. chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (400 mg, 0.58 mmol) followed by sodium tert-butoxide (1.66 g, 17.4 mmol) were added sequentially during the purge. The reaction mixture was stirred at 30 °C for 2 hours under nitrogen. To this mixture was added sodium tert-butoxide (1 g, 10.5 mmol) and the reaction was stirred at 30 °C for an additional hour. The reaction mixture was diluted with methanol and all solvents removed under reduced pressure. The crude residue was stirred in water overnight and isolated via suction filtration. The precipitate was dissolved in minimal dichloromethane and purified by silica gel chromatography (0- 100% ethyl acetate/dichloromethane) to give l-(2-methyl-4-nitro-phenyl)-4-(oxetan- 3-yl)piperazine (860 mg, 2.791 mmol, 24.12). ¾ NMR (300 MHz, CDCh) δ 8.04 (dd, J = 6.7, 2.5 Hz, 2H), 7.11 - 6.93 (m, 1H), 4.68 (p, J = 6.4 Hz, 4H), 3.60 (p, J = 6.4 Hz, 1H), 3.22 - 2.90 (m, 4H), 2.67 - 2.42 (m, 4H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 277.14264, found 278.0 (M+l) ⁺ ; Retention time: 0.59 minutes.

Preparation of 3-methyl-4-[4-(oxetan-3-yl)piperazin-l-yllaniline (RG-39c)

[00559] l-(2-Methyl-4-nitro-phenyl)-4-(oxetan-3-yl)piperazine (900 mg, 2.921 mmol) was dissolved into a mixture of methanol/dichloromethane (50 mL/25 mL), and the solution was placed under an atmosphere of carbon dioxide before addition of 10% Palladium on Carbon (50% water ) (150 mg. 0.146 mmol). Hydrogen gas was bubbled through the reaction for approximately 2 minutes and the reaction was allowed to stir overnight at ambient temperature under a balloon of hydrogen. The catalyst was removed by suction filtration, washed with methanol and the filtrates were concentrarted under reduced pressure to afford 3-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]aniline (720 mg, 2.620 mmol, 80.72%). ¾ NMR (300 MHz,

CDCh) δ 6.90 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 2.7 Hz, 1H), 6.51 (dd, J = 8.3, 2.7 Hz, 1H), 4.68 (d, J = 6.5 Hz, 4H), 3.57 (p, J = 6.5 Hz, 1H), 2.94 - 2.84 (m, 4H), 2.47 (s, 4H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 247.16846, found 248.0 (M+l) ⁺ ; Retention time: 0.24 minutes.

Preparation of l-(3,4-difluorophenyl)-N-[3-methyl-4-[4-(oxetan-3-yl)piperaz in-l- yl1phenyl1-L2,4-triazol-3 -amine (Compound 370)

[00560] 3-Methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]aniline (277.8 mg, 1.011 mmol) was placed into a vial containing a solution of 3-bromo-l-(3,4-difluorophenyl)-l,2,4- triazole (239.0 mg, 0.9191 mmol) in 1,4-dioxane (3 mL) and tert-butanol (12 mL) (both anhydrous). The vial was purged with nitrogen for several minutes and treated sequentially with chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2- (2-aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (60 mg, 0.0919 mmol) followed by sodium tert-butoxide (135 mg, 1.38 mmol). The vial was sealed and heated at approximately 30 °C for 1 hour. The reaction mixture was diluted with methanol and solvents removed under reduced pressure. The crude product was suspended in water. The precipitate was washed with additional water and isolated via suction filtration. The precipitate was washed with acetonitrile, methanol, dichloromethane and the desired product was isolated via suction filtration. The precipitate was dissolved in a large amount of tetrahydrofuran and stirred with MP- TMT resin (Biotage 801471) for several hours. The suspension was filtered and the filtrate was concentrated under reduced pressure. The solid was triturated in dichloromethane and isolated via suction filtration (air dried) to afford l-(3,4- difluorophenyl)-N-[3-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl ]phenyl]-l,2,4-triazol- 3-amine (192 mg, 0.4142 mmol, 41.5%). ¾ MR (300 MHz, DMSO- d ₆ ) δ 9.27 (s, 1H), 9.05 (s, 1H), 8.07 - 7.89 (m, 1H), 7.66 (dt, J = 17.4, 6.3 Hz, 2H), 7.50 (dd, J = 8.6, 2.6 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.53 - 3.38 (m, 1H), 2.81 (t, J = 4.5 Hz, 4H), 2.40 (s, 4H), 2.22 (s, 3H) ppm. ESI-MS m/z calc. 426.19797, found 427.0 (M+l) ⁺ ; Retention time: 0.66 minutes.

[00561] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 39; 331, 369, 371, 372, 527, 528, 533 and 535. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 40

Preparation of l-r3-methyl-5-r(l-phenyl-L2,4-triazol-3-yl)amino1phenyl1prop an-2- one (Compound 653) and 1 3-methyl-5 (l-phenyl-L2,4-triazol-3- l)amino ^" |phenyl ^" |propan-2-ol (Compound 654)

Cmpd 653

Cmpd 654 (a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH ₂ C1 ₂ , RT; (b) [(Cinnamyl)PdCl] ₂ , ZhedaPhos, Cs ₂ C0 ₃ , 108 °C; (c) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 108°C; (d) EtOH, NaBH ₄ , 70 °C. Preparation of l-(3-amino-5-methyl-phenyl)propan-2-one (RG-40b)

[00562] In a vial equipped with a stir bar was placed 3-bromo-5-methyl-aniline (510 mg, 2.741 mmol), bis[cinnamyl palladium(II) chloride], (33 mg, 0.064 mmol), 2- dicyclohexylphosphino-3-methoxy-N-methyl-N-phenylbenzenamine (ZhedaPhos) (1 13 mg, 0.276 mmol), and cesium carbonate (1.78 g, 5.463 mmol). The vial was sealed and purged with nitrogen. To it was added acetone (10 mL) via syringe and the mixture was heated to 108 °C overnight. The reaction was extracted with ethyl acetate and water. The organics were washed with brine and treated with MP-TMT (0.65 g) at 100 °C to capture residual palladium. The organics were filtered and concentrated to crude (687 mg). This was purified by silica gel chromatography(40 g column; 10-100% ethyl acetate/heptane) to give l-(3-amino-5-methyl-phenyl)propan- 2-one (158 mg, 0.533 mmol, 19%), as a brown oil. ESI-MS m/z calc. 163.09972, found 164.05 (M+l) ⁺ ; Retention time: 0.53 minutes.

Preparation of l-r3-methyl-5-r(l-phenyl-L2,4-triazol-3-yl)amino1phenyl1prop an-2- one (Compound 653)

[00563] In a vial with a stir bar was placed 3 -bromo-1 -phenyl- 1,2,4-triazole (173 mg, 0.772 mmol), sodium tert-butoxide (82 mg, 0.8532 mmol), and chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (22 mg, 0.0338 mmol). The vial was sealed and purged with nitrogen. To this was added l-(3-amino-5- methyl-phenyl)propan-2-one (77 mg, 0.472 mmol) in tert-butanol (2.5 mL) via syringe. The reaction was heated to 108 °C for 1 hour. The reaction was extracted with methylene chloride and water. To the organic phase was added MP-TMT (ca 0.5 g) to capture residual palladium and the mixture was heated to 80 °C overnight. The organics were dried over sodium sulfate, filtered and concentrated to crude. The crude was purified by silicagel chromatography (40 g column; 10-100%ethyl acetate/heptane), to give l-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]propan-2-one (69 mg, 42%). ¾ MR (300 MHz, OMSO-d ₆ ) δ 9.38 (s, 1H), 9.08 (s, 1H), 7.97 - 7.76 (m, 2H), 7.65 - 7.46 (m, 2H), 7.43 - 7.18 (m, 3H), 6.52 (s, 1H), 3.66 (s, 2H), 2.27 (s, 3H), 2.13 (s, 3H) ppm. ESI-MS m/z calc.

306.14807, found 307.08 (M+l) ⁺ ; Retention time: 0.85 minutes. Preparation of l-[3-methyl-5-[(l -phenyl- L2,4-triazol-3-yl)aminolphenyllpropan-2-ol (Compound 654)

[00564] In a flask was placed l-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]propan-2-one (25.1 mg, 0.073 mmol). To this was added ethanol (15 mL) and the ketone was dissolved with heating from a heat gun. To this solution was added sodium borohydride (3 mg, 0.08 mmol). The reaction was aged at 70 °C for 10 minutes. The reaction was quenched with IN hydrochloric acid

(approximately 1 mL) and concentrated to dryness on a rotary evaporator. The product was dissolved in dimethyl sulfoxide and water (6: 1, 1.5 mL) and purified by reverse phase chromatography (5.5 g CI 8 column (ISCO); 30-100%

acetonitrile/water with 0.1% v/v TFA modifier). Fractions containing product were concentrated on a Genevac evaporator, to give the trifluoroacetate salt, which was passed through an SPE bicarbonate cartridge, eluted with methanol and then evaporated, to give l-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]pro pan- 2-ol (20 mg, 0.059 mmol, 81%). 1H NMR (300 MHz, Methanol-^) δ 8.76 (s, 1H), 7.90 - 7.73 (m, 2H), 7.59 - 7.45 (m, 3H), 7.43 - 7.19 (m, 4H), 6.60 (s, 1H), 3.99 (q, J = 6.3 Hz, 1H), 2.78 (dd, J = 13.2, 6.3 Hz, 1H), 2.59 (dd, J = 13.2, 6.9 Hz, 1H), 2.31 (s, 3H), 1.17 (d, J = 6.1 Hz, 3H) ppm. ESI-MS m/z calc. 308.1637, found 309.1 (M+l) ⁺ ; Retention time: 0.82 minutes.

[00565] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 40; 652, 655 and 657-659. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A. EXAMPLE 41

Preparation of N-ri-(3,5-difluorophenyl)-L2,4-triazol-3-yl1-2-(3-methoxypro poxy)-6-

(trifluoromethvDpyridin-4-amine (Compound 490)

RG-22a Cmpd

(a) HMPA, K2CO3, 112 °C; (b) 1,4-dioxane, NaH, 110 °C; (c) t-BuXPhos

Palladacycle, tBuOH, NaOtBu, 90 °C

Preparation of 2-(3-methoxypropoxy)-6-(trifluoromethyl)pyridin-4-amine (RG-4 lb)

[00566] To sodium hydride (approximately 240.0 mg of 60 %w/w, 6.000 mmol) was added a 1,4-dioxane (20 mL) solution of 3-methoxypropan-l-ol (approximately 540.7 mg, 6.000 mmol). The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-chloro-6-(trifluoromethyl)pyridin-4-amine (393.1 mg, 2 mmol) and the reaction mixture was stirred at 110 °C overnight. To the reaction mixture was added ethyl acetate and brine. The aqueous phase pH was adjusted to greater than 12 with 2M sodium hydroxide and the organic phase was extracted with ethyl acetate several times. The organic phases were combined and dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The product was purified by silica gel chromatography (80 g column; 40% ethyl acetate/heptane) to afford 2-(3-methoxypropoxy)-6-(trifluoromethyl)pyridin-4- amine (340 mg, 68%). ¾ MR (400 MHz, CDCh) δ 6.58 (d, J = 1.8 Hz, 1H), 6.04 (d, J = 1.8 Hz, 1H), 4.38 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 6.4 Hz, 2H), 3.37 (s, 3H), 2.04 (p, J = 6.4 Hz, 2H) ppm. ESI-MS m/z calc. 250.09291, found 0.71 (M+l) ⁺ ; Retention time: 251.1 minutes. Preparation of N-[l-(3,5-difluorophenyl)-L2,4-triazol-3-yll-2-(3-methoxypro poxy)-6- (trifluoromethvDpyridin-4-amine (Compound 490)

[00567] To a tert-butanol (8.81 mL) solution of 3-bromo-l-(3,5-difluorophenyl)- 1,2,4-triazole (approximately 195.0 mg, 0.7500 mmol) and 2-(3-methoxypropoxy)-6- (trifluoromethyl)pyridin-4-amine (125.1 mg, 0.5 mmol) was added t-ButyXPhos Palladacyle (approximately 16.36 mg, 0.02512 mmol) and sodium tert-butoxide

(approximately 112.2 mg, 0.9995 mmol) at 90 °C. The reaction mixture was stirred at 90 °C for 20 minutes. To the reaction mixture was added ethyl acetate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated to dryness under reduced pressure and purified by silica gel chromatography (40 g Gold column (ISCO); 45% ethyl acetate/heptane) to afford N-[l-(3,5-difluorophenyl)-l,2,4-triazol- 3-yl]-2-(3-methoxypropoxy)-6-(trifluoromethyl)pyridin-4-amin e (109.0 mg, 48%). ¹ H MR (400 MHz, CDCh) δ 8.39 (s, 1H), 7.33 - 7.29 (m, 3H), 7.21 (d, J = 1.8 Hz, 1H), 6.87 (tt, J = 8.6, 2.3 Hz, 1H), 4.48 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 6.4 Hz, 2H), 3.39 (s, 3H), 2.10 (p, J = 6.4 Hz, 2H) ppm. ESI-MS m/z calc. 429.1224, found 430.17 (M+l) ⁺ ; Retention time: 0.95 minutes.

[00568] The following compound can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 41; 491. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 42

Preparation of N-(3-isopropoxy-5-methyl-phenyl)-l -phenyl- l,2,4-triazol-3 -amine (Compound 559)

RG-lc RG-lb Cmpd 559

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 125 °C.

Preparation of N-(3-isopropoxy-5-methyl-phenyl)-l -phenyl- l,2,4-triazol-3 -amine (Compound 559)

[00569] 1 -Phenyl- l,2,4-triazol-3 -amine (73 mg, 0.4557 mmol), l-bromo-3- isopropoxy-5-methyl-benzene (77 μΐ _^ , 0.4369 mmol) and sodium tert-butoxide (87 mg, 0.9053 mmol) were suspended in 1,4-dioxane (4 mL) and purged with nitrogen for several minutes before addition of chloro(2-di-t-butylphosphino-2',4',6'-tri-i- propyl-l, -biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (t-BuXPhos

Palladacycle) (approximately 21.00 mg, 0.03058 mmol). The mixture was microwaved at 125 °C for 60 minutes. The reaction was quenched with methanol (2 mL), diluted with dichloromethane (20 mL), washed with water (5 mL), dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (12 g column; 10-100% ethyl acetate/hexanes) to provide N-(3-isopropoxy-5-methyl-phenyl)-l-phenyl-l,2,4- triazol-3 -amine (91 mg, 63%). ¾ MR (300 MHz, CDCh) δ 8.33 (s, 1H), 7.70 (dd, J = 8.6, 1.0 Hz, 2H), 7.52 (dd, J = 10.6, 5.1 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 2.0 Hz, 1H), 6.83 (s, 1H), 6.67 (s, 1H), 6.37 (s, 1H), 4.60 (dt, J = 12.1, 6.1 Hz, 1H), 2.34 (s, 3H), 1.39 (d, J = 6.1 Hz, 6H) ppm. ESI-MS m/z calc. 308.1637, found 309.1 (M+l) ⁺ ; Retention time: 0.95 minutes.

[00570] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 42; 2, 20, 21, 31-33, 36-48, 51, 54-56, 62-67, 69-82, 89- 97, 124, 131, 135, 137, 140, 149, 192, 193, 227, 245, 246, 273, 275, 293, 354-356, 358, 360, 451, 504, 541, 542, 548, 549, 552, 554, 556-558, 562-564, 581, 582, 588, 589, 596, 641, 645 and 650. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 43

Preparation of r-(oxetan-3-vn-N-(l-phenyl-lH-1.2.4-triazol-3-vn-2.3- dihydrospiroRndene-L4'-piperidin1-6-amine (Compound 320)

Cmpd 320

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on H ₂ ; (c) TFA, DCM, RT; (d)NaBH(OAc) ₃ , AcOH, DCM, RT; (e) t-BuXPhos Palladacycle, tBuOH, NaOtBu, 120 °C.

Preparation of 6-bromo-2,3-dihydrospirorindene-L4'-piperidine1 ID-43c [00571] To a solution of tert-butyl 6-bromospiro[indane-l,4'-piperidine]-l'- carboxylate (1 g, 2.730 mmol) in dichloromethane was added trifluoroacetic acid (2 mL, 25.96 mmol). The reaction mixture was stirred for 4 hours and was concentrated under reduced pressure to provide 6-bromo-2,3-dihydrospiro[indene-l,4'-piperidine] (Trifluoroacetate salt) (1.027 g, 99%). ¾ MR (300 MHz, CDCh) δ 8.34 (s, 1H), 7.37 (dd, J = 8.0, 1.8 Hz, 1H), 7.47 - 7.30 (m, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 3.56 (d, J = 12.9 Hz, 2H), 3.20 (q, J = 12.6 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H), 2.25 - 2.08 (m, 4H), 1.80 (d, J = 14.4 Hz, 2H) ppm. ESI-MS m/z calc. 265.0466, found 266.39 (M+l) ⁺ ; Retention time: 0.64 minutes.

Preparation of 6-bromo- -(oxetan-3-yl)spiroRndane-L4'-piperidine1 ID-43d

[00572] To a solution of 6-bromo-2,3-dihydrospiro[indene-l,4'-piperidine] (Trifluoroacetate salt) (1.027 g, 2.7 mmol), oxetan-3-one (approximately 1.946 g, 27.00 mmol) and acetic acid (approximately 972.8 mg, 921.2 μΐ _^ , 16.20 mmol) in dichloromethane (34.23 mL) was carefully added sodium triacetoxyborohydride

(approximately 3.433 g, 16.20 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction was diluted with dichloromethane and slowly quenched with methanol and saturated sodium bicarbonate (50 mL). The layers were separated and the organic layer was washed with water, saturated sodium chloride and dried. The crude product was purified by silica gel chromatography (40 g column; 0-10% methanol/dichloromethane) to give 6-bromo-l'-(oxetan-3-yl)spiro[indane-l,4'- piperidine] (790 mg, 91%). ¹ H MR (300 MHz, CDC13) δ 7.35 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.70 (d, J = 6.5 Hz, 4H), 3.69 - 3.45 (m, 1H), 2.86 (t, J = 7.3 Hz, 2H), 2.76 (d, J = 9.8 Hz, 2H), 2.18 - 1.86 (m, 6H), 1.59 (d, J = 12.1 Hz, 2H) ppm. ESI-MS m/z calc. 321.0728, found 322.37 (M+l) ⁺ ;

Retention time: 0.64 minutes.

Preparation of r-(oxetan-3-vn-N-(l-phenyl-lH-1.2.4-triazol-3-vn-2.3- dihydrospiro[indene-L4'-piperidinl-6-amine Compound 320)

[00573] 6-Bromo-r-(oxetan-3-yl)spiro[indane-l,4'-piperidine] (100 mg, 0.3103 mmol), 1 -phenyl- l,2,4-triazol-3 -amine (approximately 54.67 mg, 0.3413 mmol) and sodium tert-butoxide (approximately 74.16 mg, 0.7717 mmol) were suspended in 1,4- dioxane (4.000 mL) and purged with nitrogen for several minutes before addition of chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (approximately 20.21 mg, 0.03103 mmol). The mixture was microwaved at 120 °C for 35 minutes. The reaction was quenched with methanol (2 mL) and diluted with dichloromethane. After filtration over Florisil (5 g), the solvent was evaporated and the residue was purified by silicagel chromatography (12 g column, 0-10%

methanol/dichloromethane) to provide l'-(oxetan-3-yl)-N-(l-phenyl-lH-l,2,4-triazol- 3-yl)-2,3-dihydrospiro[indene-l,4'-piperidin]-6-amine(100 mg, 76%). ¾ MR (300 MHz, CDCh) δ 8.34 (s, 1H), 7.77 - 7.68 (m, 2H), 7.58 - 7.49 (m, 2H), 7.39 (ddd, J = 13.7, 12.9, 4.7 Hz, 3H), 7.19 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 4.75 (dd, J = 23.5, 16.7 Hz, 4H), 3.68 (s, 1H), 2.88 (t, J = 7.2 Hz, 4H), 2.08 (dd, J = 29.4, 22.1 Hz, 6H), 1.69 (s, 2H) ppm. ESI-MS m/z calc. 401.22156, found 402.48 (M+l) ⁺ ; Retention time: 0.65 minutes.

[00574] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 43; 323, 324 and 321. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 44

Preparation of N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yll- 1 -isopropyl- spirorindoline-3,4'-tetrahydropyran1-5-amine (Compound 315)

RG-22a

(a) HMPA, K2CO3, 112 °C; (b) NaBH(OAc) ₃ , AcOH, DCM; (c) 10% Palladium on carbon, EtOAc, H ₂ ; (d) t-BuXPhos Palladacycle, 1,4-dioxane, NaOtBu, 125 °C.

Preparation of l-isopropyl-5-nitro-spirorindoline-3,4'-tetrahydropyran1 (RG-44b)

[00575] To a solution of 5-nitrospiro[indoline-3,4'-tetrahydropyran] (670 mg, 2.860 mmol), acetone (approximately 1.661 g, 2.100 mL, 28.60 mmol) and acetic acid (approximately 1.030 g, 975.4 μΐ _^ , 17.16 mmol) in dichloromethane (10 mL) was carefully added sodium triacetoxyborohydride (253.1 mg, 1.194 mmol). The mixture was stirred for 4 hours. The reaction was diluted with dichloromethane and slowly quenched with methanol and saturated aqueous sodium bicarbonate (3 mL). After separation, the organic layer was washed with water, saturated aqueous sodium chloride and dried with sodium sulfate. The organics were concentrated to dryness under reduced pressure and the crude product was purified by silicagel

chromatography (12 g column; 0-10% of methanol/dichloromethane) to provide 1- isopropyl-5-nitro-spiro[indoline-3,4'-tetrahydropyran] (600 mg, 2.171 mmol, 75.92%). ¾ MR (300 MHz, CDCh) δ 8.10 (dd, J = 8.9, 2.3 Hz, 1H), 7.90 (t, J = 2.3 Hz, 1H), 6.33 (d, J = 8.9 Hz, 1H), 4.09 - 3.89 (m, 3H), 3.63 - 3.50 (m, 4H), 2.02 (td, J = 13.7, 4.6 Hz, 2H), 1.63 (dd, J = 13.7, 2.0 Hz, 2H), 1.27 (d, J = 6.7 Hz, 6H) ppm. ESI-MS m/z calc. 276.1474, found 277.42 (M+l) ⁺ ; Retention time: 0.89 minutes. Preparation of l-isopropylspirorindoline-3,4'-tetrahydropyran1-5-amine (RG-44c)

[00576] To 10% palladium on carbon (approximately 231.0 mg, 0.2171 mmol) under nitrogen was added a solution of l-isopropyl-5-nitro-spiro[indoline-3,4'- tetrahydropyran] (600 mg, 2.171 mmol) in ethyl acetate (30 mL). The mixture was shaken under hydrogen (50 psi) for 2 hours. After filtration, the mixture was concentrated to dryness under reduced pressure and the crude product was purified by silica gel chromatography (12 g column; 10-100%) ethyl acetate/hexanes) to give 1- isopropylspiro[indoline-3,4'-tetrahydropyran]-5-amine (450 mg, 84%). ¹ H MR (300 MHz, CDCh) δ 6.60 (d, J = 36.7 Hz, 2H), 6.38 (d, J = 18.3 Hz, 1H), 3.98 (dd, J = 11.9, 2.2 Hz, 2H), 3.77 (s, 1H), 3.58 (ddd, J = 12.0, 7.2, 2.3 Hz, 2H), 3.34 - 3.01 (m, 4H), 1.94 (ddd, J = 13.4, 8.1, 4.0 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.21 - 1.08 (m, 6H) ppm. ESI-MS m/z calc. 246.17322, found 247.45 (M+l) ⁺ ; Retention time: 0.55 minutes.

Preparation of N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yll- 1 -isopropyl- spirorindoline-3,4'-tetrahydropyran1-5-amine (Compound 315)

[00577] l-Isopropylspiro[indoline-3,4'-tetrahydropyran]-5-amine (100 mg, 0.4059 mmol), 3-bromo-l-(3,5-difluorophenyl)-l,2,4-triazole (approximately 116.1 mg, 0.4465 mmol) and sodium tert-butoxide (approximately 78.02 mg, 0.8118 mmol) were suspended in 1,4-dioxane (3.478 mL) and purged with nitrogen for several minutes before the addition of tert-ButylXPhos Palladacyle (approximately 26.43 mg, 0.0406 mmol). The vial was capped and microwaved at 125 °C for 35 minutes. The reaction was quenched with methanol (0.5 mL), IN hydrochloric acid (800 uL) and diluted with dichloromethane. After filtration through Florisil (5 g), the mixture was concentrated to dryness under reduced pressure and the crude product was purified by silica gel chromatography (12 g column; 5-100% ethyl acetate/hexane) to provide N-[ 1 -(3 , 5-difluorophenyl)- 1 ,2,4-triazol-3 -yl]- 1 -isopropyl-spiro[indoline-3 ,4'- tetrahydropyran]-5-amine (78 mg, 0.1742 mmol, 42.91%). ¾ NMR (300 MHz, OMSO-de) δ 9.08 (dd, J = 14.1, 6.6 Hz, 2H), 7.59 (dd, J = 8.7, 2.2 Hz, 2H), 7.39 - 7.28 (m, 2H), 7.25 - 7.15 (m, 1H), 6.47 (dd, J = 17.6, 8.4 Hz, 1H), 3.95 - 3.66 (m, 3H), 3.53 (t, J = 10.7 Hz, 2H), 3.23 (s, 2H), 1.84 - 1.69 (m, 2H), 1.55 (d, J = 13.2 Hz, 2H), 1.09 (d, J = 6.6 Hz, 6H) ppm. ESI-MS m/z calc. 425.20273, found 426.42 (M+l) ⁺ ; Retention time: 0.67 minutes.

[00578] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 44; 312-314. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 45

Preparation of 2-methyl-N-[3-methyl-5-[(l-phenyl-L2,4-triazol-3- vDaminolphenyllpropanamide (Compound 553)

(a) Cu(OAc) ₂ , pyridine, 4 A molecular sieves, CH2CI2, RT; (b) Palladium on carbon, H ₂ ; (c) t-BuXPhos Palladacycle, NaOtBu, tBuOH, 70 °C; (d) DCM, TFA, RT; (e) EtOAc, 80 °C.

Preparation of fert-butyl N-[3-methyl-5-[(l-phenyl-L2,4-triazol-3- yl)amino1phenyl1carbamate (Compound 549)

[00579] 1 -Phenyl- l,2,4-triazol-3 -amine (approximately 585.0 mg, 3.652 mmol), tert-butyl N-(3-bromo-5-methyl-phenyl)carbamate (lg, 3.320 mmol) and sodium tert- butoxide (643 mg, 6.691 mmol) were suspended in 1,4-dioxane (16 mL) and purged with nitrogen for several minutes before the addition of chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (150 mg, 0.2303 mmol). The mixture was microwaved at 70 °C for 8 hours. The reaction was quenched with methanol (2 mL) and diluted with dichloromethane. After filtration through Florisil (5 g), the mixture was concentrated to dryness under reduced pressure. The crude product was triturated with water, diethyl ether and methanol to give tert-butyl N-[3- methyl-5-[(l-phenyl-l,2,4-triazol-3-yl)amino]phenyl]carbamat e (1.15 g, 90%). ¾ NMR (300 MHz, methanol-^) δ 8.47 (s, 1H), 7.82 - 7.71 (m, 2H), 7.61 - 7.47 (m, 3H), 7.41 - 7.32 (m, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 2.34 (s, 3H), 1.54 (s, 9H) ppm. ESI-MS m/z calc. 365.18518, found 365.98 (M+l) ⁺ ; Retention time: 0.93 minutes. Preparation of 5-methyl-N3-(l -phenyl- l,2,4-triazol-3-yl)benzene- 1,3 -diamine Compound 550)

[00580] A mixture of tert-butyl N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]carbamate (1050 mg, 2.730 mmol) and trifluoroacetic acid (4 mL, 51.92 mmol) in dichloromethane (36 mL) was stirred for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure. The solids were dissolved in dichloromethane (200 mL) and basified with aqueous saturated sodium bicarbonate (60 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure to give 5-methyl-Nl-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3-diamine (745 mg, 93%). ¾ NMR (300 MHz, OMSO-de) δ 9.66 (s, 1H), 9.1 1 (s, 1H), 7.94 - 7.84 (m, 2H), 7.56 (t, J = 7.9 Hz, 3H), 7.37 (t, J = 7.4 Hz, 1H), 7.19 (s, 1H), 6.51 (s, 1H), 2.28 (s, 3H) ppm. ESI-MS m/z calc. 265.13275, found 266.04 (M+l) ⁺ ; Retention time: 0.62 minutes. Preparation of 2-methyl-N-[3-methyl-5-[(l-phenyl-L2,4-triazol-3- vDaminolphenyllpropanamide (Compound 553)

[00581] 2-Methylpropanoyl 2-methylpropanoate (88 μΕ, 0.5307 mmol) and 5- methyl-Nl-(l-phenyl-l,2,4-triazol-3-yl)benzene-l,3-diamine (70 mg, 0.2638 mmol) in ethyl acetate (3 mL) were microwaved at 80 °C for 15 minutes. Solvent was removed under reduced pressure. The residue was dissolved in 20 mL of methanol/dichloromethane (1/9), filtered through a PL-HCO3 MP SPE (500 mg, 6 mL) cartridge and concentrated to dryness under reduced pressure. The compound was purified by silica gel chromatography (12 g column; 10-100%) of ethyl acetate/hexane) to provide 2-methyl-N-[3-methyl-5-[(l-phenyl-l,2,4-triazol-3- yl)amino]phenyl]propanamide (49 mg, 53%). ¾ NMR (300 MHz, OMSO-d ₆ ) δ 9.66 (s, 1H), 9.32 (s, 1H), 9.06 (s, 1H), 7.90 (dd, J = 8.6, 1.0 Hz, 2H), 7.75 (s, 1H), 7.55 (dd, J = 10.7, 5.2 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 14.5 Hz, 2H), 2.62 (dt, J = 13.6, 6.8 Hz, 1H), 2.24 (s, 3H), 1.10 (d, J = 6.8 Hz, 6H) ppm. ESI-MS m/z calc. 335.17462, found 336.1 (M+l) ⁺ ; Retention time: 0.83 minutes.

[00582] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, and using procedures analogous to those described in Example 45; 547 and 551. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 46

Preparation of 2-methyl-N-(l -phenyl- 1.2.4-triazol-3-yl)-5-tetrahydropyran-4-yl- pyridin-3 -amine (Compound 168)

R -46C RG-20a _C mpd 168

(a) Cu(OAc) ₂ , pyridine, DCM, RT; (b) Pd(PPh ₃ ) ₄ , Na ₂ C03, 1,4-dioxane, 80 °C; (c) Palladium on carbon, H ₂ , MeOH, 50 psi; (d) t-BuXPhos Palladacycle, 1,4-dioxane, NaOtBu, 120-135 °C.

Preparation of 5-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-pyridin-3-amine (RG-46b)

[00583] 5-Bromo-2-methyl-pyridin-3-amine (430 mg, 2.272 mmol) and 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborola ne (525 mg, 2.5 mmol) were dissolved in dry 1,4-dioxane (4 mL) and purged with nitrogen gas for several minutes. During the purge, degassed 2M sodium carbonate solution (1.7 mL) was added, followed by tetrakis (triphenylphosphine)palladium(O) (262 mg, 0.2272 mmol). The vessel was capped and the reaction was heated at 80 °C overnight. The reaction was diluted with methanol, filtered through a pad of diatomaceous earth, the pad was washed with methanol and the solvents were removed under reduced pressure. The crude material was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The crude material was partially purified by silica gel chromatography (0-6% (methanol/0.1% 7N aqueous ammonium

hydroxide)/dichloromethane) to yield 5-(3,6-dihydro-2H-pyran-4-yl)-2-methyl- pyridin-3 -amine (250 mg, 1.314 mmol, 86.75%). ESI-MS m/z calc. 190.1 1061, found 191.51 (M+l) ⁺ ; Retention time: 0.45 minutes. Preparation of 2-methyl-5-tetrahvdropyran-4-yl-pyridin-3-amine (RG-46c)

[00584] 5-(3,6-Dihydro-2H-pyran-4-yl)-2-methyl-pyridin-3-amine (250 mg, 1.314 mmol) was dissolved in methanol (25 mL) and placed under an atmosphere of carbon dioxide before adding Degussa type 10% palladium on carbon (50% water) (100 mg) to the solution. The Parr bottle was placed under 50 psi hydrogen overnight. The material was isolated and re-subjected to fresh catalyst under the same conditions for and additional 48 hours. The reaction was filtered through a pad of diatomaceous earth, washed with methanol and concentrated under reduced pressure to yield 2- methyl-5-tetrahydropyran-4-yl-pyridin-3-amine (165 mg, 0.7724 mmol, 58.79%). ¾ MR (400 MHz, OMSO-de) δ 7.57 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 1.9 Hz, 1H), 4.92 (s, 2H), 3.92 (dd, J = 10.3, 3.2 Hz, 2H), 3.40 (td, J = 1 1.4, 2.8 Hz, 2H), 2.67 - 2.54 (m, 1H), 2.55 - 2.43 (m, 3H), 1.71 - 1.46 (m, 4H) ppm. ESI-MS m/z calc. 192.12627, found 193.53 (M+l) ⁺ ; Retention time: 0.27 minutes.

Preparation of 2-methyl-N-(l -phenyl- L2,4-triazol-3-yl)-5-tetrahydropyran-4-yl- pyridin-3 -amine Compound 168)

[00585] 3 -Bromo-1 -phenyl- 1,2,4-triazole (100 mg, 0.446 mmol) and 2-methyl-5- tetrahydropyran-4-yl-pyridin-3-amine (100 mg, 0.52 mmol) were dissolved into dry 1,4-dioxane (4.0 mL) and purged with nitrogen for several minutes. Sodium tert- butoxide (65 mg, 0.67 mmol) was added during the purge, followed by chloro(2-di-t- butylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2-(2- aminoethyl)phenyl]palladium(II) (t-BuXPhos Palladacycle) (30 mg, 0.045 mmol). The vial was sealed and heated in the microwave for 20 minutes at 120 °C, then for 15 minutes at 135 °C. The reaction was diluted with methanol, filtered through a pad of diatomaceous earth and washed with methanol. The filtrates were concentrated under reduced pressure and the residue was partitioned between a saturated sodium carbonate solution and ethyl acetate. The organics were washed with brine, dried with sodium sulfate and concentrated to dryness under reduced pressure. The crude material was purified by silica gel chromatography (0-100% ethyl

acetate/dichloromethane), then repurified by reverse phase chromatography (CI 8 column (ISCO); 0-100%) acetonitrile/ water with trifluoroacetic acid modifier) to yield 2-methyl-N-(l -phenyl- l,2,4-triazol-3-yl)-5-tetrahydropyran-4-yl-pyridin-3-amine (14 mg, 0.03388 mmol, 7.59%). ¾ MR (400 MHz, OMSO-de) δ 9.67 (s, 1H), 9.26 (s, 1H), 9.01 (s, 1H), 8.25 (s, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 8.0 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 3.99 (d, J = 10.9 Hz, 3H), 3.47 (t, J = 1 1.6 Hz, 2H), 3.06 (s, 1H), 2.75 (s, 3H), 1.88 - 1.61 (m, 4H) ppm. ESI-MS m/z calc. 335.17462, found 336.0 (M+l) ⁺ ; Retention time: 0.56 minutes.

[00586] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, using procedures analogous to those described in Example 46 but omitting the optional Step 3 (reduction of the Suzuki product); 202 and 203. Those skilled in the art will recognize that these methods may be extended to prepare amino triazoles with further variations in the substitutions of R ⁸ and A.

EXAMPLE 47

Preparation of Ν-Γ 1 -r2-(azepan- 1 -νΠ-4-pyridyll- 1 ,2,4-triazol-3 -yl1-4,6-dimethyl- pyridin-2-amine (Compound 266)

ID-47b

Cmpd 266

(a) K2CO3, DMF, 50 °C; (b) CH3CN, 80 °C; (c) BrettPhos Precatalyst, NaOtBu, 1,4- dioxane, 90 °C.

Preparation of 4-(3-bromo-L2,4-triazol-l-yl)-2-fluoro-pyridine (ID-47a)

[00587] 3-bromo-4H-l,2,4-triazole (98 g, 662.3 mmol) and potassium carbonate (approximately 274.6 g, 1.987 mol) were added to a 5L flask. Dimethylformamide was added followed by 2,4-difluoropyridine (approximately 152.5 g, 1.325 mol) all at once. The reaction mixture was heated to -50 °C for -16 hours then at room temperature for 48 hours. Most of the dimethylformamide was removed under vacuum and the residue was taken in ethanol (1 L) and filtered. The filtrate was evaporated under vacuum and the residue was triturated with water (-400 mL), filtered and washed with water (200 mL) to provide 76 g of crude product, which was purified by silica gel chromatography (1600 g column, 0-60% ethyl

acetate/dichloromethane) to yield 4-(3-bromo-l,2,4-triazol-l-yl)-2-fluoro-pyridine (61 g, 38%). ¹ H MR (300 MHz, Methanol-^) δ 9.27 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 7.88 ? 7.71 (m, 1H), 7.58 (t, J = 1.3 Hz, 1H) ppm.

Preparation of l-(4-(3-bromo-lH-L2,4-triazol-l-yl)pyridin-2-yl)azepane (ID-47b)

[00588] 4-(3-bromo-l,2,4-triazol-l-yl)-2-fluoro-pyridine (2 g, 8.229 mmol) and azepane (approximately 2.449 g, 2.783 mL, 24.69 mmol) were mixed in acetonitrile (19.13 mL) and the mixture was heated to 80 ⁰ C over the weekend. Dichloromethane and water were added and the phases were separated via a phase separator. Celite was added to to the organic layer and the suspension was concentrated to dryness and purified by silica gel chromatography (40g Gold (ISCO) column; 0-100% ethyl acetate in heptane over 20 minutes via dry loading). The pure fractions were concentrated to dryness to provide l-(4-(3-bromo-lH-l,2,4-triazol-l-yl)pyridin-2- yl)azepane_(2.129 g, 80%). ¹ H MR (400 MHz, OMSO-de) δ 9.48 (s, 1H), 8.19 (d, J = 5.5 Hz, 1H), 6.97 (dd, J = 5.5, 1.8 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 3.70 - 3.63 (m, 4H), 1.74 (m, 4H), 1.49 (m, 4H) ppm. ESI-MS m/z calc. 321.0589, found 322.13 (M+l) ⁺ ; Retention time: 0.56 minutes.

Preparation of N-[ 1 -| ^" 2-(azepan- 1 -νΠ-4-pyridyl - 1 ,2,4-triazol-3 -yl ^" |-4,6-dimethyl- pyridin-2-amine Compound 266)

[00589] Sodium tert-butoxide (approximately 17 mg, 0.17 mmol), chloro[2- (dicyclohexylphosphino)-3,6-dimethoxy-2',4', 6'-triisopropyl-l, 1 '-biphenyl][2-(2- aminoethyl)phenyl]palladium(II) (BrettPhos Precatalyst) (approximately 9 mg, 0.07 mmol) and l-[4-(3-bromo-l,2,4-triazol-l-yl)-2-pyridyl]azepane (approximately 55 mg, 0.17 mmol) were weighed into a vial and diluted with 1,4-dioxane (2 mL). The vial was degassed with nitrogen for 10 minutes, then treated with 4,6- dimethylpyridin-2-amine (approximately 33 mg, 0.27 mmol) and the mixture was heated to 90 °C overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was passed through a phase separator, treated with Celite and concentrated to dryness. The residue was diluted with dimethylsulfoxide (2 mL) and purified by HPLC (30 x 150 mm Sunfire Ci8. column, water/acetonitrile gradient with 0.1% trifluoroacetic acid). The pure, concentrated fractions were diluted with dichloromethane, washed with saturated sodium bicarbonate and the organics were collected through a phase separator, acidified with 2M HCl in diethyl ether and concentrated to dryness to provide N-[l- [2-(azepan-l-yl)-4-pyridyl]-l,2,4-triazol-3-yl]-4,6-dimethyl -pyridin-2-amine 266. ¾ NMR (400 MHz, OMSO-de) δ 9.80 (s, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.49 (dd, J = 6.9, 1.7 Hz, 1H), 7.13 (s, 1H), 3.83 (t, J = 5.9 Hz, 4H), 2.61 (s, 3H), 2.49 (s, 3H), 1.84 (m, 4H), 1.56 (m, 4H) ppm. ESI-MS m/z calc. 363.22, found 364.31 (M+l) ⁺ ; Retention time: 0.5 minutes.

[00590] The following compounds can be synthesized from the appropriate intermediates according to Schemes A and B, using procedures analogous to those described in Example 47: 84, 85, 86, 136, 267, 268 and 269. Those skilled in the art will recognize that these methods may be extended to prepare aminotriazoles with further variations in the substitutions of R ⁸ and A.

Table 3. Analytical Data

15 Method G 312.4 2.42 1H NMR (300 MHz, Methanol-^) δ

(m, 2H), 7.07 (ddd, J = 7.6, 2.0, 1.3

3.67 (hept, J = 6.3 Hz, 1H), 2.59 (s,

225 Method B 380.52 0.71 I IH NMR (400 MHz, DMSO-^e) δ

231 Method D 365 0.59 I IH NMR (400 MHz, DMSO-^e) δ

3H), 7.51 (ddd, J = 9.0, 5.6, 1.9 Hz,

434 I Method A j 357. 14 \ 0.98 IH NMR (400 MHz, OMSO-de) δ

463 Method A ! 411.16 0.67

487 I Method A ! 41 5.23 0.65 1H NMR (300 MHz, OMSO-de) δ

550 Method A j 266.04 0.62 ! IH NMR (300 MHz, DMSO-^e) δ

659 Method A 306.99 1.02 IH NMR (400 MHz, OMSO-de) δ LC/MS

Cmpd LC/MS

M+l Ret. ¾ NMR (peaks shifts in ppm) No. method

Time

9.73 (s, 1H), 9.17 (s, 1H), 8.09 (ddd, J = 11.4, 6.4, 3.1 Hz, 1H), 7.90 - 7.78 (m, 2H), 7.57 (dd, J = 8.4, 7.6 Hz, 2H), 7.44 - 7.34 (m, 1H), 7.04 (ddd, J = 8.2, 5.1, 3.1 Hz, lH) ppm.

ASSAYS FOR DETECTING AND MEASURING REMYELINA TION

PROPERTIES OF COMPOUNDS In vivo Mouse Cuprizone Assay:

[00591] Cuprizone Feeding Protocol:

[00592] 2 month old female C57BL/6 mice (Stock Number: 000664) are purchased from Jackson Labs and fed for 4-10 months with a 0.2% cuprizone chow (provided by Research Diets, Product # Dl 0020701R, Description AIN-76A Rodent Diet with 0.2% cuprizone) using cuprizone purchased from Sigma (Cat# 14690-100G). Chow is provided ad libitum, and refreshed every 4 days to ensure stability of the cuprizone. Mice are maintained on this diet for 4 -10 months before initiation of the experiments.

[00593] Dosing and PK:

[00594] 1) 24 hours prior to the start of dosing, 6 to 10 mice are switched from cuprizone chow to normal chow (Picolab rodent diet 20 EXT IRR 5053, irradiated) without added cuprizone. These mice are maintained on normal chow throughout the course of dosing.

[00595] 2) 6 to 10 mice per group are randomized into new cages such that mice that are housed in one cage during the cuprizone diet are not housed together in one dose group during the study.

[00596] 3) Mice can be dosed with compound in one of two regimens: Regimen A: mice are dosed QD or BID for 14 days via oral gavage. Regimen B: mice are dosed QD or BID for 14 days via IP injection. However, other dosing schedules and/or routes of administration can also be used.

[00597] 4) On the last day of dosing, dried blood spots are collected at multiple time points following the last dose. Often this is 30 minutes, 2, 6 and 24 hours following the final dose on day 14 via the tail vein.

[00598] Perfusion and sectioning: [00599] 1) The day after the last day of dosing, mice are transcardially perfused with 12 ml of PBS (Sigma, P4417) followed by 20 ml of 3.2% paraformaldehyde in PBS (Electron Microscopy Sciences # 15714-S). The brains are removed via standard dissection techniques and each is postfixed in 3.2% paraformaldehyde (20 ml) for 24- 48 hours at room temperature in sealed scintillation vials.

[00600] 2) Serial 50 micron sections are collected through the anterior posterior extent of the brain, from just behind the olfactory bulb, through visual cortex using a vibrating microtome, the V-STAR (described in International Publication No. WO 2013/012799 and US Patent number US 8,967,024 both of which are incorporated herein by reference in their entirety). Sections are collected in phosphate buffered saline (PBS). Vibratome speed is set to 1.1 mm/s and amplitude is set to 0.8 mm.

[00601] 3) A series of every 24th section is removed for staining yielding 5 sections per brain.

[00602] Staining:

[00603] 1) Tissue sections are stained using an automated system for processing blots (hereinafter the "blotinator") (described in WO2011/087646 and US Patent numbers US 8,337,754 and US 8,679,406 each of which is incorporated herein by reference in its entirety). Brain sections are placed in the blotinator plate and bathed in PBS. The blotinator can apply primary antibodies (MOG and MBP together) and Hoechst nuclear stain for 12 hours at room temperature with constant shaking.

[00604] The following stains are diluted in blocking buffer (described below):

[00605] Hoechst nuclear stain (0.5 mg/ml)(bisBenzimide H 33342 trihydrochloride Sigma # 33342).

[00606] Myelin basic Protein (MBP) antibody (Abeam Cat # ab7349) is diluted at a 1 :750 ratio in blocking buffer).

[00607] Myelin Oligodendrocyte Glycoprotein (MOG) (R&D systems Cat # AF2439) is diluted at a 1 :250 ratio in blocking buffer.

[00608] Antibodies are diluted in blocking buffer, which consists of 0.3% Triton X-100 (Sigma Cat # 234729), 0.02% Sodium Azide (Sigma Cat# S2002) and 8% fetal bovine serum in PBS (Sigma Cat# F2442).

[00609] 2) The blotinator washes the samples 4 times for 5 minutes each with a wash buffer (0.2% Triton X-100 in PBS). [00610] 3) The blotinator can apply secondary antibodies diluted in blocking buffer and incubate them for 2 hours with constant shaking.

[00611] Alexa 488 donkey anti-rat secondary (Life technologies Cat# A-21208) is diluted at 1 : 1000 in blocking buffer.

[00612] Alexa 568 donkey anti-goat secondary (Life technologies Cat# A- 11057) is diluted at 1 : 1000 in blocking buffer.

[00613] Antibodies are also diluted in blocking buffer described above.

[00614] 4) The samples are then washed 4 times for 5 minutes each with wash buffer (0.2% Triton X-100 in PBS).

[00615] 5) All 5 sections are mounted on a slide (Fisherbrand Superfrost Plus microscope slide Cat# 12-550-15) and coverslip with 50 microliters Fluormount (Sigma cat# F4680-25ml) in preparation for scanning.

[00616] Scanning:

[00617] Images are scanned using an Olympus CS120 flourescent scanning microscope. Entire sections are scanned at lOx magnification, with 500 millisecond exposures for the 488 and 568 nanometer fluorescent channels. The Hoechst signal is detected using a 100 millisecond exposure.

[00618] In vivo Myelin Detection Software:

[00619] A custom algorithm developed in house is used to quantify the amount of new myelin in mice that had been demyelinated with cuprizone and subsequently treated with compounds. Conceptually, the software can subtract a mature myelin marker from a pan-myelin (young and old myelin) marker, and measure the area of the remaining "new" myelin. Myelin oligodendrocyte glycoprotein ("MOG") is specific to old myelin, while myelin basic protein ("MBP") is a pan myelin marker, expressed in more immature myelin as well as more mature myelin. This process accounts for the variability inherent in the demyelination process, in which some animals experience more demyelination than others. It more accurately measures myelin generated in response to compound treatment.

[00620] The algorithm can be written using Definiens Tissue Studio and Definiens Developer XD. There are several steps to the algorithm, each of which is discussed below. [00621] Three channels of information for each sample is loaded. The intensity levels of the three images are summed, and the resulting image is used to determine the "tissue" area. Subsequent analyses may be done exclusively on the tissue area.

[00622] The MOG channel is loaded and the Definiens "Auto Threshold" function is used to distinguish MOG positive regions from background. Regions of putative white matter with areas < 50 pixels are returned to the tissue class. Thus, remaining white matter tracts that resist demyelination from cuprizone are excluded from subsequent analyses.

[00623] The ratio of MBP signal to MOG signal is calculated. This consists of the mean MBP intensity value divided by the mean MOG intensity value over the entirety of the image. This MBP:MOG ratio is used to normalize the intensity between the MBP and MOG channels. The normalized MOG signal multiplied by 0.5 is subtracted from the MBP signal, creating a new image, "MBP-MOG". The "Auto Threshold" function is used on the MBP-MOG image, and the 'new' myelin consisting of pixels with intensities above the threshold is delineated. Regions of putative new myelin with areas <2 pixels are returned to the tissue class, and the number of pixels positive for "new" myelin is measured.

[00624] The algorithm returns the area of the tissue and the MBP positive, MOG negative 'new' myelin. Each section is normalized by area relative to its comparable tissue (e.g., the first). Most anterior sections are normalized relative to other first anterior sections. The 5 normalized MBP+/MOG- areas are summed, yielding a total positive area per sample. This yields a representation of myelin synthesis over the whole extent of the brain, excluding the olfactory bulb and the cerebellum.

[00625] Compound of the present invention may be tested in the in vivo Mouse Cuprizone assay described above.

In vitro Myelination Assay

[00626] Compounds were screened for their ability to induce myelination using a primary rat mixed cortical cell culture assay, which contains neurons, oligodendrocyte precursor cells, oligodendrocytes, astrocytes and microglia. The assay quantifies myelination by measuring myelin basic protein (MBP) immunofluorescent positive myelin strands from images taken using a Cellomics Array Scan (model Arrayscan VTI HCS Reader) or a Molecular Devices Image Xpress (model IXM XL) high content imager. The myelin strands were quantitated using a custom created myelin detection software program. Test compounds were dissolved in DMSO to make a 10 mM initial stock solution. Dilutions were made in myelination medium to obtain the final solutions for the assay and were tested in primary rat mixed cortical cells at selected doses.

[00627] Primary rat mixed cortical cells were prepared from harvested cerebral cortices from postnatal day 1 (PI) rats (PI Rat CD® IGS pups) were purchased from Charles River) in Complete Dissociation Medium, wherein the meninges were removed and the cortical tissue chopped with a razor blade into ~1 mm ³ pieces.

Tissue from 1-3 pups was collected and placed into 15 ml conical tubes in a total volume of 5 ml of Complete Dissociation Medium. Activated papain (3 ml) was added to each 15 ml conical tube and tissue was incubated at 37°C for 30 minutes. After the 30 minute incubation, DNase (Sigma D4527; 75 μΐ of a 1 mg/ml stock) was added to each tube, followed by mechanical trituration using a 2 ml serological pipette and autopipettor to gently dissociate the tissue. Following trituration, larger tissue pieces were allowed to settle by gravity, and the supernatant containing dissociated cells was transferred to a 50 ml conical tube with 4 ml of trypsin inhibitor. Cells were pelleted by centrifugation, resuspended in myelination medium and filtered through a 40 μπι filter. Cells were then seeded in 96-well plates (BD Biosciences, Black, PDL- coated, Cat. No. 356640) or in some cases in 384-well plates at 87,500-95,000 cells/well in a final volume of 200μ1 of Myelination Medium in the presence or absence of compound and cultured for 14 days in a humidified 37°C incubator with 5% CO2. Half the medium was removed and replaced with fresh medium containing IX compound on days 6 and 10. Using a Biotek automatic plate washer (model Biomek® FXP Laboratory Automation Workstation), cells were fixed with 4% paraformaldehyde on day 14, washed with PBS and blocked in 5% normal goat serum (Vector Laboratories, S-1000) in 0.1% PBS-TritonX-100 (PBST) for 1 hour. Cells were stained with 1 :500 anti-MBP (Covance, cat #SMI99) primary antibody in 1% normal goat serum in 0.1% PBST for 2 hours at room temperature followed by 2 washes with PBST. A final incubation in secondary antibody (1 : 1000, Invitrogen, Alexa-488 anti-mouse IgG2b) and 1 : 10,000 Hoechst dye in 1% normal goat serum in 0.1% PBST was performed for 2 hours at room temperature. Plates were washed with PBS and then scanned on a Cellomics Array Scan using a 10X objective (25 images per well) or the Image Xpress using a 10X objective (9 image per well). Images were analyzed using Vertex myelin detection software (described below) to quantify total MBP myelin pixels per well. Fold myelin pixels above background at two concentrations (1.0 μΜ and 10.0 μΜ) relative to baseline of no added compound are reported below in Table 4. Standard deviation for each compound concentration was calculated using all replicates and using a standard deviation formula commonly used in the art.

[00628] One of skill in the art would recognize that for this type of primary neuronal mixed cell assay variability between different assay runs is to be expected even though the protocol is the same for each assay run. For instance, variability may be due to small differences in cell viability, cell density, age of the animals, etc.

[00629] Vertex Myelin Detection Software:

[00630] The Vertex myelin detection software was used to quantify the amount of myelin wrapping axons in a digital image that was obtained from our in-house microscope. Conceptually, the software identified and traced MBP positive ridge like structures in the image that were indicative of myelinating axons. A confounding factor in the analysis was the large debris fields typically occurring in the images. These fields resulted from the assay conditions required to achieve myelination. Special care was taken to ensure that noise in the image induced by the debris field was appropriately suppressed so that the signal that arose from the myelination could be recovered. The software was written in the Jython programming language and made significant utilization of the Fiji image analysis toolkits (see, Schindelin, J.; Arganda-Carreras, I. & Frise, E. et al., "Fiji: an open-source platform for biological- image analysis", Nature Methods 9(7): 676-682, 2012). There were several steps to the algorithm, each of which are discussed below.

[00631] Initially the image was loaded and converted to a 256-bit grey scale representation. Image contrast was enhanced by performing standard histogram stretching. The saturation parameter for the enhancement was set at 0.35, meaning the upper and lower 3.5% of the distribution of the gray scale values present in the image were removed prior to enhancement. The Frangi[2] vesselness measure, which computes the likelihood of a pixel belonging to a ridge-like structure, was applied to the resulting image (see, Frangi AF, Niessen WJ, Vincken KL, Viergever MA "Multiscale vessel enhancement filtering", Proceedings of Medical Image Computer- Assisted Intervention (MICCAI), Lecture notes in computer science 1496: 130-137, 1998). The Frangi process created a "vessel likeness image" which was then converted to a binary image mask. The threshold of the Frangi measure for conversion to the mask was adjusted so that appropriate regions of the input image were selected. Once the mask was created, morphological closing was applied to remove small holes. Small structures were removed from the mask by deleting regions containing less than 40 connected pixels. The resulting mask overlaps regions of the original image that had a high likelihood of containing myelin strands.

[00632] Morphological skeletonization was applied to the binary mask and the resulting image was then converted to a graph data structure. Each node of the graph represented a pixel of the image. Owing to the skeletonizaiton process, each node was connected to at most 4 neighboring pixels. Nodes connected to one other node indicated the end of a myelin strand ("end nodes"); nodes connected to exactly two other nodes indicated a pixel contained in a myelin strand ("myelin node"); while nodes connected to 3 or 4 other nodes indicated regions where myelin strands intersect ("join nodes"). Neighboring 'myelin nodes' that were adjacent to the same "join node" were merged into longer strands of myelin. This process was done in a greedy fashion. The longest strand of myelin originating from an "end node" in the graph were identified. If this strand terminated in an end node the strand was extracted from the graph. If the strand terminated at a "join node" then it was joined with one of the other myelin strands adjacent to the same join node. The largest angle between the growing strand and all other strands adjacent to the join node was determined. If this angle was greater or equal to 140 degrees, then the growing strand and the strand that made this large angle were merged into one strand. The two strands that were merged were removed from being adjacent to the "join node". If the angle was less than 140 degrees, the growing strand was extracted from the graph and removed as being adjacent to the join node. The entire process was repeated until all strands were removed from the graph. Various geometric properties of the strand such as length and maximum curvature were computed from the number of pixels in the strand and the connectivity of the graph.

[00633] Before a putative myelin strand was quantified as myelin it was subjected to several quality control measures. The strand needed to be of a sufficient length (at least greater than 40 pixels). To ensure the strand was not overly curved, the ratio of the geometric distance between strand endpoints to the length of the strand needed to be greater than or equal to 0.8. Finally, to ensure the strand was not overly thick, the gray scale gradient at each point on the strand in the directions orthogonal to the strand direction needed to decay sufficiently rapidly. Specifically, the gray scale needed to decrease by 25% from the gray scale value of pixel intersected by the orthogonal line and the putative myelin strand. This decrease needed to occur within 5 pixels. If a strand passes all quality checks it was quantified as myelin.

[00634] Reagent and media preparation and animal source for the in vitro

Myelination Assay

[00635] lOx Dissociation Media (DM): lOx DM was prepared on a 1 liter scale by combining 900 mM Na2S04, 300 mM K2S04, 58 mM MgC12, 2.5 mM CaC12, 10 mM HEPES and 20 mL of a phenol red solution (0.5%). The pH was adjusted with . IN NaOH by eye until orange-red. The solution was then sterilized by Alteration through a 0.2uM filter (prewashed with 100 ml of deionized sterile water which was discarded prior to filtration of the DM media solution.

[00636] lOx KyMg Stock: KyMg stock was prepared on a 200 mL scale as follows. To a 250 mL flask was added 190 mL of water, 1 mL of phenol red (Sigma P0290), stock, 1.75 mL of IN NaOH, 378 mg of kynurenic acid, and 2 mL 500 mM HEPES. The mixture was then sonicated to dissolve the kynurenate and then MgC12 (4.1 ml of a 4.9 M solution) was added. The pH was adjusted to 7.4 by adding up to 1 ml of 0. IN NaOH and the mixture sterilized by filtration through a prewashed nylon filter (0.2 μπι pore).

[00637] Complete dissociation medium (DM): 5 mL Ky Mg to 45 mL IX DM media

[00638] Papain Enzyme Solution (Worthington Biochemical LK003178), A 10 units/mL stock solution was made fresh the day of dissection by adding lmL of lOmM NaOH and Complete Dissociation Medium to one vial of papain (-100 units) to give a 10 units/mL final concentration. The papain was activated at 37 °C for 10- 15 minutes prior to use.

[00639] Trypsin Inhibitor Solution : 9.6mL of Complete Dissociation Medium was added to 100 mg of trypsin inhibitor (type II-O; Sigma T-9253) and the mixture was sonicated. The pH was adjustedto -5.75 using IN NaOH and pH strips. Aliquots (4 mL) were measured out and and stored at -20 °C. [00640] DNase I Solution lmg/mL): Added 25 mL DMEM/F12 medium (Corning, 10-092-CM) to 20 KU DNAse I (Sigma D4527) and aliquoted into one time use aliquots stored at -20° C.

Myelination Medium:

DMEM (Invitrogen, Cat #11960-051)

1 :50 B27 (Invitrogen, Cat #17504-044)

1% FBS (HyClone)

2 mM Glutamax (1 : 100) (Cat # Gibco 25030081)

Pen Strep (1 : 100) 10,000 units/mL (Cat # Gibco 15140122)

PDGF/FGF 0.3 ng/mL each (3 uL per 100 mL; PeproTech, cat #100-13A and cat #100-18B

Myelination medium was made fresh the day of use from a stock bottle of DMEM containing pencillin/streptomycin and Glutamax, which was stored at 4° C for up to one month. On the day of use, 1 :50 B27, 1% FBS and 0.3ng/mL of PDGF and FGF were added to the DMEM containing pencillin/streptomycin and Glutamax.

[00641] Other in vitro and in vivo assays and models known in the art may also be used to show induction of remyelination in response to treatment with compounds such as those of the present invention (see, Nairn, F. J. et al., Nature (Letter), published online 20 April 2015, doi: 10.1038/naturel4335 and Macklin, W.B. et al., Developmental Cell, 32, pp 447-458 (2015))

[00642] The activities of the compounds below were determined by testing groups of compounds in different test batches. Compounds with no asterisk were part of one in vitro assay testing batch. Compound numbers indicated with an asterisk were all part of a different in vitro assay test batch. Compounds in Table 4 below have between less than 1 fold to greater than 10,000 fold myelin pixels above background at two concentrations (1.0 μΜ and 10.0 μΜ) relative to baseline of no added compound. Table 4. Remyelination in vitro data.

Fold relative to baseline Activity

D not determined

<1

>1 to lOx +

>10 to lOOx ++

> 100 to lOOOx +++

>1000 to 10,000x ++++

[00643] All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms in this disclosure are intended to be controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments of the invention. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.