EA046421B1 - ION CHANNEL MODULATORS - Google Patents

Description

Cross references to related applications

This application claims the priority and benefit of U.S. Provisional Patent Application Number 62/738508, filed September 28, 2018, which is incorporated herein by reference in its entirety.

State of the art

Sodium ion (Na+) channels generally open transiently and are quickly inactivated, thereby generating a rapid Na+ current that initiates an action potential. The late or constant sodium current (INaL) is the sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal amplification of INaL, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, for example, Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceutical compounds that selectively modulate sodium channel activity, such as abnormal INaL, are useful in the treatment of such disease states.

The essence of the invention

Disclosed herein are fused heteroaryl compounds and compositions useful for the prevention and/or treatment of a disease, disorder or condition, for example, a disease, disorder or condition associated with aberrant sodium ion channel function, for example, abnormal late sodium current (INaL).

In one aspect of the present invention there is provided a compound having Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X and Y are each independently CR ^d or N;

R ¹ represents

CF3, monocyclic _C3 . ₆ cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C ₁ . ₄ haloalkyl or monocyclic _C3 . ₆ cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C ₁ . ₄ alkyl or C ₁ . ₄ haloalkyl;

R ⁴ represents hydrogen or C ₁ . ₄ alkyl;

R ⁵ represents halogen, C ₃ . ₆ cycloalkyl or _C1 . ₄ alkyl optionally substituted O-C ₁ . ₄ alkyl or O-C ₃ . ₆ cycloalkyl;

R ⁶ represents C ₁ . ₄ alkyl or C ₁ . ₄ haloalkyl, where each C is ₁ . ₄ alkyl or C ₁ . ₄ haloalkyl is substituted with ORc;

t is 1 or 2;

R ^a and R ^b are each independently selected from halogen, C ₁ . ₄ alkyl, C ₁ . ₄ haloalkyl, C ₁ . ₄ alkoxy and C ₁ . ₄ haloalkoxy,

R ^c represents C ₁ . ₄ alkyl, optionally substituted with C ₃ . ₆ cycloalkyl or phenyl, or C ₃ . ₆ cycloalkyl; And

R ^d represents hydrogen or C ₁ . ₄ alkyl;

In another aspect, this disclosure provides a compound having formula II:

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents '

CF3, monocyclic _C3 . ₆ cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C ₁ . ₄ haloalkyl or monocyclic _C3 . ₆ cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C ₁ . ₄ alkyl or C ₁ . ₄ haloalkyl;

R ⁴ represents hydrogen or C ₁ . ₄ alkyl;

- 1 046421

R ⁵ represents halogen, C _3-6 cycloalkyl or C _1-4 alkyl optionally substituted with O-C _1-4 alkyl or O-C _3-6 cycloalkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, wherein each said C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

t is 1 or 2;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy, and

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl.

In another aspect, this disclosure provides a compound having formula III:

or a pharmaceutically acceptable salt thereof, where a< ^r2

R ¹ represents ^RR ,

CF3, monocyclic C _3-6 cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C _1-4 haloalkyl or monocyclic C _3-6 cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;

R ⁴ represents hydrogen or C _1-4 alkyl;

R ⁵ represents halogen, C _3-6 cycloalkyl or C _1-4 alkyl optionally substituted with O-C _1-4 alkyl or O-C _3-6 cycloalkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, where each C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

t is 1 or 2;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy, and

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl.

In another aspect, this disclosure provides a compound having Formula IV:

G 11 ^r6

CHAUCHU

T( _IV ).

or a pharmaceutically acceptable salt thereof, wherein

X and Y are each independently CR ^d or N;

a< ^r2

R ¹ represents ^RR '

CF ₃ , monocyclic C _3-6 cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C _1-4 haloalkyl or monocyclic C _3-6 cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;

R ⁴ represents hydrogen or C _1-4 alkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, wherein each C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy,

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl; And

R ^d represents hydrogen or C _1-4 alkyl;

provided that the connection is not

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or a pharmaceutically acceptable salt thereof.

Also provided herein is a pharmaceutical composition containing a compound disclosed herein (eg, a compound of formula I, II, III or IV) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In another aspect, provided herein is a method of treating a condition associated with aberrant sodium ion channel function in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, II, III, or IV), or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

In some embodiments, the condition is a neurological or mental disorder. In some embodiments, the condition is epilepsy or an epileptic syndrome. In some embodiments, the condition is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is pediatric epilepsy or pediatric epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.

In some embodiments, the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, incurable childhood epilepsy with generalized tonics - clonic seizures, infantile seizures, benign familial neonatal infantile seizures, epileptic encephalopathy SCN2A, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, epileptic encephalopathy SCN8A, sudden unexpected death in epilepsy, Rasmussen encephalitis, qualitative migratory partial seizures of infancy, autosomal -dominant nocturnal frontal epilepsy, sudden expected death in epilepsy (SUDEP), epileptic encephalopathy KCNQ2 and epileptic encephalopathy KCNT1.

In another aspect, provided herein is a method of treating a neurological disorder or mental disorder, the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of formula, I, II, III, or IV), or a pharmaceutical thereof. an acceptable salt, or pharmaceutical composition disclosed herein.

In another aspect, provided herein is a method of treating pain, the method comprising administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula I, II, III, or IV), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition disclosed herein.

Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims.

Detailed description of the invention

As generally described herein, the present invention provides compounds and compositions useful for the prevention and/or treatment of a disease, disorder or condition described herein, for example, a disease, disorder or condition relating to aberrant sodium ion channel function. such as abnormal late sodium current (INaL). Examples of diseases, disorders, or conditions include a neurological disorder (eg, epilepsy or epileptic syndrome, neurodevelopmental disorder, or neuromuscular disorder), mental disorder, pain, or gastrointestinal disorder.

Definitions.

Chemical definitions.

Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed., inside the cover, and specific functional groups are usually identified as described therein. In addition, the general principles of organic chi

- 3 046421 functions, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March Advanced Organic Chemistry, 5th ed., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

The compounds described herein may contain one or more asymmetric centers and, therefore, may exist in various isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be obtained by asymmetric synthesis. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention further covers the compounds described herein as individual isomers, substantially free from other isomers and, alternatively, as mixtures of different isomers.

As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (ie, in enantiomeric excess). In other words, the S form of the compound is essentially free from the R form of the compound and is thus in an enantiomeric excess of the R form. The term enantiomerically pure or pure enantiomer means that the compound contains more than 75 wt.%, more than 80 wt.%, more than 85 wt.%, more than 90 wt.%, more than 91 wt.%, more than 92 wt.%, more than 93 wt.%, more than 94 wt.%, more than 95 wt.%, more more than 96 wt.%, more than 97 wt.%, more than 98 wt.%, more than 98.5 wt.%, more than 99 wt.%, more than 99.2 wt.%, more than 99.5 wt.%, more than 99.6 wt.%, more than 99.7 wt.%, more than 99.8 wt.%, or more than 99.9 wt.% of the enantiomer. In some embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R compound in such compositions may contain, for example, at least about 95 weight percent R compound and no more than about 5 weight percent S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S compound in such compositions may contain, for example, at least about 95 weight percent S compound and no more than about 5 weight percent R compound, based on the total weight of the compound. In some embodiments, the active ingredient may be formulated with little or no excipient or carrier.

The compound described herein may also include one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, ^2H (D or deuterium), and ^3H (T or tritium); C can be in any isotopic form, including ¹² C, ¹³ C and ¹⁴ C; O can be in any isotopic form, including ¹⁶ O and ¹⁸ O, F can be in any isotopic form, including ¹⁸ F and ¹⁹ F; etc.

The following terms are intended to have the meanings set forth below and are useful in understanding the description and intended scope of the present invention. In describing the invention, which may include the compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that, as described herein, any of the moieties defined below may be substituted by a variety of substituents, and that the corresponding definitions are intended to include such substituted moieties within their scope as set forth below. Unless otherwise specified, the term substituted is defined as follows. It should also be understood that the terms groups and radicals may be considered interchangeable when used herein. Singular forms of an object may include corresponding plural forms (ie, at least one) of the object. By way of example, analogue means one analogue or more than one analogue.

When a range of values is specified, it must cover every value and subrange within the range. For example, C^^km is intended to cover C1, _C2 , _C3 , _C4 , C5, _C6 , _{C1-6 , C1-5} , _C1-4 , _C1-3 , _C1-2 ,

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C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and ^C 5-6 ^alkyl .

As used herein, alkyl refers to a straight or branched saturated hydrocarbon group radical that, for example, has 1 to 20 carbon atoms (C _1-20 alkyl). In some embodiments, the alkyl group has from 1 to 10 carbon atoms (C _1-10 alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms (C _1-9 alkyl).

In some embodiments, the alkyl group has 1 to 8 carbon atoms (C _1-8 alkyl).

In some embodiments, the alkyl group has 1 to 7 carbon atoms (C _1-7 alkyl).

In some embodiments, the alkyl group has 1 to 6 carbon atoms (C _|-6 alkyl).

In some embodiments, the alkyl group has 1 to 5 carbon atoms ( _C1-5 alkyl).

In some embodiments, the alkyl group has 1 to 4 carbon atoms ( _C1-4 alkyl).

In some embodiments, the alkyl group has 1 to 3 carbon atoms ( _C1-3 alkyl).

In some embodiments, the alkyl group has 1 to 2 carbon atoms ( _C1-2 alkyl).

In some embodiments, the alkyl group has 1 carbon atom (Calkyl). Examples of Ci _-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.

As used herein, alkenyl refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally one or more carbon-carbon triple bonds (eg, 1, 2, 3 or 4 carbon-carbon triple bonds) (C _2-20 alkenyl). In some embodiments, alkenyl does not contain triple bonds. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms (C _2-10 alkenyl). In some embodiments, the alkenyl group has from 2 to 9 carbon atoms (C _2-9 alkenyl). In some embodiments, the alkenyl group has from 2 to 8 carbon atoms (C _2-8 alkenyl). In some embodiments, the alkenyl group has from 2 to 7 carbon atoms (C _2-7 alkenyl). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms (C _2-6 alkenyl). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (C _2-5 alkenyl). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (C _2-4 alkenyl). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (C _2-3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms (C ₂ alkenyl). One or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2butenyl ( _C4 ), butadienyl ( _C4 ) and the like. Examples of _C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6) and the like. Additional examples of alkenyls include heptenyl ( _C7 ), octenyl (C8), octatrienyl (C8) and the like.

As used herein, alkynyl refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally one or more carbon-carbon double bonds (eg, 1, 2, 3 or 4 carbon-carbon double bonds) (C _2-20 alkynyl). In some embodiments, the alkynyl does not contain double bonds. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms (C2-10 alkynyl). In some embodiments, the alkynyl group has from 2 to 9 carbon atoms (C _2-9 alkynyl). In some embodiments, the alkynyl group has from 2 to 8 carbon atoms (C _2-8 alkynyl). In some embodiments, the alkynyl group has from 2 to 7 carbon atoms (C _2-7 alkynyl). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (C _2-6 alkynyl). In some embodiments, the alkynyl group has 2 to 5 carbon atoms (C _2-5 alkynyl). In some embodiments, the alkynyl group has 2 to 4 carbon atoms (C _2-4 alkynyl). In some embodiments, the alkynyl group has 2 to 3 carbon atoms (C _2-3 alkynyl). In some embodiments, the alkynyl group has 2 carbon atoms (C ₂ alkynyl). One or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C _2-4 alkynyl groups include, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and etc. Examples of _C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyls include heptynyl (C ₇ ), octinyl (C ₈ ), and the like.

As used herein, alkylene, alkenylene and alkynylene refer to the divalent radical of the alkyl, alkenyl and alkynyl group, respectively. When a range or number of carbon atoms is provided for a particular alkylene, alkenylene or alkynylene group, it is intended that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. Alkylene, alkenylene and alkynylene groups may be substituted or unsubstituted in one or more combinations

- 5 046421 titers as described in this document.

As used herein, aryl refers to a radical monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring system) having 6-14 ring carbon atoms and zero heteroatoms , included in the aromatic ring system (C _{6-1 4} aryl). In some embodiments, the aryl group has six ring carbon atoms (C ₆ aryl; eg, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (Suaryl; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (Cvaryl; e.g., anthracyl). Aryl also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms still indicates the number of atoms carbon in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, az-indacene, s-indacene, indane, indane , indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl.

As used herein, heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms represented by in an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (5-10 membered heteroaryl). In a heteroaryl group that contains one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence allows. Heteroaryl bicyclic ring systems may include one or more heteroatoms on one or both rings. Heteroaryl includes ring systems in which the heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to denote the number of ring members in the heteroaryl ring system. also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups, in which one ring does not contain a heteroatom (for example, indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on any ring, that is, either on a ring bearing a heteroatom (for example, 2-indolyl) or on a ring that does not contain a heteroatom (for example, 5-indolyl).

In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (5-10 member heteroaryl). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms present in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (5-8 membered heteroaryl). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms present in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (5-6 membered heteroaryl). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Typical 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Typical 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Typical 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Typical 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Typical 6-membered heteroaryl groups containing three or four

- 6,046,421 thousand heteroatoms include, without limitation, thiazinyl and tatrazinyl, respectively. Typical 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Typical 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzimidazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzthiadiazolyl, zinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of heteroaryl representatives include the following:

O Ό Ό X ίχ 0

Z Z' Z N 'Ύ N

where each Z is selected from carbonyl, N, NR ⁶⁵ , O and S; and R ⁶⁵ independently represents hydrogen, C^alkyl, C3. ₁₀ carbocyclyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl.

As used herein, carbocyclyl or carbocyclic refers to a non-aromatic cyclic hydrocarbon group radical containing 3 to 10 ring carbon atoms (C ₃ to ₁₀ carbocyclyl) and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has from 3 to 8 ring carbon atoms (C _{3 8} carbocyclyl). In some embodiments, the carbocyclyl group has from 3 to 7 ring carbon atoms (C ₃ . ₇ carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms (C ₃ . ₆ carbocyclyl). In some embodiments, the carbocyclyl group has from 5 to 10 ring carbon atoms (C ₅ to ₁₀ carbocyclyl). Typical C ₃ . ₆ carbocyclyl groups include, but are not limited to, cyclopropyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl ( _C6 ), cyclohexenyl ( _C6 ), cyclohexadienyl (C ₆ ), and the like. Typical C ₃ . The ₈ carbocyclyl groups include, without limitation, the aforementioned _C3 . ₆ carbocyclyl groups, as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cyclosheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2,2,1] heptanyl (C ₇ ), bicyclo[2,2,2]octanyl (C ₈ ), and the like. Typical C ₃ . The ₁₀ carbocyclyl groups include, without limitation, the aforementioned _C3 . ₈ carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl ( _C10 ), cyclodecenyl ( _C10 ), octahydro-III-indenyl (C9), decahydronaphthalenyl ( _C10 ), spiro[4.5]decanyl (C ₁₀ ) and the like. As can be seen from the above examples, in specific embodiments, the carbocyclyl group is either monocyclic (monocyclic carbocyclyl) or contains a fused, bridged or spiro ring system such as a bicyclic system (bicyclic carbocyclyl) and may be saturated or may be partially unsaturated , carbocyclyl also includes ring systems in which the carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbon atoms still indicates the number of carbon atoms in a carbocyclyl ring system.

The term cycloalkyl refers to a monovalent saturated cyclic, bicyclic or bridged cyclic (eg adamantyl) hydrocarbon group of 3-12, 3-8, 4-8 or 4-6 carbon atoms, referred to herein, for example, as C ₄ . ₈ cycloalkyl, a cycloalkane derivative. Typical cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

In the context of this document C ₃ . ₆ monocyclic C ₃ . ₆ cycloalkyl refers to a 3-7 membered monocyclic hydrocarbon ring system that is saturated. 3-7 membered monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If cycloalkyl is indicated to be optionally substituted or substituted, then substituents on the cycloalkyl (eg, in the case of optionally substituted cycloalkyl) may be present at any substitutable position and include, for example, the position at which a cycloalkyl group is attached.

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As used herein, heterocyclyl or heterocyclic refers to a 3- to 10-membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (3 -10-membered heterocyclyl). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence allows. The heterocyclyl group may be either monocyclic (monocyclic heterocyclyl) or fused, bridged or spiro ring system such as a bicyclic system (bicyclic heterocyclyl) and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms on one or both rings. Heterocyclyl also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or heterocyclyl ring, or ring systems, wherein a heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclic ring, and in such cases the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. The terms heterocycle, heterocyclyl, heterocyclyl ring, heterocyclic group, heterocyclic moiety, and heterocyclic radical may be used interchangeably.

In some embodiments, the heterocyclyl group is a 4-7 membered non-aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (4-7 membered heterocyclyl). In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (5-10 membered heterocyclyl) . In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (5-8 membered heteroaryl). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (5-6 membered heteroaryl). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Typical 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Typical 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Typical 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Typical 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Typical 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Typical 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Typical 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Typical 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl and tiepanil. Typical 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Typical 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Typical 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. If it is stated that

- 8 046421 heterocyclyl is optionally substituted or substituted, then substituents on the heterocyclyl (eg in the case of optionally substituted heterocyclyl) may be present at any substitutable position and include, for example, the position at which the heterocyclyl group is attached.

Hetero, when used to describe a compound or group present in a compound, means that one or more carbon atoms in the compound or group have been replaced by a heteroatom of nitrogen, oxygen, or sulfur. Hetero can apply to any of the hydrocarbyl groups described above, such as alkyl, eg heteroalkyl; carbocyclyl, for example heterocyclyl; aryl, for example heteroaryl; etc., containing from 1 to 5, in particular from 1 to 3 heteroatoms.

As used herein, cyano refers to -CN.

The terms halo and halogen as used herein refer to an atom selected from fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) and iodine (iodine, -I). In some embodiments, the halogen group is fluorine or chlorine.

The term alkoxy as used herein refers to an alkyl group that is attached to another moiety via an oxygen atom (-O(alkyl)). Non-limiting examples include, for example, methoxy, ethoxy, propoxy and butoxy.

A haloalkoxy is a haloalkyl group that is attached to another moiety via an oxygen atom, such as, for example, but not limited to -OCHCF2 or _-OCF3 .

The term haloalkyl includes mono, poly and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogens are independently selected from fluorine, chlorine, bromine and iodine. For a _C1-4 haloalkyl-O- _C1-4 alkyl group, the point of attachment is on the alkyl moiety, which is halogenated.

In the context of this document, nitro refers to -NO2.

In the context of this document, oxo refers to -C=O.

In general, the term substituted, whether optionally preceded by a term or not, means that at least one hydrogen present in a group (such as a carbon or nitrogen atom) is replaced by an acceptable substituent, such as a substituent that, when substituted, results in to a stable compound, for example, to a compound that does not spontaneously undergo transformation, such as rearrangement, cyclization, elimination, or other reaction. Unless otherwise stated, a substituted group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

The nitrogen atoms may be substituted or unsubstituted as valency permits and include primary, secondary, tertiary and quaternary nitrogen atoms. Examples of substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, -OR ³³ , -N(R ^cc )2, -Cn, -C(=O)R ^aa , -C(=O)N(R ^cc )2, -CO2R ^aa , -SO2R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc )2, -SO2N(R ^cc )2, -SO2R ^cc , -SO2OR ^cc , -SOR ³³ , -C(=S)N(R ^cc )2, -C(=O)SR ^cc , -C(=S)SR ^cc , -P(= O)2R ^aa , -P(=O)(R ^aa )2, -P(=O)2N(R ^cc )2, -P(=O)(NR ^cc )2, C1-yualkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 member heteroaryl, or two R ^cc groups attached to a nitrogen atom, connected to forming a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl ring is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, and where R ^aa , ^Rbb , ^Rcc and ^Rdd are as defined above.

These and other typical substituents are described in more detail in the Detailed Description, Examples, and Claims. The present invention is in no way limited to the above list of typical substituents.

Other definitions.

As used herein, a pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant or carrier vehicle that does not interfere with the pharmacological activity of the compound of which it is included. Pharmaceutically acceptable carriers, adjuvants, or carrier vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine. , sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances , polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

As used herein, a pharmaceutically acceptable salt refers to those salts which, within the bounds of reasonable medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, or the like, and are commensurate with a reasonable benefit/benefit ratio. risk. Pharmaceutically acceptable salts are well known in the art. For example,. Berge, et al., describe in detail the pharmaceutical

- 9 046421 highly acceptable salts in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid , citric acid, succinic acid or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbat, aspartate, benzophulus, benzoate, bisulfate, borat, butyrate, kmforates, campfordfonet, citrate, cyclopentanepropionate, diglyaconate, predezil sulfate, ethangent, format, fumarat, glucogheptonate, claw Cerofosphate, gluconate, hemysulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, 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. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C _{1 4} alkyl) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and counterionic amine cations such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As used herein, the term subject to be administered includes, but is not limited to, humans (i.e., men or women of any age group, e.g., pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult , middle-aged adult or elderly adult)) and/or a non-human animal, for example, a mammal such as primates (e.g. cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats and/ or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms person, patient, and subject are used interchangeably throughout this document.

Disease, disorder and condition are used interchangeably in this document.

As used herein, unless otherwise specified, the terms treat, cure, and cure mean an action that occurs when a subject is suffering from a specified disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or slows or delays the progression of the disease, disorder or condition (therapeutic treatment), and also involves an action that occurs before the subject begins to suffer from the specified disease, disorder or condition (preventive treatment).

As used herein, an effective amount of a compound refers to an amount sufficient to cause the desired biological response. Those skilled in the art will appreciate that the effective amount of a compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject. The effective amount covers therapeutic and prophylactic treatment.

As used herein and unless otherwise indicated, a therapeutically effective amount of a compound is an amount sufficient to provide a therapeutic effect in treating a disease, disorder or condition, or to delay or minimize one or more symptoms associated with a disease, disorder or condition. condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic effect in treating a disease, disorder or condition. The term therapeutically effective amount may include that amount that improves overall therapy, reduces or eliminates symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

Connections.

In one aspect of the present invention there is provided a compound having Formula I:

or a pharmaceutically acceptable salt thereof, wherein

- 10 046421

X and Y are each independently CR ^d or N;

R ¹ represents

CF ₃ , monocyclic C _3-6 cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C _1-4 haloalkyl or monocyclic C _3-6 cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;

R ⁴ represents hydrogen or C _1-4 alkyl;

R ⁵ represents halogen, C _3-6 cycloalkyl or C _1-4 alkyl optionally substituted with O-C _1-4 alkyl or O-C _3-6 cycloalkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, wherein each C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

t is 1 or 2;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy,

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl; And

R ^d represents hydrogen or C _1-4 alkyl;

In another aspect, the present invention provides a compound having formula II:

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents >

CF ₃ , monocyclic C _3-6 cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C _1-4 haloalkyl or monocyclic C _3-6 cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;

R ⁴ represents hydrogen or C _1-4 alkyl;

R ⁵ represents halogen, C _3-6 cycloalkyl or C _1-4 alkyl optionally substituted with O-C _1-4 alkyl or O-C _3-6 cycloalkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, wherein each said C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

t is 1 or 2;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy, and

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl.

In another aspect, the present invention provides a compound having formula III:

or a pharmaceutically acceptable salt thereof, wherein

R ¹ represents

CF3, monocyclic C _3-6 cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C _1-4 haloalkyl or monocyclic C _3-6 cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;

R ⁴ represents hydrogen or C _1-4 alkyl;

- 11 046421

R ⁵ represents halogen, C _3-6 cycloalkyl or C _1-4 alkyl optionally substituted with O-C _1-4 alkyl or O-C _3-6 cycloalkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, wherein each C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

t is 1 or 2;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy, and

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl.

In another aspect, the present invention provides a compound having Formula IV:

or a pharmaceutically acceptable salt thereof, wherein

X and Y are each independently CR ^d or N;

x< ^r2

R ¹ represents ^RR '

CF3, monocyclic C _3-6 cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more R ^a ;

R ² represents hydrogen, C _1-4 haloalkyl or monocyclic C _3-6 cycloalkyl, optionally substituted with one or more R ^b ;

R ³ represents hydrogen, C _1-4 alkyl or C _1-4 haloalkyl;

R ⁴ represents hydrogen or C _1-4 alkyl;

R ⁶ represents C _1-4 alkyl or C _1-4 haloalkyl, wherein each C _1-4 alkyl or C _1-4 haloalkyl is substituted with OR ^c ;

R ^a and R ^b are each independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy;

R ^c represents C _1-4 alkyl, optionally substituted with C _3-6 cycloalkyl or phenyl, or C _3-6 cycloalkyl; And

R ^d represents hydrogen or C _1-4 alkyl;

provided that the connection is not

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is N and Y is CR ^d. In some embodiments, X is CR ^d and Y is N.

x< ^r2

In some embodiments, R ¹ is ·

In some embodiments, R ¹ is cyclobutyl, optionally substituted with one or more R ^a . In some embodiments, R ¹ is CF ₃ .

In some embodiments, R ² is C _1-4 haloalkyl. In some embodiments, ^R2 is CF3. In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is C1-4alkyl and ^R4 is hydrogen or C1-4alkyl. In some embodiments, R ³ and R ⁴ are each C _1-4 alkyl. In some embodiments, R ³ and R ⁴ are each methyl. In some embodiments, R ³ is methyl and R ⁴ is hydrogen. In some embodiments, R ³ and R ⁴ are each hydrogen.

In some embodiments, R ⁶ is CF2-OR ^c . In some embodiments, R ^c is C1-4 alkyl, optionally substituted with cyclopropyl. Somehow

- 12 046421 In some embodiments, R ^c is cyclopropyl. In some embodiments, R ⁶ is CF2OCH3, CF2OCH2CH3, CF2OCH(CH3)2, or CF2OCH2C3H5.

In some embodiments, R ⁶ is CH2-OR ^c . In some embodiments, R ^c is C1.4 alkyl, optionally substituted with cyclopropyl or phenyl. In some embodiments, R ^c is cyclopropyl. In some embodiments, R ⁶ is CH2OCH3, CH2OCH2CH3, CH2OCH2C3H5, CH2OCH ₂ CH(CH ₃ ) ₂ , or CH2OCH2C6H5.

In some embodiments, R ⁶ is C(CH3)2-OR ^c . In some embodiments, R ^c is C1.4alkyl. In some embodiments, R ⁶ is C(CH3)2-OCH2CH3.

In some embodiments, R ^a is fluorine.

In some embodiments, t is 1. In some embodiments, t is 2.

In some embodiments, ^R5 is halogen or C1.4alkyl, optionally substituted with OCH3 or OCH3H5. In some embodiments, R ⁵ is fluorine. In some embodiments, R ⁵ is methyl. In some embodiments _, ^R5 is fluorine, _{CH3, CH2CH3 , CH2OCH3 ,} CH( _CH3 ) _OCH3 , or _{CH2OC3H5 .}

In some embodiments, R ^d is hydrogen.

In some embodiments, the connection is

- 13 046421

- 14 046421

or a pharmaceutically acceptable salt of any of the above. In some embodiments, the connection is

or a pharmaceutically acceptable salt of any of the above.

Pharmaceutical compositions and methods of administration.

The compounds of the present invention are typically administered in the form of pharmaceutical compositions. Thus, the present invention provides pharmaceutical compositions that contain as an active ingredient one or more of the described compounds or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and excipients, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared by a method well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3- e ed. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions can be administered in single or multiple doses by any of the accepted routes of administration of agents having similar uses, for example, as described in these patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, inhalant, or through an impregnated or coated device such as a stent, for example, or a cylindrical polymer inserted into an artery.

One route of administration is parenteral, in particular by injection. Forms in which the new compositions of the present invention may be formulated for injection include aqueous or oleaginous suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution and similar pharmaceutical carriers. Aqueous solutions in physiology

- 15 046421 chemical solution is also commonly used for injection, but is less preferred in the context of the present invention. Ethanol, glycerin, propylene glycol, liquid polyethylene glycol, etc. can also be used. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils. Suitable fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.

Sterile injection solutions are prepared by incorporating the compound of the present invention in the required amount in a suitable solvent with various other ingredients listed above, if necessary, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile stock solution that contains the basic dispersion medium and other necessary ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze drying technologies, which result in a powder of the active ingredient plus any additional active ingredient from its previously sterile-filtered solution.

Oral administration is another route of administration for the compounds of the invention. Administration may be in the form of capsules or enteric-coated tablets and the like. In the manufacture of pharmaceutical compositions that include at least one compound described herein, the active ingredient is typically diluted with an excipient and/or enclosed in such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material (as defined above) that serves as a carrier, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, dragees, powders, lozenges, sachets, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, for example, up to 10 wt. %, active compound, soft and hard gelatin capsules, sterile injection solutions or sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The compositions may further include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners and flavorings.

The compositions of this invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are provided in US Pat. No. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. In another formulation, transdermal delivery devices (patches) are used for use in the methods of the present invention. Such transdermal patches can be used to provide continuous or intermittent infusion of the compounds of the present invention in controlled amounts. The design and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art, see, for example, US patent No. 5023252; 4992445 and 5001139. Such patches can be designed for continuous delivery, pulsatile delivery or on-demand delivery of pharmaceutical substances.

The compositions are preferably formulated in unit dosage form. The term unit dosage forms refers to physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are typically administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound described herein. It should be understood, however, that the amount of compound actually administered will generally be determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration chosen, the compound actually administered and its relative potency, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .P.

To prepare solid compositions such as tablets, the main active ingredient is mixed

- 16 046421 are combined with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of the compound of the present invention. When these preformulated compositions are referred to as homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills and capsules.

The tablets or dragees of the present invention may be coated or otherwise formulated to provide a dosage form that provides the benefit of a sustained release or to protect against acidic conditions of the stomach. For example, a tablet or dragee may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating for the former. The two components can be separated by an enteric layer, which prevents decomposition in the stomach and allows the internal component to enter the duodenum intact or be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, such materials containing a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic action. Compositions in preferably pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions may be inhaled directly from the nebulization device, or the nebulization device may be attached to a cloth face mask or intermittent positive pressure breathing apparatus. The compositions, in the form of a solution, suspension or powder, can be administered, preferably orally or nasally, from devices that deliver the composition appropriately.

In some embodiments, the pharmaceutical composition contains the described compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Methods of treatment.

The compounds and compositions described herein are generally useful for modulating sodium channel activity and are useful in the treatment of conditions associated with aberrant sodium channel ion channel function, such as abnormal late sodium current (INaL). In some embodiments, a compound of the present invention is effective in treating epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. The present compound, a pharmaceutically acceptable salt or composition thereof, may also modulate all sodium ion channels or may be specific for only one or more sodium ion channels, for example, NaV 1,1, 1,2, 1,3, 1,4, 1.5, 1.6, 1.7, 1.8 and/or 1.9.

In exemplary embodiments, the present invention is intended to cover the compounds described herein and pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, an addition salt solvate (e.g., a hydrate), a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer, or a mixture of stereoisomers (pure or as a racemic or non-racemic mixture) a compound described herein (eg, a compound of formula I, II, III or IV).

Epilepsy and epileptic syndrome.

The compounds described herein are useful in the treatment of epilepsy and epileptic syndromes. Epilepsy is a disease of the central nervous system in which the activity of nerve cells in the brain is disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Symptoms of a seizure can range from simply staring blankly for a few seconds to repeated jerking of the arms or legs during a seizure.

Epilepsy may include a generalized seizure, a partial seizure, or a focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may scream or make noises, tense for a few seconds to a minute, and then make rhythmic movements of their arms and legs. The eyes are usually open, the person may appear not to be breathing and may even turn blue. Return to consciousness occurs gradually, and the person may be confused from several minutes to several hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence and atonic. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain that has abnormal electrical activity, symptoms may vary.

Epilepsy as described herein includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, epileptic

- 17 046421 status, absence seizures, febrile seizures or temporal lobe epilepsy.

The compounds described herein (eg, a compound of formula I, II, III or IV) may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least in part, by some aspect of epilepsy are also called epileptic encephalopathies. They are associated with frequent seizures that do not respond to treatment and severe cognitive dysfunction such as West syndrome.

In some embodiments, the epileptic syndrome includes epileptic encephalopathy such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or deficiency Glut1.

In some embodiments, the epilepsy or epileptic syndrome is a genetic epilepsy or genetic epileptic syndrome. In some embodiments, epilepsy or epileptic syndrome includes epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, incurable childhood epilepsy with generalized tonics oclonic seizures , infantile seizures, benign familial neonatal-infantile seizures, epileptic encephalopathy with SCN2A mutation, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, epileptic encephalopathy with SCN8A mutation, sudden unexpected death in encephalopathy, lit Rasmussen, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), epileptic encephalopathy KCNQ2 or epileptic encephalopathy KCNT1.

In some embodiments, the methods described herein further include identifying a subject suffering from epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation , generalized epilepsy with febrile seizures, incurable childhood epilepsy with generalized tonic-clonic seizures, infantile seizures, benign familial neonatal-infantile seizures, epileptic encephalopathy with SCN2A mutation, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3 mutation A, epileptic encephalopathy with SCN8A mutation, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal epilepsy, sudden unexpected death in epilepsy (SUDEP), epileptic encephalopathy KCNQ2 or epileptic encephalopathy KCNT1) before administration of a compound described in this document (for example, compounds of formula I, II, III, or IV).

In one aspect, the present invention provides a method for treating epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, incurable childhood epilepsy with generalized tonic-clonic seizures, infantile seizures, benign familial neonatal-infantile seizures, epileptic encephalopathy with SCN2A mutation, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, epileptic encephalopathy with SCN8A mutation, sudden unexpected th death due to epilepsy , Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal epilepsy, sudden expected death in epilepsy (SUDEP), epileptic encephalopathy KCNQ2 or epileptic encephalopathy KCNT1) comprising administering to a subject in need thereof a compound of formula (I):

or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

A compound of the present invention (eg, a compound of formula I, II, III or IV) can also be used for the treatment of epileptic encephalopathy when the subject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2 , CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, ERM2A, ERM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1,

- 18 046421

KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

In some embodiments, the methods described herein further include identifying a subject having a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB , DEPDC5, DNM1, EEF1A2, ERM2A, ERM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, 1, MEF2C , NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, , SPTAN1, SRPX2 , ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX before administration of a compound described herein (eg, a compound of Formula I, II, III, or IV).

Neuropsychiatric development disorders.

The compounds described herein may be useful in the treatment of a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder includes autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith syndrome -Lemli-Opitz or neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further include identifying a subject suffering from a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13 deletion syndrome .3, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorder with epilepsy) before administration of a compound described herein (e.g., a compound of formula I, II, III, or IV).

In one aspect, the present invention provides a method for treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome or neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound of formula (I):

or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

Pain.

The compounds described herein may be useful in the treatment of pain. In some embodiments, the pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a headache-related disorder. In some embodiments, the methods described herein further include identifying a subject suffering from pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia , cerebellar ataxia or headache-related disorder) before administration of a compound described herein (eg, a compound of formula I, II, III or IV).

In one aspect, the present invention provides a method for treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia or headache-related disorder) comprising administering to a subject in need thereof a compound of formula (I):

- 19 046421

or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

Neuromuscular disorders.

The compounds described herein may be useful in the treatment of a neuromuscular disorder. In some embodiments, the neuromuscular disorder includes amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-stress myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or SCN4A mutated laryngospasm. In some embodiments, the methods described herein further include identifying a subject having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-enhanced myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis paralysis or laryngospasm with SCN4A mutation) before administration of a compound described herein (eg, a compound of formula I, II, III or IV).

In one aspect, the present invention provides a method for treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-stress myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or SCN4A mutated laryngospasm), comprising administering to a subject in need thereof a compound of formula (I):

or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

Other disorders.

In some embodiments, a compound of the present invention (eg, a compound of formula I, II, III or IV) may have appropriate pharmacokinetic properties such that they are active in the central and/or peripheral nervous system. In some embodiments, the compounds provided herein are used for the treatment of cardiovascular disease, such as atrial and ventricular arrhythmias, including atrial fibrillation, (variant) Prinzmetal angina, stable angina, unstable angina, ischemia and reperfusion injury of the heart, kidneys, liver, and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, recurrent ischemia, cerebral ischemia, stroke, renal ischemia, organ transplant-associated ischemia, acute coronary syndrome, peripheral arterial disease, intermittent claudication and myocardial infarction. In some embodiments, the compounds provided herein may be used to treat diseases affecting the neuromuscular system resulting in itching, cramps or paralysis, or to treat diabetes or reduce insulin sensitivity, as well as disease states associated with diabetes , such as diabetic peripheral neuropathy. In some embodiments, the disclosed method includes administering a pharmaceutical composition.

In some embodiments, provided herein is a method of treating a neurological disorder or mental disorder, the method comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

Combination therapy.

A compound or composition described herein (eg, for use in sodium ion channel modulation, eg, late sodium (INaL) current) may be administered in combination with another agent or therapy. A subject to whom a compound disclosed herein is administered may have a disease, disorder or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions may relate to epilepsy or epilepsy syndrome, neurodevelopmental disorder, pain or neuromuscular disorder.

- 20 046421

Antiepileptic drugs.

Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, lin, primidone, rufinamide, tigabin, topiramate , valproic acid, vigabatrin, zonisamide and cannabidiol.

Combination therapy with cardiovascular drugs.

Diseases or conditions associated with cardiovascular disease that may benefit from combination treatment of the sodium channel blockers of this invention with other therapeutic agents include, but are not limited to, angina, including stable angina, unstable angina (UA), exercise-induced angina , variant angina, arrhythmias, intermittent claudication, myocardial infarction, including non-St segment elevation myocardial infarction (NSTEMI), pulmonary hypertension, including pulmonary arterial hypertension, heart failure, including congestive (or chronic) heart failure, and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure or recurrent ischemia.

Therapeutics suitable for the treatment of cardiovascular diseases or conditions include antianginal agents, anti-heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents and agents, and lipid-lowering agents.

Co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for the treatment of diseases associated with the cardiovascular system allows for an increase in the standard of medical therapy that the patient currently receives.

Antianginal agents.

Antianginal agents include beta blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload, resulting in a lower heart rate and less forceful heart contractions. Examples of beta blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

Nitrates dilate arteries and veins, thereby increasing coronary blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate and isosorbide-5-mononitrate.

Calcium channel blockers interfere with the normal flow of calcium into heart cells and blood vessels, causing the blood vessels to relax, thereby increasing the flow of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil, (Calan , Isoptin, Verelan) and nicardipine.

Medicines for heart failure.

Drugs used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics remove excess fluid from the tissues and circulation, thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (inspra).

Angiotensin-converting enzyme (ACE) inhibitors reduce the workload of the heart by dilating blood vessels and reducing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace) and trandolapril (Mavik).

Vasodilators reduce pressure on blood vessels, causing them to relax and dilate. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

Cardiac glycosides are compounds that increase the force of heart contraction. These compounds enhance the pumping function of the heart and improve irregular heartbeats. Examples of cardiac glycosides include digitalis, digoxin and digitoxin.

Antithrombotic agents.

Antithrombotics suppress the blood's ability to clot. There are three main types of antithrombotics - platelet inhibitors, anticoagulants and thrombolytics.

Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing blood clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid

- 21 046421 acid (aspirin), ticlopidine, clopidogrel (Plavix), dipyridamole, cilostazol, persanthinsulfinpyrazone, dipyridamole, indomethacin and glycoprotein IIb/IIIa inhibitors such as abciximab, tirofiban and eptifibatide (integrelin). Beta blockers and calcium channel blockers also have platelet inhibitory effects.

Anticoagulants prevent blood clots from growing and prevent new blood clots from forming. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytics break up an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase and tenecteplase (TNK) and tissue plasminogen activator (t-PA).

Antiarrhythmic drugs.

Antiarrhythmic drugs are used to treat abnormal heart rates and rhythms. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic agents.

Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amiodarone and dronedarone.

Antihypertensive drugs.

Antihypertensive drugs are used to treat hypertension, a condition in which blood pressure is persistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and thrombosis. Examples of antihypertensive agents include alpha-1 adrenergic receptor antagonists such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha-adrenergic agonists such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenzacetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), and methyldopa and hydrochlorothiazide (Aldoril); combined alpha/beta adrenergic receptor antagonists such as labetalol (Normodyne, Trandate), carvedilol (Coreg); adrenergic neuron blocking agents such as guanethidine (Ismelin), reserpine (Serpasil); antihypertensives acting on the central nervous system, such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents; ACE inhibitors such as perindopril (Aseop), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin II receptor antagonists such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan); calcium channel blockers such as verapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat, Procardia); diuretics; direct vasodilators such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators such as apricalim, bimacalim, cromacalim, emakalim, nicorandil and pinacidil.

Lipid-lowering drugs.

Lipid-lowering drugs are used to reduce cholesterol or fatty sugars in the blood. Examples of lipid-lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim) and statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava), pravastatin (Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor).

In the present invention, a patient with an attack of acute coronary disease often suffers from secondary medical conditions, such as one or more of metabolic disorders, pulmonary disorders, peripheral cardiovascular disorders, or gastrointestinal disorders. Such patients may benefit from treatment with combination therapy comprising administering ranolazine to the patient in combination with at least one therapeutic agent.

Combination therapy for pulmonary disorders.

A pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis and emphysema.

Examples of therapeutic agents used to treat pulmonary disorders include bronchodilators, including beta2-agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary diseases include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu -Medrol, Medrol), magnesium and potassium.

- 22 046421

Combination therapy for metabolic disorders.

Examples of metabolic disorders include, but are not limited to, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents, as described above under Combination Therapy with Cardiovascular Agents. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.

Combination therapy for peripheral vascular disorders.

Peripheral vascular disorders are disorders associated with blood vessels (arteries and veins) located outside the heart and brain, including, for example, peripheral arterial disease (PAD), a condition that develops when the arteries supplying blood to the internal organs, arms, and the legs are completely or partially blocked as a result of atherosclerosis.

Combination therapy for gastrointestinal disorders.

Gastrointestinal disorders refer to diseases and conditions related to the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcers, and pancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins such as misoprostol (Cytotec); sucralfate; and antacids.

Combination therapy with antibiotics, analgesics, antidepressants and sedatives.

Patients with acute coronary disease may have conditions that benefit from administration of a therapeutic agent or agents that include antibiotics, analgesics, antidepressants, and sedatives in combination with ranolazine.

Antibiotics.

Antibiotics are therapeutic agents that kill or stop the growth of microorganisms, including bacteria and fungi. Examples of antibiotics include β-lactam antibiotics including penicillins (Amoxicillin), cephalosporins such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cefradine (Velosef), cefaclor (Ceclor), cefuroxime axetil (Ceftin), cefprozil ( Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems and monobactams; tetracyclines such as tetracycline; macrolide antibiotics such as erythromycin; aminoglycosides such as gentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin; cyclic peptides such as vancomycin, streptogramins, polymyxins; lincosamides such as clindamycin; oxazolidinones such as linezolid; and sulfonamide antibiotics such as sulfisoxazole.

Analgesics.

Analgesics are therapeutic agents that are used to relieve pain. Examples of analgesics include opiates and morphinomimetics such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain through inhibition of Na _V 1,7 and 1,8 sodium channels, their combination with analgesics is particularly envisaged. See US Patent Application Published 20090203707.

Antidepressants and sedatives.

Antidepressants and anti-anxiety drugs include those used to treat anxiety disorders, depression, and drugs used as sedatives and tranquilizers. Examples of antidepressants and anti-anxiety drugs include benzodiazepines such as diazepam, lorazepam and midazolam; benzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Sirlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Effexor); citalopram (Celexa, Cipramil, Talogexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressants and anti-anxiety medications may include the neuroactive steroid and ketamine and related NMDA receptor antagonists.

Accordingly, one aspect of the present invention provides a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent. In an alternative embodiment, the composition contains sodium channel blockers at

- 23 046421 worthwhile invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises sodium channel blockers of the invention and at least three therapeutic agents, sodium channel blockers of the invention and at least four therapeutic agents, or sodium channel blockers of the invention and at least five therapeutic agents.

Methods of combination therapy include coadministration of a single drug containing the sodium channel blockers of the invention and a therapeutic agent or agents, substantially simultaneous administration of more than one drug containing the sodium channel blocker of the invention and the therapeutic agent or agents, and sequential administration of the sodium channel blocker of the invention and the therapeutic agent or agents in any order, wherein preferably there is a period of time during which the sodium channel blocker of the invention and the therapeutic agent or agents simultaneously exhibit their therapeutic effect.

Illustrative Examples

The specific examples that follow are intended to help illustrate the invention and are not intended and should not be construed as limiting the scope of the invention.

The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that where typical or preferred process conditions are stated (i.e., reaction temperatures, times, reactant molar ratios, solvents, pressures, etc.), other process conditions may also be used unless otherwise noted. Optimal reaction conditions may vary depending on the specific reagents or solvent used, but such conditions can be determined by one skilled in the art through standard optimization.

In addition, as will be apparent to those skilled in the art, conventional protecting groups may be needed to prevent unwanted reactions of certain functional groups. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and references cited therein.

The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Please note that flash chromatography can be performed manually or using an automated system. The compounds provided herein can be characterized by known standard techniques such as nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are obtained using methods well known to those skilled in the art.

Examples of common analytical LCMS methods include Method A (Xtimate C ₁₈ (2.1mm x 30mm, 3 µm); A= _H2O (0.04% TFA) and B= _CH3CN (0.02% TFA); 50°C ; 1.2 ml/min; 10-80% B for 0.9 minutes, then 80% B for 0.6 minutes) and Method B (Chromolith Flash RP-18 endcapped d ₈ (2mmx25mm); A=H ₂ O (0.04% TFA) and B=CH ₃ CN (0.02% TFA); 1.5 ml/min; 5-95% B for 0.7 minutes, then 95% B for 0.4 minutes).

List of abbreviations:

Pd(dppf)Cl ₂ - [1,G-bis(diphenylphosphino)ferrocene]palladium(P)dichloride.

PdCl ₂ (PPh ₃ ) ₂ - bis(triphenylphosphine) palladium(P) dichloride.

Pd ₂ (dba) ₃ - tris(dibenzylideneacetone)dipalladium(0).

Pd(t-Bu3P)2 - bis(tri-tert-butylphosphine)palladium (0).

TEA - triethylamine.

AgOTf - silver trifluoromethanesulfonate.

DMF - K,K-dcmethylformamide.

MeOH - methanol.

EtOH - ethanol.

i-Pr ₂ O - diisopropyl ether.

THF - tetrahydrofuran.

DCM - dichloromethane.

AcN or MeCN - acetonitrile.

EtOAc - ethyl acetate.

PE - petroleum ether.

DMSO - dimethyl sulfoxide.

AcOH - acetic acid.

- 24 046421

NBS - N-bromosuccinimide.

MeONa - sodium methoxide.

EtONa - sodium ethoxide.

TsOH - p-toluenesulfonic acid.

DEA - ^№diethylaniline.

TFA - trifluoroacetic acid.

KOAc - potassium acetate.

TBAI - tetrabutylammonium iodide.

MsCl - methanesulfonyl chloride.

Tf ₂ O - trifluoromethanesulfonic acid anhydride.

DIEA - ^^diisopropylethylamine.

MeI - methyl iodide.

TBAB - tetrabutylammonium bromide.

MeMgBr - methyl magnesium bromide.

PCy3 - tricyclohexylphosphine.

Ph3P - triphenylphosphine.

BnBr - benzyl bromide.

Xphos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

RuBOP - (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate.

TMSCF3 - trifluoromethyltrimethylsilane.

Example 1: Synthesis of Compound 1 - (3-[difluoro(methoxy)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a] pyrazine)

A2: 2-chloro-5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazine.

Mixture of 2-bromo-5-chloropyrazine (250 mg, 1.29 mmol), 2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2 -dioxaborolane (429.25 mg, 1.29 mmol), cesium carbonate (842.22 mg, 2.58 mmol) and Pd(dppf)Cl ₂ (141.85 mg, 0.19 mmol) in a mixed solvent of 1 ,4-dioxane (10 ml) and water (2 ml) were stirred at 50°C for 4 hours. After cooling to RT, the reaction mixture was diluted with water (20 ml), and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (15 ml), dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the title product (300 mg, 0.31 mmol, 24% yield) as an oil. LCMS R _t =0.95 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₃ HnCIF ₃ N ₂ O ₂ [M+H]+ 319.0, determined 319.0.

A3: [5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

Mixture of 2-chloro-5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazine (300 mg, 0.94 mmol) and hydrazine (301.71 mg, 9.41 mmol) in MeCN (8 ml) heated to 90°C and stirred for 16 hours. After cooling to RT, the reaction mixture was concentrated to give a residue. The residue was then diluted with H ₂ O (15 ml) and extracted with EtOAc (15 ml x 2). The combined organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the product (300 mg, 0.25 mmol, 27% yield) as an oil. LCMS R _t =0.74 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₃ H ₁₄ F ₃ N ₄ O ₂ [M+H] ⁺ 315.1, determined 315.1.

A4: 3-[chloro(difluoro)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a mixture of [5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (300 mg, 0.95 mmol) in toluene (10 ml), (2-chloro-2,2 -difluoroacetyl) 2-chloro-2,2-difluoroacetate (0.35 g, 1.43 mmol) and molecular sieves 4A (400 mg, 0.95 mmol). The reaction mixture was stirred at 110°C for 48 hours. After cooling to RT, the reaction mixture was concentrated to give a residue. The residue was diluted with water (20 ml) and the mixture was extracted with EtOAc (20 mlx2). Combined organic phase

- 25 046421 washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20%) to give the product (154 mg, 0.22 mmol, 23% yield) as an oil. LCMS R _t =0.92 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for С^НцС^^Оз [M+H]+ 409.0, determined 409.1.

Compound 1: 3-[difluoro(methoxy)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

Mixture of 3-[chloro(difluoro)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3a]pyrazine (154 mg, 0.38 mmol) and AgOTf (0.97 g, 3.77 mmol) in methanol (1 ml) and DMF (1 ml) were stirred at 90°C for 72 hours. After cooling to RT, the reaction mixture was treated with brine (15 ml) and the resulting precipitate was filtered. The filtrate was extracted with EtOAc (15 mlx2). The combined organic phase was dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by pre-HPLC (Waters Xbridge 150 mmx25 mm 5 μm) A=H2O (10 mM NH4HCO ₃ ) and B=CH ₃ CN; 48-62% B in 8 minutes) to give the product (5.58 mg, 0.01 mmol, 4% yield) as a solid. ¹ H NMR (400 MHz, CDO3) δн 9.52 (d, 1H), 8.63 (s, 1H), 7.71 (d, 1H), 7.46 (s, 1H), 7.35 ( d, 1H), 4.48 (s, 2H), 3.94 (s, 3H), 3.45 (s, 3H). LCMS R _t =1.21 min with chromatography 2 min, 10-80AV, MS ESI calc. for C ₁₆ H ₁₄ F ₅ N ₄ O ₃ [M+H] ⁺ 405.1, determined 404.9.

Example 2: Synthesis of compound 2 - (3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine).

Ab A7

О О ^cl vW' FFFF toluene, 110°С, 48 h

A8

AgOTf

DMF, MeOH 90°С, 48 h

A6: 2-chloro-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazine.

A mixture of 2-bromo-5-chloropyrazine (1000 mg, 5.17 mmol), 4,4,5,5-tetramethyl-2-[2-methyl-4(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane ( 1561.81 mg, 5.17 mmol), cesium carbonate (3368.87 mg, 10.34 mmol), Pd(dppf)Cl ₂ (567.41 mg, 0.78 mmol) in 1,4-dioxane (50 ml) and water (10 ml) were stirred at 50°C for 8 hours. After cooling to RT, the reaction mixture was diluted with water (30 ml), and extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (1200 mg, 1.75 mmol, 34% yield) as an oil. LCMS R _t =0.96 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₂ H ₉ ClF ₃ N ₂ O [M+H] ⁺ 289.0, determined 288.9.

A7: [5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

Mixture of 2-chloro-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazine (1.2 g, 4.16 mmol) and hydrazine (1.33 g, 41.57 mmol) in MeCN (20 ml) heated to 90°C and stirred for 16 hours. After cooling to RT, the reaction mixture was concentrated to give a residue. The residue was then diluted with H ₂ O (30 ml) and the mixture was extracted with EtOAc (30 ml x 2 ). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (1200 mg, 2.08 mmol, 50% yield) as an oil. LCMS R _t =0.73 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C12H12F3N4O [M+H] ⁺ 285.1, determined 285.1.

A8: 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

To a mixture of [5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (1 g, 3.52 mmol) in toluene (20 ml) was added (2-chloro-2,2-difluoroacetyl ) 2-chloro-2,2-difluoroacetate (1.28 g, 5.28 mmol) and molecular sieves 4A (1000 mg, 3.52 mmol). The reaction mixture was stirred at 110°C for 48 hours. After cooling to RT, the reaction mixture was concentrated to give a residue. The residue was diluted with saturated aqueous NaHCO ₃ (30 ml) and the mixture was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to leave a residue. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20%) to give the product (900 mg, 1.53 mmol, 44% yield) as a solid. LCMS R _t =0.93 min with chromatography 1.5 min, 5-95AV MS ESI calc. for C ₁₄ H ₉ ClF ₅ N ₄ O [M+H] ⁺ 379.0, determined 379.0.

Compound 2: 3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

- 26 046421

Mixture of 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (900 mg, 2.38 mmol ) and AgOTf (6.11 g, 23.77 mmol) in methanol (7 ml) and DMF (7 ml) were stirred at 90°C for 48 hours. After cooling to RT, the reaction mixture was treated with brine (20 ml) and the resulting precipitate was filtered. The filtrate was extracted with EtOAc (20 mlx2). The combined organic phase was dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified using pre-HPLC (Waters Xbridge 150 mm x 25 mm 5. μm) A=H2O (10 mM NH4HCO ₃ ) and B=CH ₃ CN; 52-62% B in 8 minutes) to obtain the product (39.44 mg, 0.10 mmol, 4% yield). ¹ H NMR (400 MHz, CDCI3) δн 9.51 (d, 1H), 8.22 (d, 1H), 7.47 (d, 1H), 7.25-7.17 (m, 2H), 3.94 (s, 3H), 2.43 (s, 3H). LCMS R _t =1.21 min during chromatography, 2 min, 10-80АВС ESI calc. for C ₁₅ H ₁₂ F ₅ N ₄ O ₂ [M+H]+375.1, determined to be 374.9.

Example 3: Synthesis of compound 3 - (3-(methoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine).

A mixture of [5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (1.19 g, 4.19 mmol) and 2-methoxyacetyl chloride (500 mg, 4.61 mmol) in toluene ( 20 ml) was stirred for 1 hour. TsOH (216.38 mg, 1.26 mmol) was then added and the mixture was heated to 120°C and stirred for 16 hours. After cooling to RT, the mixture was concentrated under reduced pressure. Water (30 ml) was added and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 60% to 80%) to give a product containing the impurity. The product containing the impurity was purified by prep HPLC (Phenomenex Gemini-NX (150 mmx30 mm, 5 µm). A=H ₂ O (0.05% NH4OH) and B=CH ₃ CN; 40-70% B in 8 min) yielding product (190.54 mg, 563.3 μmol, 95% yield) as a solid. 1H NMR (400 MHz, CDCI3) δκ 9.43 (d, 1H), 8.21 (d, 1H), 7.47 (d, 1H), 7.21-7.19 (m, 2H), 5.10 (s, 2H), 3.45 (s, 3H), 2.44 (s, 3H). LCMS R _t =1.19 min during chromatography, 2 min, 1080AV, MS ESI calc. for C15H14F3N4O2 [M+H] ⁺ 339.1, determined 338.9.

Example 4: Synthesis of compound 4 - (3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine).

Solution of 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (500 mg, 1.32 mmol ), EtONa (179.7 mg, 2.64 mmol) and TBAI (146.3 mg, 0.79 mmol) in DCM (10 ml) were stirred at 20°C for 3 hours. The solution was added to saturated aqueous NH ₄ Cl (20 ml). After phase separation, the organic phase was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a solid. The crude product was purified by preparative HPLC (Waters XBridge (150 mm x 25 mm, 5 μm) A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 45-75% B in 10 minutes) to obtain the product (96.32 mg , 0.25 mmol, yield 48%) as a solid. 1H NMR (400 MHz, CDCI3) δκ=9.51 (d, 1H), 8.24 (d, 1H), 7.49 (d, 1H), 7.25-7.17 (m, 2H), 4.34 (q, 2H), 2.45 (s, 3H), 1.47 (t, 3H). LCMS R _t =1.36 min with chromatography 2.0 min, 10-80AV, MS PER calc. for C16H14F5N4O2 [M+H] ⁺ 389.1, determined 389.0.

Example 5: Synthesis of compound 5 - (3-(ethoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine).

A solution of [5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (500 mg, 1.76 mmol) and 2ethoxyacetyl chloride (237.13 mg, 1.93 mmol) in toluene (20 ml ) was stirred at 20°C for 1 hour. TsOH (90.87 mg, 0.53 mmol) was then added to the mixture, and the mixture was heated to 120° C. and stirred for 16 hours. After cooling to RT, the mixture was concentrated to give a residue. The residue was diluted with H ₂ O (20 ml) and extracted with EtOAc (20 mlx2). The combined organic phase was washed

- 27 046421 brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 60% to 80%) to give the product (150 mg, 0.38 mmol, 21% yield) as a solid. The product was further purified by preparative HPLC (Phenomenex Gemini-NX (150 mm x 30 mm, 5 µm) A=H2O (0.05% NH4OH) and B=CH ₃ CN; 46-76% B in 8 min) to obtain the product (87, 43 mg, 0.25 mmol, 58% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 9.42 (d, 1H), 8.25 (d, 1H), 7.48 (d, 1H), 7.23-7.16 (m, 2H ), 5.14 (s, 2H), 3.63 (q, 2H), 2.44 (s, 3H), 1.25 (t, 3H). LCMS Rt=1.22 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₁₆ H ₁₆ F ₃ N ₄ O ₂ [M+H]+ 353.1, determined 353.0.

Examples 6 and 7: Synthesis of compounds 6 and 7 toxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine and toxy)phenyl]-[1,2,4]triazolo[4,3- a]pyrazine).

(3-(benzyloxymethyl)-6-[2-methyl-4-(trifluorome3-(isobutoxymethyl)-6-[2-methyl-4-(trifluorome-

A7 Η Ίζυο,ΊοΜ

A11

Compound 6: 3-((benzyloxy)methyl)-6-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3a]pyrazine.

A solution of [5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (4 g, 14.07 mmol) and 2-benzyloxyacetyl chloride (2.86 g, 15.48 mmol) in toluene (100 ml ) stirred for 1 hour. TsOH (726.99 mg, 4.22 mmol) was then added to the mixture, and the mixture was heated to 120° C. and stirred for 16 hours. After cooling to RT, the mixture was concentrated to give a residue. The residue was diluted with H ₂ O (100 ml), extracted with EtOAc (100 mlx2). The combined organic phase was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 60% to 80%) to give the product. The product was purified by preparative HPLC (Phenomenex Gemini-NX (150 mm x 30 mm, 5 µm) A=H ₂ O (0.05% NH4OH) and B=CH ₃ CN; 49-79% B in 8 min) to obtain the product (119 .34 mg, 0.29 mmol, 75% yield) as a solid. 1H NMR (400 MHz, DMSO-d^ δ _π 9.51 (d, 1H), 8.64 (d, 1H), 7.58 (d, 1H), 7.41-7.34 (m, 2H ), 7.32-7.24 (m, 5H), 5.16 (s, 2H), 4.62 (s, 2H), 2.38 (s, 3H) LCMS Rt=1.32 min at. chromatography, 2 min, 10-80АВ, MS ESI calc. C ₂₁ H ₁₈ F ₃ N ₄ O ₂ [M+H] ⁺ 415.13, determined 415.0.

A9: [6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]methyl acetate.

A solution of 3-(benzyloxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.5 g, 6.03 mmol) and HBr/AcOH (5 ml, 6.03 mmol) was stirred at 20°C for 12 hours. The mixture was diluted with H ₂ O (20 ml), extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (2 g, 3 mmol, 49% yield) as an oil. LCMS Rt=0.84 min with chromatography 1.5 min, 5-95AV, MS ESI calc. C16H14F3N4O3 [M+H] ⁺ 367.09, determined 367.1.

A10: [6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]methanol.

A solution of [6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-α]pyrazin-3-yl]methyl acetate (2 g, 5.46 mmol) and LiOH -H ₂ O (0.92 g, 21.84 mmol) in THF (5 ml) and water (5 ml) was stirred at 40°C for 2 hours. After cooling to RT, the mixture was concentrated to give a residue. The residue was diluted with H ₂ O (30 ml) and extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 60% to 100%) to give the product (450 mg, 1.35 mmol, 24% yield) as a solid. LCMS Rt=0.79 min with chromatography 1.5 min, 5-95AV, MS ESI calc. C ₁₄ H ₁₂ F ₃ N ₄ O ₂ [M+H] ⁺

- 28 046421

325.08, determined 324.8.

A11: 3-(chloromethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

Mixture of [6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]methanol (600 mg, 1.85 mmol), MsCl (0.59 ml, 7.68 mmol) and TEA (0.51 ml, 3.7 mmol) in DCM (10 ml) were stirred at 20°C for 5 hours. The mixture was concentrated to remove DCM under reduced pressure and H2O (20 ml) was added, and then the mixture was extracted with EtOAc (20 ml x 2). The combined organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (550 mg, 1.6 mmol, 87% yield) as a solid. LCMS Rt=0.87 min with chromatography 1.5 min, 5-95AV, MS ESI calc. C ₁₄ HnClF ₃ N ₄ O [M+H]+ 343.05, determined 342.8.

Compound 7: 3-(isobutoxymethyl)-6-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3a]pyrazine.

A mixture of 3-(chloromethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (50 mg, 0.15 mmol), isobutanol ( 5 ml, 16.86 mmol) and AgOTf (374.88 mg, 1.46 mmol) in MeCN (5 ml) were stirred at 80°C for 16 hours. After cooling to RT, the mixture was concentrated to give a residue. The residue was diluted with H ₂ O (20 ml) and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 40% to 60%) to give the product. The product was purified by preparative HPLC (Phenomenex Gemini-NX (150 mm x 30 mm, 5 µm) A=H ₂ O (0.05% NH4OH) and B=CH ₃ CN; 51-81% B in 8 min) to obtain the product (46 .35 mg, 0.12 mmol, yield 46%) as a solid. 1H NMR (400 MHz, CDCI3) δκ 9.43 (d, 1H), 8.24 (d, 1H), 7.45 (d, 1H), 7.23-7.16 (m, 2H), 5 .14 (s, 2H), 3.31 (d, 2H), 2.43 (s, 3H), 1.95-1.84 (m, 1H), 0.90 (d, 6H). LCMS Rt=1.33 min during chromatography, 2.0 min, 1080АВ, MS ESI calc. C18H20F3N4O2 [M+H] ⁺ 381.15, determined 381.0.

Example 8: Synthesis of compound 8 - (3-(methoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-b]pyridazine).

Pd(tBu ₃ P) ₂ K3PO4 A12 doxane/H ₂ 0.75°C,

16h

Mixture of 4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (296.61 mg, 0.98 mmol), 6-chloro-3 -(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.76 mmol), Pd(r-Bu ₃ P) ₂ (57.90 mg, 0.11 mmol ) and K3PO4 (320.68 mg, 1.51 mmol) in 1,4-dioxane (7.5 ml) and water (1.5 ml) were stirred at 75°C under N ₂ atmosphere for 16 hours. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated to obtain a residue. Water (10 ml) was added to the residue and extracted with EtOAc (20 mlx2). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters XBridge (150 mm x 25 mm, 5 µm) A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 3562% B in 9 min) to obtain the product (76.62 mg, 0 .23 mmol, yield 29%) as a solid. 1H NMR (400 MHz, DMSOC ₆ ) δ _Η 8.48 (d, 1H), 7.69 (d, 1H), 7.64 (d, 1H), 7.48-7.37 (m, 2H) , 4.93 (s, 2H), 3.35 (s, 3H), 2.44 (s, 3H). LCMS R _t =1.20 min with chromatography 2 min, 10-80AV, MS ESI calc. for C15H14F3N4O2 [M+H] ⁺ 339.1, determined 338.9.

Example 9: Synthesis of compound 9 - (3-[ethoxy(difluoro)methyl]-6-[3-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine).

3-[chloro(difluoro)methyl]-6-[3-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine solution (500 mg, 1.32 mmol ), EtONa (179.7 mg, 2.64 mmol) and TBAI (292.62 mg, 0.79 mmol) in DCM (10 ml) were stirred at 20°C for 3 hours. Saturated aqueous NH ₄ Cl (30 ml) was added to the solution. After phase separation, the organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20% to 50%) to give the product (61.05 mg, 154.0 μmmol, 11% yield) as a solid. 1H NMR (400 MHz, CDC13) _δΗ 9.52 (d, 1H),

- 29 046421

8.47 (d, 1H), 7.88 (d, 1H), 7.78 (dd, 1H), 7.37 (dd, 1H), 4.37 (q, 2H), 2.44 (s , 3H), 1.51 (t, 3H). LCMS Rt=1.40 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₁₆ H ₁₄ F ₅ N ₄ O ₂ [M+H]+ 389.1, determined 389.0.

Example 10: Synthesis of compound 10 - (3-(difluoro(isopropoxy)methyl)-6-(2-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine) .

F. Ό.. FF yONa F ^F fV t 1 G ^C1 ! _F

N ^{TVA1, DCM}

25°C, 2 hours

A8 10

Mixture of 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.53 mmol ), sodium propan-2-olate (86.7 mg, 1.06 mmol) and TBAI (117.05 mg, 0.32 mmol) in DCM (2 ml) were stirred at 25°C for 2 hours. The mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Kromasil Waters XBridge (150 mm x 25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH ₃ CN; 50-80% B in 10 min) to obtain the product (26.4 mg, 0.07 mmol, yield 52%) as a solid. ¹ H NMR (400 MHz, CDCI3) δн 9.51 (d, 1H), 8.23 (d, 1H), 7.50 (d, 1H), 7.25-7.18 (m, 2H), 5.02-4.95 (m, 1H), 2.46 (s, 3H), 1.48 (d, 6H). LCMS Rt=1.39 min with chromatography 2.0 min, 10-80AV, MS ESI calc. C17H16F5N4O2 [M+H] ⁺ 403.1, determined 403.0.

Example 11: Synthesis of compound 11 - (3-[difluoro(methoxy)methyl]-6-[3-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine) .

Whoa o-ooh

U v-v U ^F ou ou _F

Pd(dppf)CI ₂ KOAc ,

1,4-dioxane/water d-|4 U 1,4-dioxane, 60°C, 5 h A15 ^N<iz OI

1) (F ₂ CICCO) ₂ O, toluene F °C, 2 h ^F

2) TsOH, toluene, 130°C h ^Ν Χ/%\Ϊ

A17

A14: 4,4,5,5-tetramethyl-2-[3-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane.

A mixture of 1-bromo-2-methyl-4-(trifluoromethoxy)benzene (5 g, 19.61 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5tetramethyl-1,3, 2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (14.94 g, 58.82 mmol), KOAc (3.85 g, 39.21 mmol) and Pd(dppf)Cl ₂ (1, 43 g, 1.96 mmol) in 1,4-dioxane (20 ml) was stirred at 85°C for 16 hours under N2. After cooling to RT, the mixture was concentrated, filtered through Celite and eluted with EtOAc (100 mlx2) and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 3% to 5% to 10%) to give the product (4.56 g, 14.36 mmol, 73% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) _δH 7.71 (s, 1H), 7.66 (d, 1H), 7.20 (d, 1H), 2.32 (s, 3H), 1.35 (s, 12H).

A15: 2-chloro-5-[3-methyl-4-(trifluoromethoxy)phenyl]pyrazine.

A mixture of Pd(dppf)Cl ₂ (1 g, 1.37 mmol), Cs ₂ CO ₃ (8.93 g, 27.4 mmol), 4,4,5,5-tetramethyl-2-[3-methyl- 4(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (4.55 g, 15.05 mmol) and 2-bromo-5-chloropyrazine (2.65 g, 13.7 mmol) in 1,4-dioxane (280 ml) and water (28 ml) under N ₂ atmosphere were stirred at 60°C for 5 hours. The mixture was cooled to RT and diluted with EtOAc (40 ml) and then filtered through a celite pad which was washed with EtOAc (40 ml). The filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 3% to 5%) to give the product (3.5 g, 12.12 mmol, 88% yield) as a solid. 1H NMR (400 MHz, CDCI3) δ, 8.77 (d, 1H), 8.64 (d, 1H), 7.91 (d, 1H), 7.83 (dd, 1H), 7.35 (dd, 1H), 2.42 (s, 3H).

A16: [5-[3-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

Mixture of 2-chloro-5-[3-methyl-4-(trifluoromethoxy)phenyl]pyrazine (3.5 g, 12.13 mmol) and N2H4H2O (7.13 g, 121.25 mmol) in MeCN (50 ml) stirred at 90°C for 16 hours at N ₂ . The mixture was cooled to RT, quenched with saturated aqueous NH ₄ Cl (40 ml) and the mixture was extracted with EtOAc (40 mlx2). United

- 30 046421 the organic phase was washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0 to 5% to 10% to 30%) to give the product (2.5 g, 8.79 mmol, 72% yield) as a solid. 1H NMR (400 MHz, CDCI3) δκ 8.46 (d, 1H), 8.28 (d, 1H), 7.80 (d, 1H), 7.71 (dd, 1H), 7.29 (d , 1H), 6.05 (s, 1H), 3.92 (s, 2H), 2.39 (s, 3H).

A17: 3-[chloro(difluoro)methyl]-6-[3-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A solution of (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (1.96 g, 8.08 mmol) and [5-(4-tert-butoxy-3-methylphenyl)pyrazin-2-yl ]hydrazine (2 g, 7.34 mmol) in toluene (30 ml) was stirred at 90°C for 2 hours. TsOH (379.36 mg, 2.2 mmol) was then added to the mixture, and the mixture was heated to 130° C. and stirred for 16 hours. After cooling to RT, the mixture was concentrated to give a residue. The residue was diluted with H ₂ O (50 ml), extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 10% to 20%) to give the product (600 mg, 1.58 mmol, 21% yield) as an oil. 1H NMR (400 MHz, CDCI3) δκ 9.58 (s, 1H), 8.43 (s, 1H), 7.89 (s, 1H), 7.82 (d, 1H), 7.38 (d , 1H), 2.45 (s, 3H).

Compound 11: 3-(difluoro(methoxy)methyl)-6-(3-methyl-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3a]pyrazine.

3-[chloro(difluoro)methyl]-6-[3-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine solution (500 mg, 1.32 mmol ), MeONa (142.65 mg, 2.64 mmol) and TBAI (292.62 mg, 0.79 mmol) in DCM (10 ml) were stirred at 20°C for 3 hours. The solution was added to saturated aqueous NH ₄ Cl (40 ml). After phase separation, the organic phase was washed with brine (40 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (71.66 mg, 191.5 μmol, 14% yield) as a solid. 1H NMR (400 MHz, CDC13) _δH 9.53 (d, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.79 (dd, 1H), 7.40- 7.34 (m, 1H), 3.98 (s, 3H), 2.45 (s, 3H). LCMS Rt=1.35 min with chromatography 2.0 min, 10-80АВ, MS ESI calc. for C ₁₅ H ₁₂ F ₅ N ₄ O ₂ [M+H]+ 375.1, determined 375.0.

Example 12: Synthesis of Compound 12 - (3-[cyclopropoxy(difluoro)methyl]-6-[2-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine).

A8 12

To a mixture of cyclopropanol (70.54 mg, 1.21 mmol), 3-[chloro(difluoro)methyl]-6-[2-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4, 3-a]pyrazine (250 mg, 0.61 mmol) in DMF (3 ml) was added potassium tert-butoxide (272.56 mg, 2.43 mmol). The reaction mixture was stirred at 20°C for 10 minutes. The mixture was diluted with H2O (10 ml) and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mmx25 mmx5 μm) A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 60-80% B in 6.5 min) to obtain the product (18.81 mg, 0.05 mmol, yield 37%) as an oil. 1H NMR (400 MHz, CDC13) δΗ 9.51 (d, 1H), 8.20 (s, 1H), 7.48 (d, 1H), 7.24-7.19 (m, 2H), 4.21 -4.11 (m, 1H), 2.44 (s, 3H), 1.01-0.95 (m, 2H), 0.84-0.78 (m, 2H). LCMS R _t =1.37 min with chromatography 2.0 min, 10-80AV, MS ESI calc. C ₁₇ H ₁₄ F ₅ N ₄ O ₂ [M+H] ⁺ 401.1, determined 401.0.

Example 13: Synthesis of Compound 13 - (3-(ethoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-b]pyridazine).

A19: 6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine.

To a solution of 2-methoxyacetyl chloride (1.24 g, 11.41 mmol) in toluene (40 ml) was added dropwise (6chloropyridazin-3-yl)hydrazine (1.5 g, 10.38 mmol) at 25°C. The solution was stirred at 25°C for 30 min and TsOH (0.54 g, 3.11 mmol) was added. The mixture was refluxed at 120°C for 16 hours. After cooling to RT, the mixture was diluted with H ₂ O (40 ml) and extracted with EtOAc (40 ml x 2). The combined organic phase was washed with brine (40 ml), dried over Na ₂ SO ₄ , filter

- 31 046421 was divided and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 90% to 100%) to give the product (1.2 g, 5.64 mmol, 54% yield) as a solid. ^1H NMR (400 MHz, CDCl3) _δH 8.10 (d, 1H), 7.16 (d, 1H), 5.09-5.02 (m, 2H), 3.71 (q, 2H) , 1.26 (t, 3H).

Compound 13: 3-(ethoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3b]pyridazine.

Mixture of 4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (277.04 mg, 0.92 mmol), Pd(t-Bu ₃ P) ₂ (54.08 mg, 0.11 mmol), K3PO4 (299.52 mg, 1.41 mmol) and 6-chloro-3-(ethoxymethyl)[1,2,4]triazolo[4,3 d]pyridazine (150 mg, 0.71 mmol) in 1,4-dioxane (7.5 ml) and water (1.5 ml) was stirred at 85°C under N2 for 16 hours. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated to obtain a residue. Water (10 ml) was added to the residue and extracted with EtOAc (20 mlx2). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters XBridge (150 mm x 25 mm, 5 cm) A=H2O (10 mM NH4HCO3) and B= _CH3CN ; 35-65% B in 10 min) to obtain the product (172.63 mg, 488.6 μmol, 69% yield) as a solid. ^1H

NMR (400 MHz, DMSO^) δн=8.48 (d, 1H), 7.69 (d, 1H), 7.63 (d, 1H), 7.45 (s, 1H), 7.41 ( d, 1H), 4.97 (s, 2H),

3.59 (q, 2H), 2.45 (s, 3H), 1.11 (t, 3H). LCMS R _t =1.24 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for m C16H16F3N4O2 [M+H]+ 353.1, determined 353.0.

Example 14: Synthesis of compound 14 - (3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-b]pyridazine) .

A20: 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine.

To a mixture of (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (20.17 g, 83.01 mmol) in toluene (120 ml) was added (6-chloropyridazin-3-yl)hydrazine (10 g, 69.18 mmol). The reaction mixture was stirred at 110°C for 12 hours. After cooling to RT, the reaction mixture was concentrated to give a residue. The residue was diluted with saturated aqueous NaHCO ₃ (100 ml) and the mixture was extracted with EtOAc (100 ml x 2). The combined organic phase was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 50%) to give the product (14 g, 58.6 mmol, 85% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ _π 8.22 (d, 1H), 7.34 (d, 1H).

A21: 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-b]pyridazine.

Mixture of Pd(t-Bu ₃ P) ₂ (962.2 mg, 1.88 mmol), K ₃ PO ₄ (5.33 g, 25.1 mmol), 4,4,5,5-tetramethyl-2- [2-methyl4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (4.93 g, 16.32 mmol) and 6-chloro-3-[chloro(difluoro)methyl][1,2,4] Triazolo[4,3-b]pyridazine (3 g, 12.55 mmol) in water (25 ml) and 1,4-dioxane (125 ml) was stirred at 85°C under N2 for 16 hours. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated to obtain a residue. Water (40 ml) was added to the residue and the mixture was extracted with EtOAc (30 mlx2). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give the product (4 g, 7.43 mmol, 59% yield) as a solid. ^1H NMR (400 Hz, CDC13) δ _π 8.31 (m, 1H), 7.54 (dd, 1H), 7.48 (d, 1H), 7.28-7.17 (m, 2H) , 2.53 (s, 3H).

Compound 24: 3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3b]pyridazine.

Mixture of 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-b]pyridazine (500 mg, 1.32 mmol ) and AgBF ₄ (2.57 g, 13.2 mmol) in methanol (5 ml) were stirred at 90°C for 6 hours in a sealed tube. After cooling to RT, the mixture was quenched with brine (20 ml), diluted with EtOAc (20 ml) and filtered through celite. The filtrate was separated and the aqueous phase was extracted with EtOAc (20 ml). The combined organic phase was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) with semi

- 32 046421 product information. The product was triturated with i-Pr ₂ O (2 ml) to obtain the product (81.22 mg, 0.21 mmol, 16% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δн 8.26 (d, 1H), 7.54 (d, 1H), 7.40 (d, 1H), 7.267.21 (m, 2H), 3.89 ( s, 3H), 2.52 (s, 3H). LCMS Rt=1.29 min with chromatography 2 min, 10-80АВ, MS PER calc. for C ₁₅ H ₁₂ F ₅ N ₄ O ₂ [M+H]+ 375.1, determined 375.0.

Example 15: Synthesis of compound 15 - (3-[ethoxy(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-b]pyridazine).

A21 15

Mixture of AgBF4 (2.57 g, 13.2 mmol) and 3-[chloro(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3 -b]pyridazine (500 mg, 1.32 mmol) in ethanol (5 ml) was stirred at 90°C for 6 hours in a sealed tube. After cooling to RT, the mixture was quenched with brine (20 ml), diluted with EtOAc (20 ml) and filtered through celite. After separating the filtrate, the aqueous phase was extracted with EtOAc (20 ml). The combined organic phase was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give the product. The product was triturated with i-Pr2O (2 mL) to give the product (39.96 mg, 0.10 mmol, 7% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) _δH 8.26 (d, 1H), 7.56-7.51 (m, 1H), 7.39 (d, 1H), 7.26-7.20 ( m, 2H), 4.29 (q, 2H), 2.52 (s, 3H), 1.43 (t, 3H). LCMS R _t =1.33 min with chromatography 2 min, 10-80AV, MS ESI calc. for C ₁₆ H ₁₄ F ₅ N ₄ O ₂ [M+H]+ 389.1, determined 389.0.

Example 16: Synthesis of compound 16 - (3-(cyclopropylmethoxymethyl)-6-[2-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine).

A11 16

A mixture of 3-(chloromethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (50 mg, 0.15 mmol), cyclopropanemethanol ( 5 ml, 17.33 mmol) and AgOTf (374.88 mg, 1.46 mmol) in MeCN (5 ml) were stirred at 80°C for 16 hours. After cooling to RT, the mixture was concentrated to obtain a residue. The residue was diluted with H ₂ O (10 ml) and the mixture was extracted with EtOAc (10 mlx2). The combined organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=0% to 40% to 60%) to obtain the crude product.

The crude product was purified by preparative HPLC (Phenomenex Gemini-NX (150 mm x 30 mm, 5 µm) A=H ₂ O (0.05% NH4OH) and B=CH ₃ CN; 45-75% B in 8 min) to obtain the product ( 32.55 mg, 0.09 mmol, 32% yield) as a solid. ^1H NMR (400 MHz, CDCl ₃ ) δπ 9.42 (d, 1H), 8.29 (d, 1H), 7.48 (d, 1H), 7.23-7.16 (m, 2H) , 5.19 (s, 2H), 3.41 (d, 2H), 2.45 (s, 3H), 1.11-1.00 (m, 1H), 0.59-0.52 (m , 2H), 0.23-0.17 (m, 2H). LCMS Rt=1.27 min with chromatography 2 min, 10-80AV, MS ESI calc. C ₁₈ H ₁₈ F ₃ N ₄ O ₂ [M+H]+ 379.13, determined 379.0.

Example 17: Synthesis of compound 17 - (3-(methoxymethyl)-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine).

Cl

Br

A22

EUN, 80°C, 32 h

Pd(dppf)CI ₂

TEA, CO (50 psi)

LiAIH _4THF

-40°C, 1 hour

NaH, Mel, THF

Cl 0-20°C, 16 h

A24

A

Pd ₂ (dba) ₃ X-Phos, KOAc, dioxane, 80°C, 16 h

Pd(dppf)CI ₂ , CS2CO3 1,4-dioxane, 50°C, 5 h

A25

A1a

A2a

N

ACN,

C.I.

TsOH, toluene, 120 °C, 16 h

AZA

- 33 046421

A23: 4,4,5,5-tetramethyl-2-[3-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane.

A mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (40.0 g, 145.22 mmol), Pd(dppf)Cl ₂ (10.63 g, 14.52 mmol) and TEA (40.37 ml, 290.43 mmol) in ethanol (50.00 ml) was stirred at 80°C for 32 hours under a CO atmosphere (50 psi). The mixture was cooled to 25°C and concentrated to obtain a residue. The residue was diluted with saturated aqueous NaCl (50 ml) and the mixture was extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0 to 3% to 5% to 10%) to give the product (13.00 g, 48.40 mmol, 33% yield) as an oil. ¹ H NMR (400 MHz, CD ₃ OD) δ _H 7.69 (d, 1H), 7.52-7.46 (m, 1H), 7.32-7.27 (m, 1H), 4, 49-4.37 (m, 2H), 1.42 (t, 3H).

A24: [2-(chloromethyl)-5-(trifluoromethoxy)phenyl]methanol.

LiAlH ₄ (1.93 g, 50 .95 mmol). The reaction mixture was stirred at -40°C for 1 hour. The reaction was quenched with saturated aqueous NH ₄ Cl (0.4 ml) and diluted with EtOAc (30 ml). A solid formed and the mixture was filtered through a celite pad and eluted with EtOAc (30 mL). The filtrate was concentrated to obtain a residue. The residue was purified on a silica gel column (EtOAc in PE=0% to 10% to 20%) to give the product (10.00 g, 39.54 mmol, 93% yield) as a solid. 1H NMR (400 MHz, CD3OD) δн 7.47-7.41 (m, 1H), 7.40-7.35 (m, 1H), 7.15-7.07 (m, 1H), 4, 80 (d, 2H).

A25: 1-chloro-2-(methoxymethyl)-4-(trifluoromethoxy)benzene.

NaH (355.9 mg, 14.83 mmol) was slowly added to a solution of [2-chloro-5-(trifluoromethoxy)phenyl]methanol (2.8 g, 12.36 mmol) in THF (30 mL) at 0°C. . The mixture was stirred at 0°C for 30 after which MeI (5.26 mg, 37.07 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. The mixture was quenched with saturated aqueous NH ₄ Cl (40 ml) and the mixture was extracted with EtOAc (40 mlx2). The combined organic phase was washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0 to 3% to 10% to 20% to 50%) to give the product (1.65 g, 6.86 mmol, 55% yield) as an oil. 1H NMR (400 MHz, CD3OD) _δH 7.43-7.33 (m, 2H), 7.15-7.05 (m, 1H), 4.54 (s, 2H), 3.50 (s , 3H).

A1a: 2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.58 g, 14.11 mmol), KOAc (2.31 g, 23.52 mmol), 1-chloro-2-(methoxymethyl)-4-(trifluoromethoxy)benzene (2.83 g, 11.76 mmol) and Pd ₂ ( dba) ₃ (1.08 g, 1.18 mmol) in 1,4-dioxane (20.00 ml) was stirred at 80°C for 16 hours under N2. The mixture was cooled to 25°C and concentrated to obtain a residue. The residue was quenched with saturated aqueous NH ₄ Cl (40 ml) and the mixture was extracted with EtOAc (40 mlx2). The combined organic phase was washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (DCM in PE=0 to 10% to 50% to 80%) to give the product as an oil. 1H NMR (400 MHz, CD ₃ Cl ₃ ) δн 7.82 (d, 1H), 7.33 (s, 1H), 7.11 (d, 1 H), 4.72 (s, 2H), 3 .44 (s, 3H), 1.35 (s, 12H).

A2a: 2-chloro-5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazine.

A mixture of Pd(dppf)Cl ₂ (330.47 mg, 0.45 mmol), Cs ₂ CO ₃ (1.96 g, 6.02 mmol), 2-bromo-5-chloropyrazine (640.65 mg, 3. 31 mmol) and 2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane (1.00 g, 3.01 mmol) in 1, 4-dioxane (10 ml) and water (2.5 ml) were stirred at 50°C for 5 hours under N2 atmosphere. After cooling to 25°C, the reaction mixture was diluted with EtOAc (100 ml) and filtered through a pad of celite, which was eluted with EtOAc (100 ml). The filtrate was concentrated to give a residue, and the residue was purified by flash chromatography (EtOAc in PE, 0% to 10%) to give the product (610.00 mg, 1.81 mmol, 60% yield) as a solid. 1H NMR (400 MHz, CD ₃ Cl ₃ ) δ _H 8.66-8.70 (m, 1H), 8.56-8.63 (m, 1H), 7.53-7.56 (m, 1H ), 7.50-7.52 (m, 1H), 7.28-7.33 (m, lH), 4.55 (s, 2H), 3.38 (s, 3H).

A3a: [5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

A mixture of 2-chloro-5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazine (1.10 g, 3.45 mmol) and hydrazine (860.00 mg, 17.26 mmol) in MeCN (5 ml) was stirred at 90°C for 16 hours under N ₂ atmosphere. After cooling to 25°C, the reaction mixture was diluted with water and extracted with EtOAc (30 mlx3). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (1.00 g, 3.18 mmol, 74% yield) as a liquid. LCMS Rt=0.71 min at 1.5 min chromatography, 5-95AV, MS ESI calc. for C ₁₃ H ₁₄ F ₃ N ₄ O ₂ [M+H]+ 314.8, determined 314.8.

Compound 17: 3-(methoxymethyl)-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A solution of [5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (200 mg, 0.64 mmol) and 2-methoxyacetyl chloride (82.88 mg, 0.76 mmol) in toluene (5 ml) was stirred at 25°C for 1 hour. TsOH (219.18 mg, 1.27 mmol) was then added to the mixture, the mixture was heated to 120°C and stirred

- 34 046421 within 16 hours. After cooling to 25°C, the reaction mixture was diluted with water (30 ml) and extracted with EtOAc (30 mlx3). The combined organic phase was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (150 mg, 0.40 mmol, 64% yield) as a liquid. The crude product was purified by preparative HPLC (Boston Green ODS (150 mm x 30 mm, 5 µm) A=H2O (0.075% NH4OH) and B=CH ₃ CN; 46-76% B in 7 min) to obtain the product (21.54 mg, 0.06 mmol, yield 43%) as a solid. ¹ H NMR (400 MHz, CD ₃ Cl ₃ ) δ _H 9.26-9.58 (m, 1H), 8.37-8.62 (m, 1H), 7.60-7.75 (m, 1H), 7.38-7.54 (m, 1H), 7.30-7.36 (m, 1H), 4.98-5.18 (m, 2H), 4.43-4.59 ( m, 2H), 3.34-3.54 (m, 6H). LCMS Rt=1.164 min with chromatography 2 min, 10-80AV, MS ESI calc. for C ₁₆ H ₁₆ F ₃ N ₄ O ₃ [M+H]+ 369.0, determined 369.0.

Example 18: Synthesis of compound 18 - (3-[cyclopropylmethoxy(difluoro)methyl]-6-[2-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-α]pyrazine).

°F, s n pF

D ^{1) THF c} 'Z, ρΥ ΥΊ U ^N AZ _n -NH ₂ 2) TsOH, toluene, | I ι N

H 120°С, 16 h

A7 A26

A26: 3-[bromo(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

[5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (1 g, 3.52 mmol) was added to a solution of 2-bromo-2,2-difluoroacetyl chloride (1.2 g, 6 .21 mmol) in THF at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was poured into water (30 ml) and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (30 ml), dried over Na ₂ SO ₄ filtered and concentrated to give the crude product (1.5 g, 3.4 mmol, 97% yield) as a solid, which was used without purification in the next step .

A solution of 2-bromo-2,2-difluoro-N-[5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]acetohydrazide (1.2 g, 2.72 mmol) and TsOH (140 .52 mg 0.82 mmol) in toluene (20 ml) was stirred at 120°C for 16 hours. After cooling to RT, the mixture was concentrated to give a residue. The residue was diluted with H ₂ O (30 ml) and extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to give the product (600 mg, 1.3371 mmol, 57% yield) as an oil. LCMS Rt=2.86 min with chromatography 4.0 min, 10-80АВ, MS ESI calc. C ₁₄ H ₉ BrF ₅ N ₄ O [M+H] ⁺ 422.98, determined 424.7.

Compound 18: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

To a light-protected suspension of 3-[bromo(difluoro)methyl]-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine (150 mg 0. 35 mmol) in cyclopropanemethanol (127.81 mg, 1.77 mmol) was added AgBF4 (138.02 mg, 0.71 mmol) at 25°C under N2 atmosphere. The mixture was stirred at 60°C for 2 hours. The solution was added to saturated aqueous NaCl (20 ml) and filtered. The filtrate was extracted with EtOAc (10 mlx2). The combined organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini-NX (150 mm x 30 mm, 5 μm) A=H ₂ O (0.05% NH4OH) and B=CH ₃ CN; 51-81% B in 8 min) to obtain the product ( 55.12 mg, 0.13 mmol, 38% yield) as a solid. ^1H NMR (400 MHz, CDCl ₃ ) δ, 9.52 (d, 1H), 8.30 (s, 1H), 7.49 (d, 1H), 7.25-7.17 (m, 2H), 4.09 (d, 2H), 2.46 (s, 3H), 1.36-1.24 (m, 1H), 0.74-0.64 (m, 2H), 0.48 -0.35 (m, 2H). LCMS Rt=1.37 min during chromatography, 2.0 min, 10-80АВ, MS ESI calculated. C ₁₈ H ₁₆ F ₅ N ₄ O ₂ [M+H] ⁺ 415.11, determined 415.0.

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Example 19: Synthesis of compound 19 - (3-[ethoxy(difluoro)methyl]-6-[2-(methoxymethyl)-4(trifluoromethoxy)phenyl] - [1,2,4]triazolo[4,3-a]pyrazine ).

A27: 2-bromo-2,2-difluoro-N-[5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]acetohydrazide.

A mixture of 2-bromo-2,2-difluoroacetic acid (267.19 mg, 1.53 mmol), DMF (0.05 ml) and oxalyl chloride (323.12 mg, 2.55 mmol) in THF (5 ml) was stirred at 25°C for 2 hours under N ₂ . [5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (400 mg, 1.27 mmol) was then added to the mixture, and the mixture was stirred at 25°C for 2 hours in atmosphere N ₂ . The reaction was quenched with saturated aqueous NaCl (10 ml) and diluted with EtOAc (20 ml). The mixture was filtered and the filtrate was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the product (500 mg, 1.06 mmol) as an oil. ZhSMS Rt=0.96 min with chromatography 1.5 min, 5-95 AB, MS ESI calc. for C ₁₅ H ₁₃ BrF ₅ N ₄ O ₃ [M+H]+ 471.0, determined 470.8.

A28: 3-[bromo(difluoro)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a mixture of 2-bromo-2,2-difluoro-N-[5-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2yl]acetohydrazide (500 mg, 1.06 mmol) in toluene. (5 ml) TsOH (109.64 mg, 0.64 mmol) was added and the mixture was stirred at 120°C for 16 hours under N ₂ atmosphere. After cooling to 25°C, the mixture was quenched with saturated aqueous NaHCO ₃ (20 ml) and the mixture was extracted with EtOAc (20 ml x 3). The combined organic phase was washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to give the product (400 mg, 0.88 mmol) as an oil. LCMS Rt=2.80 min with chromatography 4.0 min, 10-80 AB, MS ESI calc. for C ₁₅ H ₁₁ BrF ₅ N ₄ O ₂ [M+H+2]+ 455.0, determined 454.7.

Compound 19: 3-[ethoxy(difluoro)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

To a mixture of 3-[bromo(difluoro)methyl]-6-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (400 mg 0 .88 mmol) in ethanol (5 ml), AgBF ₄ (343.67 mg, 1.77 mmol) was added and the mixture was stirred at 50°C for 5 hours under N ₂ atmosphere, protected from light. The reaction was quenched with saturated aqueous NaCl (10 ml) and diluted with EtOAc (20 ml). The mixture was filtered and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mmx25 mm, 5 μm) A=H ₂ O (0.075% NH4OH) and B=CH ₃ CN; 53-83% B in 11 min) to obtain the product (58.92 mg, 0.14 mmol) as an oil. 1H NMR (400

MHz, CDCl ₃ ) δ _H 9.51 (d, 1H), 8.62 (s, 1H), 7.70 (d, 1H), 7.47 (s, 1H), 7.32-7.37 (m, 1H), 4.50 (s, 2H), 4.34 (q, 2H), 3.44 (s, 3H), 1.47 (t, 3H). LCMS Rt=1.35 min with chromatography 2 min, 10-80AV, MS ESI calc. for C ₁₇ H ₁₆ F ₅ N ₄ O ₃ [M+H]+ 419.1, determined 418.9.

Example 20: Synthesis of Compound 20 - (3-(cyclopropoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]

[1,2,4]triazolo [4,3-a]pyrazine).

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A11a: 3-(chloromethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

To a solution of [6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]methanol (200 mg, 0.62 mmol) in DCM (5 ml) was added SOC12 (0.07 ml, 0.93 mmol) at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was poured into water (30 ml) and extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (50 ml), dried over Na ₂ SO ₄ filtered and concentrated to give the crude product (200 mg, 0.58 mmol) as a solid. ^1H NMR (400 MHz, CDCl ₃ ) 0H=9.48 (d, 1H), 8.16 (d, 1H), 7.49 (d, 1H), 7.23-7.19 (m, 2H ), 5.20 (s, 2H), 2.45 (s, 3H).

Compound 20: 3-(cyclopropoxymethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

To 3-(chloromethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (211 mg, 0.62 mmol) and K2CO3 ( 170.15 mg, 1.23 mmol) in cyclopropanol (2 ml, 0.62 mmol) at 25°C. The mixture was stirred at 40°C for 3 hours. The mixture was diluted with H ₂ O (20 ml) and extracted with EtOAc (10 mlx2). The combined organic phase was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Welch Xtimate C18 (150 mm x 25 mm, 5 μm); A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 50-80% B in 7.5 min) to obtain the product ( 74.38 mg, 0.2 mmol, 33% yield) as a solid. ¹ H NMR (400 MHz, CDCl3) δн 9.42 (d, 1H), 8.17 (d, 1H), 7.48 (d, 1H), 7.24-7.16 (m, 2H), 5.18 (s, 2H), 3.433.38 (m, 1H), 2.44 (s, 3H), 0.67-0.62 (m, 2H), 0.60-0.55 (m, 2H). LCMS R _t =1.28 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₁₇ H ₁₆ F ₃ N ₄ O ₂ [M+H]+ 365.11, determined 365.1.

Example 21: Synthesis of compound 21 - (3-(difluoro(methoxy)methyl)-6-(2-methyl-4-(2,2,2trifluoroethoxy)phenyl)-[1,2,4]triazolo[4,3- a]pyrazine).

AZZ

A30: 1-bromo-2-methyl-4-(2,2,2-trifluoroethoxy)benzene.

2,2,2-Trifluoroethyltrifluoromethanesulfonate (2.48 g, 10.69 mmol) and cesium carbonate. (4.53 g, 13.9 mmol). The reaction mixture was slowly heated to RT and stirred for 12 hours. The reaction mixture was treated with water (40 ml) and extracted with EtOAc (2x30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography with 5% EtOAc/PE to give the product as a liquid (2.7 g, 9.97 mmol, 93% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ _H 7.46 (d, 1H), 6.87 (d, 1H), 6.68 (dd, 1H), 4.33 (q, 2H), 2 .40 (s, 3H).

A31: 4,4,5,5-tetramethyl-2-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane.

To a stirred solution of 1-bromo-2-methyl-4-(2,2,2-trifluoroethoxy)benzene (2.7 g, 9.97 mmol) and bis(pinacolato)diboron (3.04 g, 11.97 mmol ) in 1,4-dioxane (30 ml) was added potassium acetate (1.96 g, 19.95 mmol). Pd(dppf)Cl ₂ ·DCM (0.81 g, 1.0 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to RT, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with 5% EtOAc/PE to give the product as a liquid (2.93 g, 9.28 mmol, 93% yield). LCMS: Column: ZORBAX XDB C-18 (50x4.6 mm), 3.5 µm; Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 ml/min; 316.2 (M+H), R _t 3.00 min.

A33: 3-(chlorodifluoromethyl)-6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine.

To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.1 g, 4.6 mmol) and 4,4,5 ,5-tetramethyl-2-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane (1.43 g, 4.6 mmol) in 1,4-dioxane (15 ml) water (1.5 ml) and Cs ₂ CO ₃ (3.02 g, 9.28 mmol) were added. Pd(dppf)Cl ₂ DCM (0.38 g, 0.46 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for

- 37 046421 hours. The reaction mixture was cooled to RT, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with 25% EtOAc/PE to give the product (205 mg, 0.52 mmol, 11% yield) as a solid. LCMS: Column: ZORBAX XDB C-18 (50x4.6 mm), 3.5 µm; Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 ml/min; 393.1 (M+H), R _t 2.42 min.

Compound 21: 3-(difluoro(methoxy)methyl)-6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine .

To a stirred solution of 3-(chlorodifluoromethyl)-6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)[1,2,4]triazolo[4,3-a]pyrazine (165 mg, 0 .42 mmol) in MeCN (8.0 ml) was added Cs ₂ CO ₃ (810 mg, 2.5 mmol) and methanol (0.17 ml, 4.2 mmol). The reaction mixture was stirred for 1 hour at RT. The reaction mixture was treated with water (20 ml) and extracted with EtOAc (2x20 ml). The organic layer was washed with brine (15 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to give the product as a solid (60 mg, 0.15 mmol, 36% yield). preparative HPLC method: Rt 8.9; Column: XBridge C8 (150x19 mm), 5.0 µm; mobile phase: 10% NH4OAc in water/acetonitrile; flow rate: 15.0 ml/min. HPLC: Rt 4.79 min. column: XBridge C8 (50x4.6) mm, 3.5 µm; mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 ml/min. LCMS: 389.0 (M+H), Rt 2.23 min, column: XBridge C8 (50x4.6 mm), 3.5 µm; mobile phase: A: 0.1% TFA in water: ACM (95:5), B: 0.1% TFA in ACN; flow rate: 1.5 ml/min. ^1H NMR (400 MHz, CD3OD): _δH 9.51 (d, 1H), 8.45 (s, 1H), 7.47 (d, 1H), 7.04-6.98 (m, 2H ), 4.62 (q, 2H), 3.95 (s, 3H), 2.41 (s, 3H).

Example 22: Synthesis of compound 22 - (3-(difluoro(methoxy)methyl)-6-(4-isopropoxy-2-methylphenyl)[1,2,4]triazolo[4,3-a]pyrazine).

V°VA ^F XCI Pd(PPh ₃ ) ₂ CI ₂

I V. _B .0H ₊ CI _V . _N J ^KgС ° ³ >

' OH n ₂ A _n ⁿ

A34 A32

A35 22

A35: 3-(chlorodifluoromethyl)-6-(4-isopropoxy-2-methylphenyl)-[1,2,4]triazolo[4,3-a]pyrazine.

To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 4.18 mmol) and (4-isopropoxy- 2-methylphenyl)boronic acid (0.97 g, 5.02 mmol) in 1,4-dioxane (18 ml) was added water (2 ml) and K2CO3 (1.16 g, 8.37 mmol). PdCl ₂ (PPh ₃ ) ₂ (0.29 g, 0.42 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 16 hours. The reaction mixture was cooled to RT, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with 18% EtOAc/PE to give the product (0.85 g, 2.41 mmol, 57% yield). LCMS: 353.2 (M+H), Rt 2.54 min; column: ZORBAX XDB,-18 (50x4.6 mm), 3.5 µm; Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: AC^flow rate: 1.5 ml/min.

Compound 22: 3-(difluoro(methoxy)methyl)-6-(4-isopropoxy-2-methylphenyl)-[1,2,4]triazolo[4,3a]pyrazine.

To a stirred solution of 3-(chlorodifluoromethyl)-6-(4-isopropoxy-2-methylphenyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.56 mmol) in MeCN (9 ml) Cs ₂ CO ₃ (1.1 g, 3.39 mmol) and methanol (0.46 ml, 11.29 mmol) were added. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with water (20.0 ml) and extracted with EtOAc (2x20 ml). The organic layer was washed with brine (15 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by 18% EtOAc/PE silica gel column chromatography to give the product (147 mg, 0.42 mmol, 74% yield) as a solid. HPLC: Rt 4.70 min, column: XBridge C8 (50x4.6) mm, 3.5 µm; mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 ml/min. LCMS: 349.1 (M+H), Rt 2.24 min, column: XBridge C8 (50x4.6 mm), 3.5 µm; mobile phase: A: 0.1% TFA in water: ACN (95:5), B: 0.1% TFA in ACN; flow rate: 1.5 ml/min. 1H NMR (400 MHz, CD3OD): _δH 9.50 (d, 1H), 8.41 (d, 1H), 7.40 (d, 1H), 6.91-6.87 (m, 2H) , 4.71-4.68 (m, 1H), 3.95 (s, 3H), 2.38 (s, 3H), 1.36 (d, 6H).

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- (3-(ethoxydifluoromethyl)-6-(4-isopropoxy-2-methylphenyl) Example 23: Synthesis of compound 23 [1,2,4]triazolo[4,3-a]pyrazine).

To a stirred solution of 3-(chlorodifluoromethyl)-6-(4-isopropoxy-2-methylphenyl)-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.56 mmol) in MeCN (9 .0 ml) Cs ₂ CO ₃ (1.1 g, 3.39 mmol) and ethanol (0.66 ml, 11.29 mmol) were added. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was treated with water (20.0 ml) and extracted with ethyl acetate (2x20 ml). The organic layer was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography with 11% EtOAc/PE to give a solid (103 mg, 0.28 mmol, 50% yield). HPLC: Rt 5.02 min. column: XBridge C8 (50x4.6) mm, 3.5 µm; mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 ml/min. LCMS: 363.2 (M+H), Rt 2.50 min. column: ZORBAX XDB C-18 (50x4.6 mm), 3.5 µm; mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 ml/min. 1H NMR (400 MHz, CD3OD): _δH 9.49 (d, 1H), 8.40 (d, 1H), 7.41 (d, 1H), 6.90-6.86 (m, 2H) , 4.72-4.66 (m, 1H), 4.34 (q, 2H), 2.39 (s, 3H), 1.44 (t, 3H), 1.35 (d, 6H).

Example 24: Synthesis of compound 24 - (3-(difluoro(methoxy)methyl)-6-(4-isopropoxyphenyl)[1,2,4]triazolo[4,3-a]pyrazine).

A37: 2-(4-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Acetate was added to a stirred solution of 1-bromo-4-isopropoxybenzene (3.0 g, 13.95 mmol) and bis(pinacolato)diboron (4.25 g, 16.74 mmol) in 1,4-dioxane (30 mL). potassium (2.74 g, 27.9 mmol). Pd(dppf)Cl ₂ ·DCM (1.14 g, 1.39 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with 5% EtOAc/PE to give the product (3.2 g, 12.1 mmol, 87% yield). ^1H NMR (400 MHz, CDCl ₃ ): _δH 7.74 (d, 2H), 6.88 (d, 2H), 4.64-4.59 (m, 1H), 1.36 (s, 12H), 1.35 (d, 6H).

A38: 3 -(chlorodifluoromethyl)-6-(4-isopropoxyphenyl)-[1,2,4]triazolo[4,3-a]pyrazine.

To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.5 g, 6.27 mmol) and 2-(4- isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 5.7 mmol) in 1,4dioxane (15 ml) added water (1.5 ml) and Cs ₂ CO ₃ (3.71 g, 11.4 mmol). Pd(dppf)Cl ₂ was added to the reaction mixture under nitrogen atmosphere. DCM (0.47 g, 0.57 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography with 8% EtOAc/PE to give the product as a solid (340 mg, 1.0 mmol, 17% yield). LCMS: 339.0 (M+H), Rt 2.33 min. Column: XBridge C8 (50x4.6 mm), 3.5 µm; mobile phase: A: 0.1% TFA in water: ACN (95:5), B: 0.1% TFA in ACN; flow rate: 1.5 ml/min.

Compound 24: 3-(difluoro(methoxy)methyl)-6-(4-isopropoxyphenyl)-[1,2,4]triazolo[4,3-a]pyrazine.

To a stirred solution of 3-(chlorodifluoromethyl)-6-(4-isopropoxyphenyl)-[1,2,4]triazolo[4,3a]pyrazine (170 mg, 0.50 mmol) in MeCN (8 ml) was added Cs ₂ CO ₃ (0.98 g, 3.0 mmol) and methanol (0.2 ml,

- 39 046421

5.0 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was treated with water (20 ml) and extracted with ethyl acetate (2x20 ml). The organic layer was washed with brine (15 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to give the product as a solid (45 mg, 0.13 mmol, 27% yield). Preparative HPLC method: Rt 11.51; column: XBridge C8 (150x19 mm), 5.0 µm; mobile phase: 0.1% TFA in water/acetonitrile; flow rate: 15.0 ml/min. HPLC: Rt 4.90 min. column: XBridge C8 (50x4.6) mm, 3.5 µm; mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 ml/min. HPLC: 335.1 (M+H), Rt 2.53 min, column: Atlantis dC18 (50x4.6 mm), 3.5 µm; mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 ml/min. ^1H NMR (400 MHz, CD3OD): δκ 9.50 (d, 1H), 8.63 (s, 1H), 8.02-7.98 (m, 2H), 7.05 (dd, 2H) , 4.75-4.68 (m, 1H), 3.99 (s, 3H), 1.37 (d, 3H). 1.36 (d, 3H).

(3-(ethoxydifluoromethyl)-6-(4-isopropoxyphenyl)25

Example 25: Synthesis of the compound [1,2,4]triazolo[4,3-a]pyrazine).

To a stirred solution of 3-(chlorodifluoromethyl)-6-(4-isopropoxyphenyl)-[1,2,4]triazolo[4,3a]pyrazine (210 mg, 0.51 mmol) in MeCN (8.0 mL) was added. Cs ₂ CO ₃ (1.0 g, 3.06 mmol) and ethanol (0.3 ml, 5.1 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was treated with water (15.0 ml) and extracted with ethyl acetate (2x25 ml). The organic layer was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to give the product as a solid (18 mg, 0.05 mmol, 10% yield). Preparative HPLC method: Rt 16.21; column: XSelect (150x19 mm), 5.0 µm; mobile phase: 0.1% TFA in water/acetonitrile; flow rate: 15.0 ml/min. HPLC: Rt 4.95 min, 98.9% Column: XBridge C8 (50 x 4.6) mm, 3.5 µm; mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 ml/min. LCMS: 349.3 (M+H), Rt 2.51 min, 99.6% Column: ZORBAX XDB C-18 (50x4.6 mm), 3.5 µm; mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 ml/min. 1H NMR (400 MHz, CD3OD): δ 9.51 (s, 1H), 8.64 (s, 1H), 7.98 (d, 2H), 7.06 (d, 2H), 4.74- 4.70 (m, 1H), 4.38 (q, 2H), 1.50 (t, 3H), 1.37 (d, 6H).

Example 26: Synthesis of compound 26 (toxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine).

(3-[difluoro(methoxy)methyl]-6-[2-ethyl-4-(trifluorome1= °

CI Br

A22

Pd(dppf)CI ₂ ZnEt ₂ K ₂ CO ₃

DMF, 80°C, 16 h

C.I.

A39

Pd ₂ dba ₃ X-Phos COAc, dioxane 80°C, 16 h

A40

Pd(dppf)CI ₂ Cs ₂ CO ₃ dioxane/H ₂ O, 55°C, 16 ^Br 'vN ^N M _C |

A41

_{N2H4.H2O ​ ​}

ACN, 100°С, 16 h Cl

A42

Ν'™* n

THF, 20°C, 1 h _F (COCI) ₂ DMF

A --- ^: --*

Br THF,20°C, 1h

A43

TsOH (0.3 eq.) toluene, 130°C, 16 h

Vg

MeOH, 60°

ABOUT

A44

A39: 1-chloro-2-ethyl-4-(trifluoromethoxy)benzene.

To a mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (4.2 g,

15.25 mmol), Pd(dppf)Cl2 (2.23 g,

3.05 mmol) and K ₂ CO ₃ (4.21 g, 30.5 mmol) in DMF (75 ml) was added diethylzinc (60.99 ml, 60.99 mmol,

- 40 046421

1M in toluene). The resulting mixture was stirred at 80°C for 16 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (100 ml). The mixture was filtered through a celite pad and eluted with EtOAc (100 ml). The filtrate was extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography (PE) to give the product (2.3 g, 10.24 mmol, 67% yield) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δн=7.36 (d, 1H), 7.11 (d, 1H), 7.01 (dd, 1H), 2.77 (q, 2H), 1, 26 (t, 3H).

A40: 2-[2-ethyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Mixture of 1-chloro-2-ethyl-4-(trifluoromethoxy)benzene (2.3 g, 10.24 mmol), 4,4,5,5-tetramethyl-2(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.12 g, 12.29 mmol), KOAc (2.01 g, 20.48 mmol), X-Phos (0. 98 g, 2.05 mmol) and Pd ₂ (dba) ₃ (0.94 g, 1.02 mmol) in 1,4-dioxane (25 ml) were stirred at 80°C for 16 hours under N2. After cooling to 25°C, the reaction mixture was filtered through a celite pad. The filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography (PE) to give the product (1.7 g, 5.15 mmol, 50% yield) as an oil. 1H NMR (400 MHz CDCl ₃ ) δ.. 7.80 (d, 1H), 7.05-6.99 (m, 2H), 2.94 (q, 2H), 1.35 (s, 12H) , 1.21 (t, 3H).

A41: 2-chloro-5-[2-ethyl-4-(trifluoromethoxy)phenyl]pyrazine.

Mixture of 2-bromo-5-chloropyrazine (600 mg, 3.1 mmol), 2-[2-ethyl-4-(trifluoromethoxy)phenyl]-4,4,5,5tetramethyl-1,3,2-dioxaborolane (1 .16 g, 3.67 mmol), Cs ₂ CO ₃ (2.02 g, 6.2 mmol) and Pd(dppf)Cl ₂ (340.45 mg, 0.47 mmol) in 1,4-dioxane ( 15 ml) and water (1.5 ml) were stirred at 55°C under N2 atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered through celite and concentrated to leave a residue. The residue was redissolved in EtOAc (50 ml), washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography (EtOAc in PE=0% to 15%) to give the product (900 mg, 2.28 mmol, 73% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) _δH 8.68 (d, 1H), 8.47 (d, 1H), 7.40 (d, 1H), 7.22 (s, 1H), 7.18 (d, 1H), 2.74 (q, 2H), 1.17 (t, 3H). LCMS R _t =0.99 min with chromatography 1.5 min, 5-95AB, MS ESI calculated for C13H11C1F3N2O [M+H]+ 303.0, determined 302.8.

A42: [5-[2-ethyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

A mixture of 2-chloro-5-[2-ethyl-4-(trifluoromethoxy)phenyl]pyrazine (900 mg, 2.29 mmol) and hydrazine hydrate (1.15 g, 22.87 mmol) in MeCN (20 ml) was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and concentrated to give a residue. Water (20 ml) was added to the residue and the mixture was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography (EtOAc in PE=0% to 50% to 80%) to give the product (680 mg, 2.28 mmol, 99% yield) as an oil. 1H NMR (400 MHz, DMSOL ₆ ) _δH 8.21-8.17 (m, 1H), 8.14-8.06 (m, 2H), 7.43 (d, 1H), 7.29 ( s, 1H), 7.24 (d, 1H), 4.33 (s, 2H), 2.71 (q, 2H), 1.05 (t, 3H).

A43: 2-bromo-H'-[5-[2-ethyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (600 mg, 3.43 mmol) in THF (10 ml) was added one drop of DMF and (COCl) ₂ (0.35 ml, 4.12 mmol). The resulting mixture was stirred at 20°C for 1 hour. [5-[2-ethyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (680 mg, 2.28 mmol) was added to the solution. The resulting mixture was stirred at 20°C for 1 hour. The mixture was poured into water (30 ml) and the mixture was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product (1 g, 2.20 mmol, 96% yield) as an oil. LCMS R _t =0.92 min with chromatography 1.5 min, 595AV, MS ESI calc. for C15H1 ₃ BrF ₃ N4O2 [M+H]+457.0, determined 456.7.

A44: 3-[bromo(difluoro)methyl]-6-[2-ethyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A mixture of 2-bromo-H'-[5-[2-ethyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide (1 g, 2.2 mmol) and TsOH (113.49 mg, 0.66 mmol) in toluene (10 ml) was stirred at 130°C for 16 hours. After cooling to room temperature, water (20 ml) was added to the solution and the mixture was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography (EtOAc in PE=0% to 15% to 30%) to give the product (660 mg, 1.51 mmol, 68% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δн 9.60 (d, 1H), 8.22 (s, 1H), 7.45 (d, 1H), 7.27 (s, 1H), 7.22 ( d, 1H), 2.76 (q, 2H), 1.23 (t, 3H).

Compound 26: 3-[difluoro(methoxy)methyl]-6-[2-ethyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3 a]pyrazine.

Mixture of 3-[bromo(difluoro)methyl]-6-[2-ethyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (660 mg, 1.51 mmol ) and AgBF ₄ (585.78 mg, 3.02 mmol) in methanol (6 ml) were stirred at 60°C for 1 hour in the dark. Brine (30 ml) and EtOAc (30 ml) were added and the mixture was filtered through celite. The filtrate was separated and the aqueous layer was extracted with EtOAc (20 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give crude

- 41 046421 puppy product. The crude product was purified by flash chromatography (EtOAc in PE=0% to 20% to 40%) to give the product (434.49 mg, 1.10 mmol, 73% yield) as a solid. 1H NMR (400 MHz, CDCI3) δ, 9.51 (d, 1H), 8.22 (d, 1H), 7.43 (d, 1H), 7.25 (s, 1H), 7.20 ( d, 1H), 3.94 (s, 3H), 2.74 (q, 2H), 1.22 (t, 3H). LCMS R _t =1.36 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C16H14F5N4O2 [M+H]+ 389.1, determined 389.2.

Examples 27 and 28: Synthesis of compounds 27 and 28 da-3-(difluoro(methoxy)methyl)-6-(2-methyl-4-((1,1,1trifluoropropan-2-yl)oxy)phenyl)-[1 ,2,4]triazolo[4,3-a]pyrazine and ^)-3-(difluoro(methoxy)methyl)-6-(2methyl-4-(( 1,1,1-trifluoropropan-2-yl)oxy )phenyl)-[1,2,4]triazolo[4,3-a]pyrazine.

o o o ^v ron - ¹²²² % ^Vg L|

NH ₂ NH ₂ ^F t ΥΊ1 D DMF.THF, FF

-------------► ¹⁾ 30 min, 25°C _>

MeCN, 100°C, 24 h | 2) THF, 25°С, 1 h

A51

A46: 2-methyl-1-nitro-4-(2,2,2-trifluoro-1-methylethoxy) benzene.

To a solution of 4-fluoro-2-methyl-1-nitrobenzene (10 g, 64.46 mmol) and 1,1,1-trifluoropropan-2-ol (8.82 g, 77.35 mmol) in DMF (150 ml ) Cs ₂ CO ₃ (42 g, 128.92 mmol) was added at 25°C. The mixture was stirred at 80°C for 16 hours. The mixture was poured into water (500 ml) and filtered. The filter cake was washed with water (100 mlx2) and concentrated to give the product (15 g, 60.2 mmol) as a solid. 1H NMR (400 MHz, CDCI3) δ, 8.10 (d, 1H), 6.88-6.85 (m, 2H), 4.80-4.74 (m, 1H), 2.64 (s , 3H), 1.56 (d, 3H).

A47: 2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)aniline.

A mixture of 2-methyl-1-nitro-4-(2,2,2-trifluoro-1-methylethoxy)benzene (15 g, 60.2 mmol), NH4C1 (6.44 g, 120.39 mmol) and Fe ( 6.72 g, 120.39 mmol) in ethanol (150 ml) and water (50 ml) was stirred at 80°C for 2 hours. The mixture was poured into water (500 ml). The mixture was extracted with EtOAc (200 mlx2). The combined organic phase was washed with brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (13 g, 59.31 mmol) as an oil. 1H NMR (400 MHz, DMSO^ ₆ ) 5h 6.70 (d, 1H), 6.66-6.63 (m, 1H), 6.56-6.53 (m, 1H), 4.85- 4.76 (m, 1H), 4.61 (brs, 2H), 2.03 (s, 3H), 1.34 (d, 3H).

A48: 1-bromo-2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)benzene.

To a mixture of TBAB (11.03 g, 34.22 mmol), CuBr ₂ (305.68 mg, 1.37 mmol) and isopentyl nitrite (1.92 g, 16.42 mmol) in MeCN (40 ml) was added 2- methyl 4-(2,2,2-trifluoro-1-methyl-ethoxy)aniline (3 g, 13.69 mmol) and TsOH-H ₂ O (3.38 g, 17.79 mmol). The mixture was stirred at 20°C for 12 hours. The mixture was diluted with H ₂ O (100 ml) and the mixture was extracted with DCM (100 ml x 2). The combined organic phase was washed with water (40 mlx2) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 2%) to give the product (3 g, 10.60 mmol, 77% yield) as an oil. 1H NMR (400 MHz, CDCI3) δ, 7.45 (d, 1H), 6.87 (d, 1H), 6.78 (dd, 8.8 Hz, 1H), 4.62-4.56 ( m, 1H), 2.38 (s, 3H), 1.50 (d, 3H).

A49: 4,4,5,5-tetramethyl-2-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,3,2-dioxaborolane.

A mixture of 1-bromo-2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)benzene (3 g, 10.6 mmol), KOAc (2080.05 mg, 21.19 mmol) and 4, 4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3229.31 mg, 12.72 mmol) and Pd(dppf)Cl ₂ (775.41 mg, 1.06 mmol) in 1,4-dioxane (30 ml) were stirred at 80° C. under N ₂ atmosphere for 16 hours. The mixture was poured into water (100 ml), and the aqueous layer was extracted

- 42 046421

EtOAc (50 mlx2). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) to give the product (2.5 g, 7.57 mmol, 71% yield) as an oil. ^1H NMR (400 MHz, CDCl3) _δH 7.75 (d, 1H), 6.77-6.74 (m, 2H), 4.72-4.69 (m, 1H), 2.53 ( s, 3H), 1.50 (d, 3H), 1.34 (s, 12H).

A50: 2-chloro-5-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]pyrazine.

A mixture of Pd(dppf)Cl ₂ (554.07 mg, 0.76 mmol), Cs ₂ CO ₃ (4.93 g, 15.14 mmol), 2-bromo-5-chloropyrazine (1.76 g, 9. 09 mmol) and 4,4,5,5-tetramethyl-2-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,3,2dioxaborolane (2.5 g, 7.57 mmol) in water (6 ml) and 1,4-dioxane (24 ml) was stirred at 55°C under N ₂ atmosphere for 16 hours. The mixture was poured into water (100 ml) and the aqueous layer was extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) to give the product (2 g, 6.31 mmol, 83% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) _δH 8.66 (d, 1H), 8.47 (d, 1H), 7.41 (d, 1H), 6.93-6.90 (m, 2H) , 4.74-4.71 (m, 1H), 2.41 (s, 3H), 1.55 (d, 3H).

A51: [5-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]pyrazin-2-yl]hydrazine.

To a solution of 2-chloro-5-[2-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)phenyl]pyrazine (2 g, 6.31 mmol) in MeCN (30 ml) was added N2H4H2O (3.16 g, 63.15 mmol) at 25°C. The mixture was stirred at 100°C for 24 hours. After cooling to 25°C, the reaction mixture was poured into water (100 ml). The mixture was extracted with EtOAc (30 ml x 2 ), washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product (1.8 g, 5.8 mmol) as a solid. LCMS Rt=0.79 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₄ H ₁₆ F ₃ N ₄ O [M+H]+ 313.1, determined 313.0.

A52: 2-bromo-2,2-difluoro-N-[5-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]pyrazin-2-yl]acetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (1.51 g, 8.65 mmol), DMF (6.32 mg, 0.09 mmol) in THF (15 ml) was added (COCl) ₂ (1, 32 g, 10.37 mmol) at 25°C. The mixture was stirred at 25°C for 30 minutes. [5-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]pyrazin-2-yl]hydrazine (1.8 g, 5.76 mmol) in THF (20 ml). was added to the above mixture at 25°C. The resulting mixture was stirred at 25°C for 1 hour. The mixture was poured into water (50 ml) and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product (2.7 g, 5.75 mmol) as a solid. LCMS Rt=0.89 min with chromatography 1.5 min, 5-95АВ, MS ESI calc. for Ci ₆ Hi ₅ BrF ₅ N ₄ O ₂ [M+H]+ 469.0, determined 468.9.

A53: 3-[bromo(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-[1,2,4]triazolo[4,3a] pyrazine

Solution of 2-bromo-2,2-difluoro-N-[5-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]pyrazin-2yl]acetohydrazide (2.7 g, 5 .75 mmol) and TsOH (297.28 mg, 1.73 mmol) in toluene (30 ml) were stirred at 130°C for 16 hours. Water (50 ml) was added and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 20%) to give the product (800 mg, 1.77 mmol, 31% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δ^.57 (s, 1H), 8.18 (s, 1H), 7.44 (d, 1H), 6.98-6.92 (m, 2H), 4.76-4.71 (m, 1H), 2.43 (s, 3H), 1.57 (d, 3H).

A54: 3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-[1,2,4]triazolo [4,3 - α]pyrazine.

To a suspension of 3-[bromo(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl][1,2,4]triazolo[4,3-a ]pyrazine (300 mg, 0.66 mmol) in methanol (3 ml), AgBF ₄ (257.98 mg, 1.33 mmol) was added at 25°C under N2 atmosphere. The mixture was protected from light and stirred at 60°C for 2 hours. The solution was added to brine (10 ml) and filtered. The filtrate was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (220 mg, 0.55 mmol, 82% yield) as a solid. LCMS Rt=1.23 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₇ H ₁₆ F ₅ N ₄ O ₂ [M+H]+ 403.1, determined 403.1.

Compounds 27 and 28: ^)-3-(difluoro(methoxy)methyl)-6-(2-methyl-4-((1,1,1-trifluoropropan-2yl)oxy)phenyl)-[1,2,4 ]triazolo[4,3-a]pyrazine and ^)-3-(difluoro(methoxy)methyl)-6-(2-methyl-4-((1,1,1trifluoropropan-2-yl)oxy)phenyl)- [1,2,4]triazolo[4,3-a]pyrazine.

3-(difluoro(methoxy)methyl)-6-(2-methyl-4-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)-[1,2,4]triazolo[4,3a ]pyrazine (220 mg, 0.55 mmol) was purified using SFC (DAICEL CHIRALCEL OJ-H (250 mmx30 mm, 5 mm); A = CO ₂ and B = 0.1% NH ₃ -H ₂ O-EtOH; 60 ml/min; 15% B; 80 injection to obtain enantiomer 1,

- 43 046421 randomly identified as compound 27 (66.33 mg, 0.16 mmol, 30% yield) (peak 1, Rt=1.450 min) as a solid, and enantiomer 2 randomly identified as compound 28 (70 .41 mg, 0.17 mmol, 32% yield (peak 2: Rt=1.609 min) as a solid. The stereochemistry of the compounds was determined randomly.

Analytical SFC: (Chiralcel OJ-3 100A, 4.6 mm ID, 3 mm, mobile phase: A: CO ₂ B: ethanol (0.05% DEA), gradient: from 5% to 40% B in 4 min and hold 40% for 2.5 min, then 5% B for 1.5 min, flow rate: 2.8 ml/min, column temperature: 35°C, ABPR: 1500 psi) showed two peaks (Peak 1: Rt=l.450 min, Peak 2: Rt= 1.609 min).

Compound 27: ^1H NMR (400 MHz, CD3CN) δκ 9.40 (d, 1H), 8.32 (d, 1H), 7.43 (d, 1H), 7.02 (s, 1H), 6 .97-6.95 (m, 1H), 5.03-4.96 (m, 1H), 3.88 (s, 3H), 2.36 (s, 3H), 1.51 (d, 3H ). LCMS Rt=1.36 min with chromatography 2 min, 10-80AV, MS ESI calc. For C ₁₇ H ₁₆ F ₅ N ₄ O ₂ [M+H]+ 403.1, determined to be 403.2.

Compound 28: 1H NMR (400 MHz, CD3CN) δκ 9.40 (d, 1H), 8.32 (d, 1H), 7.43 (d, 1H), 7.02 (s, 1H), 6. 97-6.95 (m, 1H), 5.03-4.96 (m, 1H), 3.88 (s, 3H), 2.36 (s, 3H), 1.51 (d, 3H) . LCMS Rt=1.36 min with chromatography 2 min, 10-80AV, MS ESI calc. for C ₁₇ H ₁₆ F ₅ N ₄ O ₂ [M+H] ⁺ 403.1, determined 403.2.

Examples 29 and 30: Synthesis of compounds 29 and 30 - ^)-3-(ethoxydifluoromethyl)-6-(2-methyl-4-((1,1,1trifluoropropan-2-yl)oxy)phenyl)-[1,2 ,4]triazolo[4,3-α]pyrazine and (S)-3-(ethoxydifluoromethyl)-6-(2methyl-4-(( 1,1,1-trifluoropropan-2-yl)oxy)phenyl)-[ 1,2,4]triazolo[4,3-a]pyrazine.

A53 A55

thirty

A55: 3-[difluoro(methoxy)methyl]-6-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-[1,2,4]triazolo[4,3- a]pyrazine.

To a suspension of 3-[bromo(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl][1,2,4]triazolo[4,3-a ]pyrazine (300 mg, 0.66 mmol) in ethanol (3 ml), AgBF ₄ (257.98 mg, 1.33 mmol) was added at 25°C under N2 atmosphere. The mixture was protected from light and stirred at 60°C for 2 hours. The solution was added to brine (50 ml) and filtered. The filtrate was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (222 mg, 0.53 mmol, 80% yield) as a solid. LCMS Rt=1.27 min with chromatography 1.5 min, 5-95АВ, MS ESI calc. for C ₁₈ H ₁₈ F ₅ N ₄ O ₂ [M+H] ⁺ 417.1, determined 417.1.

Compounds 29 and 30: ^)-3-(ethoxydifluoromethyl)-6-(2-methyl-4-((1,1,1-trifluoropropan-2yl)oxy)phenyl)-[1,2,4]triazolo[4 ,3-a] pyrazine and (S)-3 -(ethoxydifluoromethyl)-6-(2-methyl-4-(( 1,1,1trifluoropropan-2-yl)oxy)phenyl)-[1,2,4] triazolo[4,3-a]pyrazine.

3-(ethoxydifluoromethyl)-6-(2-methyl-4-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)-[1,2,4]triazolo[4,3a]pyrazine (222 mg, 0.53 mmol) was purified using SFC (DAICEL CHIRALCEL OJ-H (250 mmx30 mm, 5 mm); A=CO ₂ and B=0.1% NH ₃ H ₂ O-EtOH; 60 ml/min; 15% B; 80 injection to produce enantiomer 1, randomly identified as Compound 29 (peak 1, R _t =1.325 min) as a solid, and enantiomer 2, randomly identified as Compound 30 (63.55 mg, 0. 15 mmol, yield 28%) (peak 2: R _t =1.486 min) as a solid. The stereochemistry of the compounds was determined randomly.

Analytical SFC: (Chiralcel OJ-3 100A, 4.6 mm ID, 3 µm, mobile phase: A: CO ₂ , B: ethanol (0.05% DEA), gradient: from 5% to 40% B in 4 min and hold 40% for 2.5 min followed by 5% B for 1.5 min, flow rate: 2.8 mL/min, column temperature: 35°C, ABPR: 1500 psi) showed two peak (Peak 1: R _t =1.325 min, Peak 2: R _t =1.486 min).

Compound 29: 1H NMR (400 MHz, CD3CN) δκ 9.41 (d, 1H), 8.32 (s, 1H), 7.45 (d, 1H), 7.01 (s, 1H), 6. 98-6.95 (m, 1H), 5.03-4.96 (m, 1H), 4.28 (q, 2H), 2.37 (s, 3H), 1.51 (d, 3H) , 1.39 (t, 3H). LCMS Rt=1.39 min with chromatography 2 min, 10-80АВ, MS ESI calc. for C ₁₈ H ₁₈ F ₅ N ₄ O ₂ [M+H] ⁺ 417.2, determined 417.1.

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Compound 30: 1H NMR (400 MHz, CD3CN) δΗ 9.41 (d, 1H), 8.32 (s, 1H), 7.45 (d, 1H), 7.02 (s, 1H), 6.986.95 ( m, 1H), 5.03-4.96 (m, 1H), 4.28 (q, 2H), 2.37 (s, 3H), 1.51 (d, 3H), 1.39 (t , 3H). LCMS Rt=1.39 min with chromatography 2 min, 10-80АВ, MS ESI calc. for C ₁₈ H ₁₈ F ₅ N ₄ O ₂ [M+H]+ 417.3, determined 417.1.

Examples 31 and 32: Synthesis of compounds 31 and 32 - ^)-3-(difluoro(methoxy)methyl)-6-(2-(1-methoxyethyl)4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo [4,3-a]pyrazine and ^)-3-(difluoro(methoxy)methyl)-6-(2-(1methoxyethyl)-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4, 3-a]pyrazine.

_MnO2Cl ⁷⁰ °C,

Cl

A24

A56

THF, 0°C, 2h

MeMgBr

Cl

A57

NaH, Mel, THF

0-25°C, 16.5 h

Cl

A58

Pd ₂ (dba) ₃ PCy ₃ KOAc, dioxane 120°C, 16 h

ACN, 100 °C, 16 h ' Pd(dppf)CI ₂ Cs ₂ CO ₃

1,4-dioxane/ _H2O , 55°C, 16 h

A59

A60

2) THF, 20 °C, 1 h

A61 ° f (COCI) ₂ DMF )HO rF -----Br THF, 20°C, 0.5 h

TsOH (0.3 eq.) toluene, 130°C, 16 h

32

A56: 2-chloro-5-(trifluoromethoxy)benzaldehyde.

MnO ₂ (7.1 g, 81.65 mmol) was added to a solution of [2-chloro-5-(trifluoromethoxy)phenyl]methanol (3.7 g, 16.33 mmol) in chloroform (120 mL). The mixture was stirred at 70°C for 12 hours. After cooling to RT, the mixture was filtered through celite and the filter cake was eluted with DCM (20x2 ml). The filtrate was concentrated under reduced pressure to give the crude product (2.6 g, 11.58 mmol) as an oil. 1H NMR (400 MHz, DMSO-06) _δH 10.27 (s, 1H), 7.84-7.66 (m, 3H).

A57: 1-[2-chloro-5-(trifluoromethoxy)phenyl]ethanol.

To a solution of 2-chloro-5-(trifluoromethoxy)benzaldehyde (2.5 g, 11.13 mmol) in THF (30 ml) was added MeMgBr (5.57 ml, 16.7 mmol) (3 M in ether) at 0 °C. The mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated aqueous NH4Cl (20 ml). The aqueous layer was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (2.5 g, 10.39 mmol, 93% yield) as an oil. 1H NMR (400 MHz, DMSOU) δκ 7.56-7.49 (m, 2H), 7.31-7.25 (m, 1H), 5.61 (d, 1H), 5.03-4, 93 (m, 1H), 1.31 (d, 3H).

A58: 1-chloro-2-(1-methoxyethyl)-4-(trifluoromethoxy)benzene.

To a solution of 1-[2-chloro-5-(trifluoromethoxy)phenyl]ethanol (2.5 g, 10.39 mmol) in THF (20 mL) was added NaH (831.22 mg, 20.78 mmol, 60 % in oil) at 0°C. The mixture was stirred at 0°C for 30 minutes. CH ₃ I (0.97 mL, 15.59 mmol) was then added to the solution at 0°C. The mixture was stirred at 25°C for 16 hours. The mixture was quenched with saturated aqueous NH4C1 (40 ml). The aqueous layer was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (2.2 g, 8.64 mmol, 83% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δ _δ 7.41-7.33 (m, 2H), 7.12-7.02 (m, 1H), 4.71 (q, 1H), 3.28 ( s, 3Η), 1.41 (d, 3Η).

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A59: 2-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

A mixture of 1-chloro-2-(1-methoxyethyl)-4-(trifluoromethoxy)benzene (1.9 g, 7.46 mmol), 4,4,5,5-tetramethyl2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.27 g, 8.95 mmol), KOAc (1.46 g, 14.92 mmol), Pd ₂ ( dba) ₃ (683.29 mg, 0.75 mmol), tricyclohexylphosphine (523.13 mg, 1.87 mmol) in 1,4dioxane (20 ml) was stirred at 120°C for 16 hours. After cooling to 25°C, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (PE 100%) to give the product (1 g, 2.89 mmol, 38% yield) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _H 7.79 (d, 1H), 7.37-7.34 (m, 1H), 7.11-7.06 (m, 1H), 5.01 (q, 1H), 3.25 (s, 3H), 1.40 (d, 3H), 1.36 (s, 12H).

A60: 2-chloro-5-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]pyrazine.

Mixture of 2-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 2.89 mmol), 2-bromo -5-chloropyrazine (670.56 mg, 3.47 mmol), Cs ₂ CO ₃ (1.88 g, 5.78 mmol), Pd(dppf)Cl ₂ (211.38 mg, 0.29 mmol) in 1,4-dioxane (10 ml) and water (1 ml) were stirred at 55°C for 16 hours. After cooling to RT, the mixture was diluted with H ₂ O (20 ml). The aqueous layer was extracted with EtOAc (20 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10%) to give the product (400 mg, 0.97 mmol, 34% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δн 8.69 (d, 1H), 8.49 (s, 1H), 7.54 (s, 1H), 7.44-7.38 (m, 1H), 7.26-7.23(m, 1H), 4.56 (q, 1H), 3.15 (s, 3H), 1.43 (d, 3H).

A61: [5-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

To a solution of 2-chloro-5-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]pyrazine (400 mg, 0.97 mmol) in MeCN (8 ml) was added N2H4 H ₂ O (486.61 mg , 9.73 mmol) at 25°C. The mixture was stirred at 100°C for 16 hours. After cooling to 20°C, the reaction mixture was poured into water (20 ml). The aqueous layer was extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (330 mg, 0.96 mmol) as an oil. 1H NMR (400 MHz, DMSO^) δн 8.20-8.15 (m, 2H), 8.11 (s, 1H), 7.49 (d, 1H), 7.39 (s, 1H), 7.36-7.30 (m, 1H), 4.66-4.58 (m, 1H), 4.34 (brs, 2H), 3.03 (s, 3H), 1.32 (d, 3H). LCMS Rt=0.76 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₄ H ₁₆ F ₃ N ₄ O ₂ [M+H]+ 329.1, determined 328.9.

A62: 2-bromo-H-(2-bromo-2,2-difluoroacetyl)-2,2-difluoro-H'-[5-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]pyrazine- 2-yl]acetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (300 mg, 1.71 mmol) in THF (3 ml) was added DMF (6.27 mg, 0.09 mmol) and (COCl) ₂ (0. 17 ml, 2.06 mmol). The resulting mixture was stirred at 20°C for 30 minutes. The resulting solution was used directly in the next step. To the above mixture was added a solution of [5-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (330 mg, 0.96 mmol) in THF (2 ml). The mixture was stirred at 20°C for 1 hour. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (600 mg, 0.93 mmol) as an oil. LCMS Rt=1.0 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₈ H ₁₄ BrF ₇ N ₄ O ₄ [M+H]+ 642.9, determined 642.7.

A63: 3-[bromo(difluoro)methyl]-6-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a solution of 2-bromo-N-(2-bromo-2,2-difluoroacetyl)-2,2-difluoro-H'-[5-[2-(1-methoxyethyl)-4(trifluoromethoxy)phenyl]pyrazine-2 -yl]acetohydrazide (600 mg, 0.93 mmol) in toluene (20 ml) was added TsOH (48.27 mg, 0.28 mmol). The mixture was stirred at 130°C for 16 hours. Water (30 ml) was added and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~20%) to give the product (200 mg, 0.35 mmol, 37% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) _δH 9.57 (s, 1H), 8.27 (s, 1H), 7.56 (s, 1H), 7.48-7.45 (m, 1H) , 7.32-7.27 (m, 1H), 4.60-4.52 (m, 1H), 3.21 (s, 3H), 1.46 (d, 3H).

A64: 3-[difluoro(methoxy)methyl]-6-[2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a solution of 3-[bromo(difluoro)methyl]-6-[2-( 1 -methoxyethyl)-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg , 0.35 mmol) in methanol (2 ml) was added AgBF ₄ (135.12 mg, 0.70 mmol). The mixture was stirred at 60°C for 4 hours. Brine (10 ml) was added and the mixture was filtered through celite. The filtrate was separated and the aqueous phase was extracted with EtOAc (10 mlx2). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0~30%) to give the product (70 mg, 164.7 mmol, 47% yield) as a solid. LCMS Rt=0.90 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₇ H ₁₆ F ₅ N ₄ O ₃ [M+H]+ 419.1, determined 419.0.

- 46 046421

Compounds 31 and 32: ^)-3-(difluoro(methoxy)methyl)-6-(2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3- a]pyrazine and ^)-3-(difluoro(methoxy)methyl)-6-(2-(1-methoxyethyl)-4(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a] pyrazine

3-(difluoro(methoxy)methyl)-6-(2-(1-methoxyethyl)-4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3a]pyrazine (70 mg, 164.7 mmol) were separated using SFC (DAICEL CHIRALPAK AS (250 mmx30 mm, 10 mm); A=hexane and B=EtOH (0.5% ammonia); 38°C; 30 ml/min; 10% B; 11 min cycle ; 12 injection) to obtain enantiomer 1, randomly identified as Compound 31 (15.98 mg, 38.2 mmol, 23% yield) (Rt peak 1 = 6.14 min) as a solid and enantiomer 2, randomly. identified as Compound 32 (15.45 mg 36.9 mmol, 22% yield) (Rt peak 2=8.0 min) as a solid. The stereochemistry of the compounds was determined randomly.

Analytical SFC: Analysis by SFC (Chiralpak AS-3 100x46 mm ID, 3 mm; mobile phase: A: hexane (0.1% DEA) B: IPA, isocratic: A: B=90: 10, flow rate: 1 ml/min; column temperature: 25°C) showed two peaks at 6.14 min (50%) and 8.00 min (50%).

Compound 31: ^1H NMR (400 MHz, DMSO-06) δκ 9.66 (s, 1H), 8.65 (s, 1H), 7.64-7.58 (m, 1H), 7.497.42 ( m, 2H), 4.62-4.53 (m, 1H), 3.87 (s, 3H), 3.06 (s, 3H), 1.36 (d, 3H). LCMS Rt=1.22 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₁₇ H ₁₆ F ₅ N ₄ O ₃ [M+H]+ 419.1, determined 419.1.

Compound 32: 1H NMR (400 MHz DMSO-do) _δH 9.65 (s, 1H), 8.65 (s, 1H), 7.65-7.55 (m, 1H), 7.48-7 .39 (m, 2H), 4.62-4.51 (m, 1H), 3.86 (s, 3H), 3.05 (s, 3H), 1.35 (d, 3H). LCMS Rt= 1.21 min with chromatography 2.0 min, 10-80АВ, MS ESI calc. for C ₁₇ H ₁₆ F ₅ N ₄ O ₃ [M+H] ⁺ 419.1, determined 419.1.

Example 33: Synthesis of Compound 33-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A70 33

A65: 1-chloro-2-cyclopropyl-4-(trifluoromethoxy)benzene.

A mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (3 g, 10.89 mmol), cyclopropylboronic acid (982.34 mg, 11.44 mmol), K ₂ PO ₃ (8.09 g, 38 .12 mmol), Pcy ₃ (610.85 mg, 2.18 mmol) and Pd(OAc) ₂ (244.52 mg, 1.09 mmol) in toluene (50 ml) and water (5 ml) were stirred at 80 °C in N2 atmosphere for 16 hours. After cooling to RT, water (50 ml) was added and the mixture was filtered through celite. The filtrate was extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 2%) to give the product (2.57 g, 10.86 mmol, 99% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δκ 7.36 (d, 1H), 7.016.95 (m, 1H), 6.78 (d, 1H), 2.21 (tt, 1H), 1.13- 1.04 (m, 2H), 0.73-0.67 (m, 2H).

A66: 2-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Mixture of 1-chloro-2-cyclopropyl-4-(trifluoromethoxy)benzene (2.57 g, 10.86 mmol), 4,4,5,5-tetramethyl-2

- 47 046421 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.31 g, 13.03 mmol), KOAc (2, 13 g, 21.72 mmol), X-phos (1.04 g, 2.17 mmol) and Pd ₂ (dba) ₃ (0.99 g, 1.09 mmol) in 1,4-dioxane (50 ml ) was stirred at 80°C under N2 atmosphere for 16 hours. After cooling to room temperature, water (50 ml) was added and the mixture was filtered through celite. The filtrate was extracted with EtOAc (80 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 2%) to give the product (2.5 g, 7.62 mmol, 70% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δн 7.77 (d, 1H), 6.98-6.96 (m, 1H), 6.64 (s, 1H), 2.75-2.68 (m , 1H), 1.36 (s, 12H), 1.04-1.00 (m, 2H), 0.70-0.66 (m, 2H).

A67: 2-chloro-5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazine.

Mixture of 2-bromo-5-chloropyrazine (1.35 g, 6.98 mmol), 2-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]4,4,5,5-tetramethyl-1,3,2- dioxaborolane (2.5 g, 7.62 mmol), Cs ₂ CO ₃ (4.55 g, 13.96 mmol) and Pd(dppf)Cl ₂ (766.01 mg, 1.05 mmol) at 1.4 β-dioxane (20 ml) and water (1.5 ml) were stirred at 55°C under N2 atmosphere for 16 hours. After cooling to room temperature, water (20 ml) was added and the mixture was filtered through celite. The filtrate was extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 2% to 5%) to give the product (1.9 g, 4.64 mmol, 66% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δн 8.70 (d, 1H), 8.65 (d, 1H), 7.48 (d, 1H), 7.17-7.14 (m, 1H), 6.94-6.90 (m, 1H), 2.05-2.00 (m, 1H), 0.99-0.93 (m, 2H), 0.72-0.67 (m, 2H ).

A68: [5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

A solution of 2-chloro-5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazine (1.9 g, 4.64 mmol) and hydrazine hydrate (2.33 g, 46.45 mmol) in MeCN (20 ml) stirred at 100°C for 16 hours. After cooling to room temperature, water (50 ml) was added and the mixture was extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=30% to 50% to 80%) to give the product (1.44 g, 4.64 mmol, 99% yield) as an oil. 1H NMR (400 MHz, DMSOO _δH 8.23-8.18 (m, 2H), 8.11 (s, 1H), 7.47 (d, 1H), 7.25-7.19 (m, 1H), 6.93 (s, 1H), 4.33 (brs, 2H), 2.17-2.06 (m, 1H), 0.92-0.85 (m, 2H), 0.70-0 .63 (m, 2H).

A69: 2-bromo-H'-[5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (680 mg, 3.89 mmol) in THF (10 ml) was added one drop of DMF and (COCl) ₂ (0.39 ml, 4.66 mmol). The resulting mixture was stirred at 20°C for 1 hour. A solution of [5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (0.8 g, 2.58 mmol) in THF (3 ml) was then added to the above mixture. The resulting mixture was stirred at 20°C for 1 hour. The mixture was poured into water (30 ml) and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ filtered and concentrated to give the crude product (1.2 g, 2.57 mmol, 99% yield) as an oil. LCMS R _t =0.90 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₆ H ₁₃ BrF ₅ N ₄ O ₂ [M+H]+ 469.0, determined 468.7.

A70: 3-[bromo(difluoro)methyl]-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-α]pyrazine.

A mixture of 2-bromo-H'-[5-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide (1.2 g, 2.57 mmol) and TsOH (132 .69 mg, 0.77 mmol) in toluene (15 ml) was stirred at 130°C for 16 hours. After cooling to room temperature, water (30 ml) was added and the mixture was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to give the product (630 mg, 1.40 mmol, 54% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) _δH 9.63 (d, 1H), 8.47 (s, 1H), 7.61 (d, 1H), 7.25-7.18 (m, 1H) , 6.98 (d, 1H), 2.10-2.02 (m, 1H), 1.05-0.98 (m, 2H), 0.82-0.75 (m, 2H).

Compound 33: 6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3-[difluoro(methoxy)methyl][1,2,4]triazolo[4,3-a]pyrazine.

A mixture of 3-[bromo(difluoro)methyl]-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine (630 mg, 1.4 mmol) and AgBF ₄ (544.2 mg, 2.81 mmol) in methanol (10 ml) was stirred at 60°C in the dark for 1 hour. After cooling to room temperature, brine (50 ml) and EtOAc (50 ml) were added and the mixture was filtered through celite. The filtrate was separated and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified using preparative HPLC (YMC Triart C18 (150 mm x 25 mm, 5 mm) A=H ₂ O (10 mM

- 48 046421

NH4HCO3) and B=CH3CN; 53-83%B in 8 minutes) to give the product (327.19 mg, 817.4 mmol, 58% yield) as an oil. ^1H NMR (400 MHz, CDCl ₃ ) δκ 9.53 (d, 1H), 8.45 (s, 1H), 7.57 (d, 1H), 7.19 (dd, 1H), 6.95 (s, 1H), 3.94 (s, 3H), 2.09-2.02 (m, 1H), 1.02-0.96 (m, 2H), 0.80-0.75 (m , 2H). LCMS Rt=1.27 min with chromatography 2.0 min, 10-80АВ, MS PER calc. for C ₁ 7H ₁₄ F ₅ N ₄ O ₂ [M+H]+ 401.1, determined 401.0.

Example 34: Synthesis of the compound 34-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-3[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A70 34

To a solution of 3-[bromo(difluoro)methyl]-6-[2-cyclopropyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine (140 mg, 0.31 mmol) in ethanol (5 ml), AgBF4 (120.93 mg, 0.62 mmol) was added. The mixture was stirred at 60°C for 6 hours. Brine (20 ml) was added and the mixture was filtered through celite. The filtrate was separated and the aqueous phase was extracted with EtOAc (20 ml x 2). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC [Welch Xtimate C18 (150 mm x 25 mm, 5 μm) A=H ₂ O (10 mM NH ₄ HCO ₃ ) and B=CH ₃ CN; 60-80% B in 8 minutes)] to obtain the product (32.74 mg, 0.079 mmol, 25% yield) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _κ 9.52 (d, 1H), 8.45 (s, 1H), 7.57 (d, 1H), 7.22-7.15 (m, 1H ), 6.95 (s, 1H), 4.33 (q, 2H), 2.12-1.98 (m, 1H), 1.46 (t, 3H), 1.05-0.95 ( m, 2H), 0.82-0.72 (m, 2H). LCMS R _t =1.46 min at 2.0 min chromatography, 10-80AV, MS ESI calc. for C18H16F5N4O2 [M+H] ⁺ 414.9, determined 415.2.

Example 35: Synthesis of 35-6-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]-3

[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A124

TsOH.H ₂ O, TBAB isoamyl nitrite

NBS, VRO

DIEA, (EtO) _2PO

Br

CH ₃ CN, 20°С, 3 h

A71b

A71a

_CuBr2 . CH3CN, 25°С, 12 h

A125

A75

A76

A125: 1-bromo-2-methyl-4-(trifluoromethoxy)benzene.

To a mixture of 2-methyl-4-(trifluoromethoxy)aniline (5 g, 26.16 mmol), isopentyl nitrite (3.68 g, 31.39 mmol) and CuBr ₂ (584.23 mg, 2.62 mmol) and TBAB (18.55 g, 57.55 mmol) to MeCN (100 ml) was slowly added TsOH.H ₂ O (5.97 g, 31.39 mmol). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with H ₂ O (200 ml) and the mixture was extracted with EtOAc (50 mlx2). The combined organic phase was washed with water (50 ml) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 2%) to give the product (3.7 g, 14.51 mmol, 55% yield) as an oil. ^1H NMR (400 MHz, CDCI3) δκ 7.56 (d, 1H), 7.11 (s, 1H), 6.95 (d, 1H), 2.42 (s, 3H).

A72: 1-bromo-2-(bromomethyl)-4-(trifluoromethoxy)benzene.

To a mixture of 1-bromo-2-methyl-4-(trifluoromethoxy)benzene (4.4 g, 17.25 mmol) and NBS (3.68 g, 20.7 mmol) in _CCl4 (40 ml) was added BPO ( 417.92 mg, 1.73 mmol). The mixture was stirred at 80°C for 16 hours. Water (50 ml) was added and the aqueous layer was extracted with DCM (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a mixture of A71a and A71b (5.6 g, 16.77 mmol) as an oil.

To a mixture of A71a and A71b (5.6 g, 16.77 mmol) and diethyl phosphite (3471.39 mg, 25.15 mmol) in MeCN (50 ml)

- 49 046421 DIEA (8.3 ml, 50.31 mmol) was added. The mixture was stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to remove MeCN. Water (150 ml) was added and the aqueous layer was extracted with EtOAc (50 ml x 2). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel (PE) chromatography to give the product (2.5 g, 7.49 mmol, 45% yield) as an oil. ^1H NMR (400 MHz, CDCl ₃ ) _δH 7.62 (d, 1H), 7.34 (d, 1H), 7.08 (d, 1H), 4.57 (s, 2H).

A73: 1-bromo-2-(cyclopropoxymethyl)-4-(trifluoromethoxy)benzene.

To a solution of 1-bromo-2-(bromomethyl)-4-(trifluoromethoxy)benzene (2.5 g, 7.49 mmol) in DMF (25 ml) was added cyclopropanol (1.42 ml, 22.46 mmol) and K ₂ CO ₃ (3103.94 mg, 22.46 mmol). The mixture was stirred at 40°C for 16 hours. Water (50 ml) was added and the aqueous layer was extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel (PE) chromatography to give the product (1.2 g, 3.86 mmol, 52% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δ.. 7.56 (d, 1H), 7.35 (s, 1H), 7.03 (d, 1H), 4.60 (s, 2H), 3, 48-3.43 (m, 1H), 0.72-0.69 (m, 2H), 0.57-0.54 (m, 2H).

A74: 2-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

To a mixture of 1-bromo-2-(cyclopropoxymethyl)-4-(trifluoromethoxy)benzene (1.2 g, 3.86 mmol) and 4,4,5,5tetramethyl-2-(4,4,5,5-te1ramethyl) -1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.18 g, 4.63 mmol) and KOAc (757.11 mg, 7.71 mmol) and PCy ₃ (216 .34 mg, 0.77 mmol) in 1,4-dioxane (5 ml) was added Pd ₂ dba ₃ (353.33 mg, 0.39 mmol). The mixture was stirred at 100°C for 10 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel (PE) chromatography to give the product (900 mg, 2.51 mmol, 65% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δн 7.83 (d, 1H), 7.31 (s, 1H), 7.11 (d, 1H), 4.81 (s, 2H), 3.42- 3.39 (m, 1H), 1.36 (s, 12H), 0.68-0.67 (m, 2H), 0.52-0.49 (m, 2H).

A75: 2-chloro-5-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazine.

Mixture of 2-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 2.51 mmol) and 2-bromo-5 -chloro-pyrazine (583.27 mg, 3.02 mmol) and Pd(dppf)Cl ₂ (183.86 mg, 0.25 mmol) and Cs ₂ CO ₃ (1.64 g, 5.03 mmol) in 1,4-dioxane (10 ml) and water (2 ml), stirred at 50°C under N2 atmosphere for 16 hours. After cooling to 25°C, the reaction mixture was poured into water (50 ml). The mixture was extracted with EtOAc (20 mlx2). The combined organic phase was washed with water (50 ml) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 1% to 3% to 5%) to give the product (550 mg, 1.60 mmol, 63% yield) as an oil. 1H NMR (400 MHz, CDC13) δн 8.68 (s, 1H), 8.59 (s, 1H), 7.54 (d, 1H), 7.48 (s, 1H), 7.22 (d , 1H), 4.64 (s, 2H), 3.34-3.31 (m, 1H), 0.68-0.67 (m, 2H), 0.52-0.49 (m, 2H ).

A76: [5-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine.

To a solution of 2-chloro-5-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazine (550 mg, 1.6 mmol) in MeCN (5 ml) was added N2H4H2O (797.75 mg, 15.95 mmol ). at 25°C. The mixture was stirred at 100°C for 16 hours. After cooling to 25°C, the reaction mixture was poured into water (20 ml). The mixture was extracted with EtOAc (10 mlx2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product (500 mg, 1.47 mmol) as a solid. LCMS Rt=0.77 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for Ci ₅ Hi ₆ F ₃ N ₄ O ₂ [M+H]+ 341.1, determined 340.9.

A77: 2-bromo-N'-[5-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (51.25 mg, 0.29 mmol) and one drop of DMF in DCM (1 ml) was added (COCl) ₂ (44.63 mg, 0.35 mmol) at 25°C. The mixture was stirred at 25°C for 15 minutes. [5-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]hydrazine (100 mg, 0.29 mmol) in DCM (2 ml) was added to the above solution at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was poured into water (10 ml) and the aqueous layer was extracted with EtOAc (10 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (EtOAc in PE=15% to 30%) to give the product (80 mg, 0.16 mmol, 55% yield) as an oil. 1H NMR (400 MHz, _DMSOD6 ) _δH 11.41 (brs, 1H), 9.53 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 7.64 (d, 1H), 7.46 (s, 1H), 7.41 (d, 1H), 4.64 (s, 2H), 3.35-3.28 (m, 1H), 0.48- 0.45 (m, 2H), 0.43-0.41 (m, 2H).

A78: 3-[bromo(difluoro)methyl]-6-[2-methyl-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-[1,2,4]triazolo[4,3a] pyrazine

To a mixture of 2-bromo-N'-[5-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]pyrazin-2-yl]-2,2difluoroacetohydrazide (80 mg, 0.16 mmol) in DCM (2 ml ) 2-methoxypyridine (0.04 ml,

- 50 046421

0.35 mmol) and Tf ₂ O (0.03 ml, 0.19 mmol). The mixture was stirred at 25°C for 2 hours. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (10 mlx2). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 15%) to give the product (30 mg, 0.06 mmol, 39% yield) as an oil. ^1H NMR (400 MHz, CDCl ₃ ) δκ 9.59 (s, 1H), 8.69 (s, 1H), 7.73 (d, 1H), 7.45 (s, 1H), 7.37 (d, 1H), 4.62 (s, 2H), 3.38-3.35 (m, 1H), 0.63-0.62 (m, 2H), 0.54-0.53 (m , 2H).

Compound 35: 6-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]-3-[difluoro(methoxy)methyl][1,2,4]triazolo[4,3-a]pyrazine.

To a suspension of 3-[bromo(difluoro)methyl]-6-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine (30 mg, 0. 06 mmol) in methanol (1 ml) was added AgBF4 (24.29 mg, 0.13 mmol) at 25°C under N2 atmosphere. The mixture was protected from light and stirred at 60°C for 2 hours. The mixture was added to brine (10 ml) and filtered. The filtrate was extracted with EtOAc (10 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (YMC Triart C18 150x25 mmx5 µm, A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 52-82% in 9.5 minutes) to obtain the product (4.7 mg, 0 .01 mmol, yield 17%) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δκ 9.52 (s, 1H), 8.63 (s, 1H), 7.69 (d, 1H), 7.45 (s, 1H), 7.35 ( d, 1H), 4.60 (s, 2H), 3.95 (s, 3H), 3.38-3.36 (m, 1H), 0.63-0.60 (m, 2H), 0 .54-0.52 (m, 2H). LCMS Rt=1.43 min with chromatography 2 min, 10-80AV, MS ESI calc. for Ci ₈ Hi ₆ F ₅ N ₄ O ₃ [M+H]+ 431.1, determined 431.2.

Example 36: Synthesis of compound 36-6-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]-3[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

3-[bromo(difluoro)methyl]-6-[2-(cyclopropoxymethyl)-4-(trifluoromethoxy)phenyl]To suspension

[1,2,4]triazolo[4,3-a]pyrazine (35 mg, 0.07 mmol) in ethanol (1 ml) was added AgBF ₄ (28.34 mg, 0.15 mmol) at 25°C in atmosphere N2. The mixture was protected from light and stirred at 60°C for 2 hours. The solution was added to saturated aqueous NaCl (10 ml) and filtered. The filtrate was extracted with EtOAc (10 ml). The organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (YMC Triart C18 150x25 mmx5 µm, A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 60-90% in 9.5 minutes) to obtain the product (15.76 mg, 0 .04 mmol, yield 48%) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δΗ 9.52 (s, 1H), 8.60 (s, 1H), 7.68 (d, 1H), 7.45 (s, 1H), 7.35 ( d, 1H), 4.61 (s, 2H), 4.34 (q, 2H), 3.393.34 (m, 1H), 1.46 (t, 3H), 0.62-0.60 (m , 2H), 0.54-0.52 (m, 2H). LCMS Rt=1.47 min with chromatography 2 min, 10-80AV, MS ESI calc. for C ₁₉ H ₁₈ F ₅ N ₄ O ₃ [M+H] ⁺ 445.1, determined 445.3.

Example 37: Synthesis of compound 37-6-[4-(3,3-difluorocyclohexane)phenyl]-3-[ethoxy(difluoro)methyl][1,2,4]triazolo[4,3-a]pyrazine.

VgHon 'Cl o

Ν ₂ Η ₄ .Η ₂ Ο

Pd(dppf)CI ₂ , Cs ₂ CO ₃ dioxane/H ₂ O, 80°C,

1,4-dioxane, Pd(dppf)CI ₂ KOAc, dioxane, 100°C,

F F

DIAD, Ph ₃ P, toluene, 110°C, 16 h

ACN, 80°С, 16 h

A83

A84

(COCI) ₂ , DMF toluene, 28°С, 1 h toluene, 28°С, 2 h

A79: bromo-4-(2,2-difluorocyclopropyl)benzene.

To a solution of Ph ₃ P (2.67 g, 10.18 mmol) in toluene (15 ml) was added DIAD (2.1 g, 10.18 mmol) under N2. The mixture was then stirred at 0°C for 10 minutes. Then a solution of 3.3 was added to the mixture

- 51 046421 difluorocyclobutanol (1 g, 9.25 mmol) in toluene (3 ml). The mixture was stirred at 25°C for 10 minutes. Then, 4-bromophenol (1.6 g, 9.25 mmol) was added to the mixture, and the resulting mixture was stirred at 110°C for 16 hours. The mixture was extracted with EtOAc (20 mlx3). The combined organic layer was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel (PE) chromatography to give the product (380 mg, 1.44 mmol, 15% yield) as an oil. ^1H NMR (400 MHz, CDCl ₃ ) _δH 7.46-7.40 (m, 2H), 6.76-6.68 (m, 2H), 4.67-4.57 (m, 1H) , 3.15-3.03 (m, 2H), 2.87-2.70 (m, 2H).

A80: 2-[4-(3,3-difluorocyclobutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

To a mixture of 1-bromo-4-(3,3-difluorocyclobutoxy)benzene (380 mg, 1.44 mmol) and 4,4,5,5-tetramethyl-2(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (440 mg, 1.73 mmol) and KOAc (284 mg, 2.89 mmol) in 1,4-dioxane (5 ml) added Pd (dppf)Cl ₂ (106 mg, 0.14 mmol). The mixture was stirred at 100°C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated to leave a residue. The residue was purified by flash chromatography on silica gel (EtOAc in PE 0 ~10%) to give the product (400 mg, 1.29 mmol, 89% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) _δH 7.80-7.75 (m, 2H), 6.82-6.73 (m, 2H), 4.75-4.62 (m, 1H), 3.15-3.05 (m, 2H), 2.83-2.70 (m, 2H), 1.34 (s, 12H).

A81: 2-chloro-5-[4-(3,3-difluorocyclobutoxy)phenyl]pyrazine.

To a mixture of 2-[4-(3,3-difluorocyclobutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.29 mmol) and 2-bromo-5- chloropyrazine (299 mg, 1.55 mmol) and Cs ₂ CO ₃ (840 mg, 2.58 mmol) in 1,4-dioxane (5 ml) and water (0.5 ml) Pd(dppf)Cl was added ₂ (94 mg, 0.13 mmol). The mixture was stirred at 80°C for 4 hours. The mixture was filtered, and the mixture was concentrated under reduced pressure. Water (10 ml) was added and the aqueous layer was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~20%) to give the product (180 mg, 0.61 mmol, 47% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δн 8.74 (s, 1H), 8.60 (s, 1H), 7.96 (dd, 2H), 6.94 (dd, 2H), 4.78- 4.65 (m, 1H), 3.20-3.08 (m, 2H), 2.882.75 (m, 2H).

A82: [5-[4-(2,2-difluorocyclopropyl)phenyl]pyrazin-2-yl]hydrazine.

To a solution of 2-chloro-5-[4-(3,3-difluorocyclobutoxy) phenyl]pyrazine (180 mg, 0.61 mmol) in MeCN (3 ml) was added N2H4 H ₂ O (303 mg, 6.07 mmol) . The mixture was stirred at 80°C for 16 hours. After cooling to RT, water (10 ml) was added and the mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (MeOH in DCM 0~20%) to give the product (140 mg, 0.48 mmol, 79% yield) as a solid. LCMS R _t =0.78 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₄ H ₁₅ F ₂ N ₄ O [M+H]+ 293.0, determined 293.0.

A84: 2-bromo-H'-[5-[4-(3,3-difluorocyclobutoxy)phenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (0.13 g, 0.72 mmol) in toluene (2 ml) was added DMF (2.62 mg, 0.04 mmol) and (COCl) ₂ (0. 07 ml, 0.86 mmol). The resulting mixture was stirred at 28°C for 1 hour. A solution of [5-[4-(3,3-difluorocyclobutoxy)phenyl]pyrazin-2yl]hydrazine (140 mg, 0.48 mmol) in toluene (3 ml) was added to the above mixture. The mixture was stirred at 28°C for 2 hours.

TsOH (25 mg, 0.14 mmol) was added to the mixture. The mixture was stirred at 130°C for 16 hours. After cooling to RT, water (20 ml) was added and the aqueous layer was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~20%) to give the product (30 mg, 0.07 mmol, 15% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) _δH 9.55 (d, 1H), 8.37 (s, 1H), 8.00-7.96 (m, 2H), 7.02-6.95 ( m, 2H), 4.80-4.65 (m, 1H), 3.23-3.05 (m, 2H), 2.90-2.75 (m, 2H).

Compound 37: 6-[4-(3,3-difluorocyclobutoxy)phenyl]-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a solution of 3-[bromo(difluoro)methyl]-6-[4-(3,3-difluorocyclobutoxy)phenyl][1,2,4]triazolo[4,3a]pyrazine (30 mg, 0.07 mmol) in ethanol (3 ml) was added AgBF ₄ (27 mg, 0.14 mmol). The mixture was stirred at 60°C for 3 hours. After cooling to RT, brine (10 mL) and EtOAc (10 mL) were added. The mixture was filtered and the filter cake was washed with EtOAc (10 mlx3). The filtrate was separated and the organic layer was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC [YMC Triart C18 150 * 25 mm * 5 rm. A=water (10 mM NH4HCO3) and B=CH ₃ CN; 62-92% B in 9.5 minutes)] to give the product (5.04 mg, 0.013 mmol, 19% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δн 9.50 (s, 1H), 8.42 (s, 1H), 7.90 (d, 2H), 6.96 (d, 2H), 4.80-4, 67 (m, 1H), 3.36 (q, 2H), 3.21-3.10 (m, 2H), 2.90-2.72 (m, 2H), 1.50 (t, 3H) . LCMS Rt=1.39 min at 2.0 min chromatography, 10-80AV, MS

- 52 046421

IER calc. for C ₁₈ H ₁₇ F ₄ N ₄ O ₂ [M+H]+ 397.1, determined 397.2.

Example 38: Synthesis of 38-6-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-3[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine .

A8 5: 1-bromo-4-(3,3-difluorocyclobutoxy)-2-methylbenzene.

To a solution of Ph ₃ P (3.64 g, 13.88 mmol) in toluene (50 ml) DIAD (2.81 g, 13.88 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes. A solution of 3,3difluorocyclobutanol (1 g, 9.25 mmol) in toluene (5 ml) was then added to the mixture. The mixture was stirred at 25°C for 30 minutes. Then, 4-bromo-3-methylphenol (2.07 g, 11.1 mmol) was added to the mixture, and the resulting mixture was stirred at 110° C. for 16 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~30%) to give the product (770 mg, 2.78 mmol, 30% yield) as an oil. ^1H NMR (400 MHz, CDCI3) δκ 7.41 (d, 1H), 6.71 (d, 1H), 6.52 (dd, 1H), 4.65-4.55 (m, 1H), 3.16-3.00 (m, 2H), 2.81-2.67 (m, 2H), 2.37 (s, 3H).

A86: 2-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

To a solution of 1-bromo-4-(3,3-difluorocyclobutoxy)-2-methylbenzene (770 mg, 2.78 mmol) in 1,4-dioxane (10 ml) was added 4,4,5,5-tetramethyl-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (847 mg, 3.33 mmol) and KOAc (545 mg, 5.56 mmol). Pd(dppf)Cl ₂ (203 mg, 0.28 mmol) was then added to the above mixture under N ₂ atmosphere. The mixture was stirred at 100°C for 16 hours. The mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~4%) to give the product (900 mg, 2.78 mmol, 100% yield) as an oil. 1H NMR (400 MHz, CDC13) _δΗ 7.72 (d, 1H), 6.67-6.57 (m, 2H), 4.72-4.62 (m, 1H), 3.153.02 (m , 2H), 2.82-2.68 (m, 2H), 2.52 (s, 3H), 1.34 (s, 12H).

A87: 2-chloro-5-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]pyrazine.

To a solution of 2-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 2.78 mmol) in 1.4 -dioxane (10 ml) and water (1 ml) were added 2-bromo-5-chloropyrazine (591 mg, 3.05 mmol) and Cs ₂ CO ₃ (1.8 g, 5.55 mmol). Pd(dppf)Cl ₂ (203 mg, 0.28 mmol) was then added to the mixture, and the resulting mixture was stirred at 90° C. for 16 hours. Water (20 ml) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the aqueous layer was extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~10%) to give the product (500 mg, 1.61 mmol, 58% yield) as a solid. 1H NMR (400 MHz, CDC13) δΗ 8.65 (s, 1H), 8.47 (s, 1H), 7.38 (d, 1H), 6.80-6.72 (m, 2H), 4.76 -4.65 (m, 1H), 3.20-3.06 (m, 2H), 2.87-2.75 (m, 2H), 2.40 (s, 3H).

A88: [5-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]pyrazin-2-yl]hydrazine.

To a solution of 2-chloro-5-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]pyrazine (500 mg, 1.61 mmol) in acetonitrile (5 ml) was added hydrazine hydrate (806 mg, 16.09 mmol) . The mixture was stirred at 100°C for 16 hours. After cooling to RT, water (20 mL) was added and the aqueous layer was extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0 ~50%) to give the product (320 mg, 1.04 mmol, 65% yield) as a solid. 1H NMR (400 MHz, DMSOM ₆ ) δ _Η 8.16 (d, 1H), 8.05 (d, 1H), 7.97 (s, 1H), 7.28 (d, 1H), 6.83 -6.73 (m, 2H), 4.83-4.73 (m, 1H), 4.30 (brs, 2H), 3.27-3.15 (m, 2H), 2.772.60 (m , 2H), 2.30 (s, 3H).

A89: 2-bromo-N-[5-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide.

- 53 046421

To a solution of 2-bromo-2,2-difluoroacetic acid (219 mg, 1.25 mmol) in THF (2 ml) was added (COCl) ₂ (0.13 ml, 1.5 mmol) and 1 drop of DMF. The mixture was stirred at 30°C for 0.5 hour. A solution of [5-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]pyrazin-2-yl]hydrazine (320 mg, 1.04 mmol) in THF (2 mL) was then added to the mixture. The mixture was stirred at 30°C for 1 hour. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (483 mg, 1.04 mmol) as an oil, which was used in the next step.

A90: 3-[bromo(difluoro)methyl]-6-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a solution of 2-bromo-N-[5-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]pyrazin-2-yl]-2,2-difluoroacetohydrazide (483 mg, 1.04 mmol) in toluene ( 5 ml) TsOH (54 mg, 0.31 mmol) was added. The mixture was stirred at 145°C for 16 hours. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (20 ml x 3). The combined organic layer was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0~30%) to give the product (280 mg, 0.63 mmol, 60% yield) as a solid. ^1H NMR (400 MHz, CDCI3) δ, 9.56 (s, 1H), 8.17 (s, 1H), 7.50-7.37 (m, 1H), 6.85-6.75 (m, 2H), 4.80-4.68 (m, 1H), 3.23-3.05 (m, 2H), 2.90-2.72 (m, 2H), 2.43 (s , 3H).

Compound 38: 6-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

To a solution of 3-[bromo(difluoro)methyl]-6-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.31 mmol) in ethanol (2 ml), AgBF4 (122 mg, 0.63 mmol) and Na ₂ CO ₃ (67 mg, 0.63 mmol) were added. The mixture was stirred at 70°C for 1 hour. Water (10 ml) was added and the aqueous layer was extracted with EtOAc (10 ml x 3). The combined organic layer was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0~30%) to give the product (54.29 mg, 0.13 mmol, 42% yield) as a solid. 1H NMR (400 MHz, CDCI3) δ, 9.49 (s, 1H), 8.19 (s, 1H), 7.40 (d, 1H), 6.82-6.72 (m, 2H) , 4.78-4.67 (m, 1H), 4.32 (q, 2H), 3.22-3.07 (m, 2H), 2.88-2.74 (m, 2H), 2 .41 (s, 3H), 1.46 (t, 3H). LCMS Rt=1.20 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₁₉ H ₁₉ F ₄ N ₄ O ₂ [M+H]+ 411.1, determined 411.1.

Example 39: Synthesis of 39-6-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-3[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine .

A90 39

To a solution of 3-[bromo(difluoro)methyl]-6-[4-(3,3-difluorocyclobutoxy)-2-methylphenyl]-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.31 mmol) in methanol (2 ml), AgBF ₄ (122 mg, 0.63 mmol) and Na ₂ CO ₃ (67 mg, 0.63 mmol) were added. The mixture was stirred at 70°C for 1 hour. Water (10 ml) was added and the aqueous layer was extracted with EtOAc (10 ml x 3). The combined organic layer was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE 0~30%) to give the product (73.04 mg, 0.18 mmol, 57% yield) as a solid. 1H NMR (400 MHz, CDCI3) δ, 9.50 (s, 1H), 8.18 (s, 1H), 7.38 (d, 1H), 6.82-6.72 (m, 2H) , 4.78-4.67 (m, 1H), 3.94 (s, 3H), 3.22-3.07 (m, 2H), 2.87-2.72 (m, 2H), 2 .40 (s, 3H). LCMS Rt=1.17 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₁₈ H ₁₇ F ₄ N ₄ O ₂ [M+H] ⁺ 397.1, determined 397.1.

- 54 046421

Example 40: Synthesis of 40-3-[difluoro(methoxy)methyl]-6-[5-fluoro-2-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a] pyrazine

F HO tetrabutylammonium tribromide

DCM/MeOH, 25°C, 3 h

F NO

Br

A91

BnBr, K ₂ CO ₃

CH ₃ CN, 30°C, 1 4

F VPO

Br

A92

Pd ₂ dba ₃ , XPhos

COAc, dioxane, 100°C, 12 h

F VPO

A93

Pd(dppf)CI ₂ , CS2CO3 dioxane/H ₂ O, 50°C, 3 h

Cl

F

BnO

^N Cl

A94

_H2N - _NH2

90°C,24 h

F

VPO xv

Lk _N -NH ₂ H A95 ° _F (COCI) ₂ DMF ° _F %F -----'--*C|-kF

Br 30°C, 1 h Br

THF, 30°C, 10 h

F VPO

A96

Br

TsOH thick, 130°C, 16 h ^FF Br AgBF ₄ Na ₂ CO ₃ ^BnO 'U MeOH, 70°C, 5 h

F ^F ° HBr/HOAc

Jn 30°C, 2 h

A97

A98

F but

F AgOTf, CsF,

H O selective F

Ύ·Ρ _Ν 2-F Py. TMSCF ₃

N _N thick, 30°C, 16 h

A99

F

A91: 4-bromo-2-fluoro-5-methylphenol.

To a solution of 2-fluoro-5-methylphenol (20.0 g, 158.57 mmol) in DCM (1200 ml) and methanol (800 ml), tetrabutylammonium tribromide (76.46 g, 158.57 mmol) was added dropwise with stirring. . The mixture was stirred at 25°C for 3 hours. Water (150 ml) was added and the mixture was concentrated under reduced pressure. The aqueous layer was extracted with DCM (300 mlx3). The combined organic layers were washed with brine (600 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0~15%) to give the product (30.0 g, 146.33 mmol, 92% yield) as an oil. ^1H NMR (400 Hz, CDCI3) δκ 7.22 (d, 1H), 6.96 (d, 1H), 2.29 (s, 3H).

A92: 1-benzyloxy-4-bromo-2-fluoro-5-methylbenzene.

To a solution of 4-bromo-2-fluoro-5-methylphenol (29.0 g, 141.45 mmol) in MeCN (300 ml) was added BnBr (24.19 g, 141.45 mmol) and K2CO3 (29.32 g , 212.17 mmol). The mixture was stirred at 30°C for 1 hour. The mixture was filtered and the filtrate was concentrated to give the product (35.1 g, 118.92 mmol) as a solid. 1H NMR (400 MHz, CDCI3) δΗ 7.45-7.25 (m, 6H), 6.87 (d, 1H), 5.09 (s, 2H), 2.30 (s, 3H).

A93: 2-(4-benzyloxy-5-fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

To a mixture of 1-benzyloxy-4-bromo-2-fluoro-5-methylbenzene (35.0 g, 118.58 mmol) 4,4,5,5-tetramethyl-2(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (33.12 g, 130.44 mmol), KOAc (23.28 g, 237.17 mmol), XPhos (5.65 g, 11.86 mmol) in 1,4 dioxane (300 ml) was added Pd ₂ (dba) ₃ (5.43 g, 5.93 mmol). The mixture was stirred at 100°C for 12 hours under N2 atmosphere. After cooling to 30°C, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. Water (300 ml) was added and the aqueous layer was extracted with EtOAc (300 mlx3). The combined organic layer was washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0~10%) to give the product (30.0 g, 61.37 mmol, 52% yield) as a solid. 1H NMR (400 MHz, CDC13) _δΗ 7.50-7.25 (m, 6H), 6.83-6.78 (m, 1H), 5.15 (s, 2H), 2.47 (s , 3H), 1.33 (s, 12H).

A94: 2-(4-benzyloxy-5-fluoro-2-methylphenyl)-5-chloropyrazine.

To a mixture of 2-(4-benzyloxy-5-fluoro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.0 g, 51.14 mmol, 70% purity) and 2-bromo-5-chloropyrazine (9.89 g, 51.14 mmol) in 1,4-dioxane (250 ml) and water (50 ml) was added Cs ₂ CO ₃ (33.32 g, 102.28 mmol ). Pd(dppf)Cl ₂ (3.74 g, 5.11 mmol) was then added to the mixture. The resulting mixture was stirred at 50°C for 3 hours. The mixture was mixed with another batch (prepared from 5.0 g of compound A93). The mixture was filtered and the filtrate was concentrated. Water (300 ml) was added and the aqueous layer was extracted with EtOAc (300 mlx3). The combined organic layers were washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether 0 ~10%) to give the product (15.0 g, 45.62 mmol, 74% yield) as a solid. 1H

- 55 046421

NMR (400 MHz, CDC13) δ _δ 8.66 (s, 1H), 8.46 (s, 1H), 7.52-7.30 (m, 5H), 7.24 (d, 1H), 6 .95 (d, 1H), 5.20 (s, 2H), 2.36 (s, 3H).

A95: [5-(4-benzyloxy-5-fluoro-2-methylphenyl)pyrazin-2-yl]hydrazine.

To a solution of 2-(4-benzyloxy-5-fluoro-2-methylphenyl)-5-chloropyrazine (15.0 g, 45.62 mmol) in MeCN (100 ml) was added hydrazine hydrate (22.8 g, 456.25 mmol ). The mixture was stirred at 90°C for 24 hours. Water (500 ml) was added and the aqueous layer was extracted with EtOAc (300 mlx3). The combined organic layers were washed with brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether 0~60%) to give the product (9.8 g, 30.21 mmol, 66% yield). 1H NMR (400 MHz, DMSO-b6) δн 8.17 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.50-7.30 (m, 5H) , 7.24 (d, 1H), 7.18 (d, 1H), 5.21 (s, 2H), 4.30 (s, 2H), 1.99 (s, 3H). LCMS Rt=1.04 min with chromatography 2.0 min, 1080АВ, MS ESI calc. for C ₁₈ H ₁₈ FN ₄ O [M+H]+ 325.1, determined 325.2.

A96: N-[5-(4-benzyloxy-5-fluoro-2-methylphenyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (4.04 g, 23.12 mmol) in THF (40 ml) was added (COCl) ₂ (2.4 ml, 27.75 mmol) and 5 drops of DMF. The mixture was stirred at 30°C for 1 hour. A solution of [5-(4-benzyloxy-5-fluoro-2-methylphenyl)pyrazin-2-yl]hydrazine (5.0 g, 15.42 mmol) in THF (10 ml) was added dropwise to the mixture. The mixture was stirred at 30°C for 10 hours. Water (50 ml) was added and the aqueous layer was extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether 0~20%) to give the product (2.9 g, 6.03 mmol, 39% yield) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δн 8.27 (s, 1H), 8.22 (s, 1H), 7.50-7.32 (m, 5H), 7.24 (d, 1H), 6, 92 (d, 1H), 5.18 (s, 2H), 2.31 (s, 3H). LCMS Rt=1.00 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₂₀ H ₁₇ BrF ₃ N ₄ O ₂ [M+H]+ 481.0, determined 480.8.

A97: 6-(4-benzyloxy-5-fluoro-2-methylphenyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

To a solution of N-[5-(4-benzyloxy-5-fluoro-2-methylphenyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetohydrazide (2.9 g, 6.03 mmol) in toluene ( 50 ml) TsOH (311 mg, 1.81 mmol) was added. The mixture was stirred at 130°C for 16 hours. Water (50 ml) was added and the aqueous layer was extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether 0~15%) to give the product (2.2 g, 4.75 mmol, 79% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) _δH 9.56 (d, 1H), 8.17 (s, 1H), 7.50-7.25 (m, 6H), 6.99 (d, 2H) , 5.23 (s, 2H), 2.40 (s, 3H).

A98: 6-(4-benzyloxy-5-fluoro-2-methylphenyl)-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a solution of 6-(4-benzyloxy-5-fluoro-2-methylphenyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3a]pyrazine (2.2 g, 4. 75 mmol) in methanol (30 ml) AgBF ₄ (2.76 g, 14.25 mmol) and Na ₂ CO ₃ (1.51 g, 14.25 mmol) were added. The mixture was stirred at 70°C for 5 hours. Brine (100 ml) was added and the suspension was filtered. The filtrate was extracted with EtOAc (50 mlx3). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether 0~30%) to give the product (1.3 g, 3.14 mmol, 66% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δн 9.49 (s, 1H), 8.18 (s, 1H), 7.50-7.35 (m, 5H), 7.24 (s, 1H), 6.98 (d, 1H), 5.22 (s, 2H), 3.94 (s, 3H), 2.36 (s, 3H).

A99: 4-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]-2-fluoro-5-methylphenol.

6-(4-Benzyloxy-5-fluoro-2-methylphenyl)-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3a]pyrazine solution (1.3 g, 3.14 mmol) in HBr/HOAc (15 ml, 33%) was stirred at 30°C for 2 hours. Water (50 ml) was added and the aqueous layer was extracted with EtOAc (50 mlx3). The combined organic layers were washed with saturated NaHCO ₃ solution (30 mlx3) and brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether 0~90%) to give the product (710 mg, 2.19 mmol, 70% yield) as a solid. 1H NMR (400 MHz, _DMSOC6 ) _δH 10.11 (s, 1H), 9.62 (d, 1H), 8.49 (s, 1H), 7.30 (d, 1H), 6.91 (d, 1H), 3.87 (s, 3H), 2.26 (s, 3H).

Compound 40: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

AgOTf (2.38 g, 9.25 mmol) was dried at 200°C (heat gun) in vacuum for 20 minutes. 4-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]-2fluoro-5-methylphenol (600 mg, 1 .85 mmol), selective F (3.28 g, 9.25 mmol), CsF (1.69 g, 11.1 mmol), followed by toluene (10 ml), 2-fluoropyridine (0.9 g, 9 .25 mmol) and TMSCF3 (1.32 g, 9.25 mmol). The mixture was stirred at 30°C for 16 hours. The mixture was filtered through celite and filter cake

- 56 046421 washed with DXM (20 mlx4). The filtrate was concentrated and purified by flash chromatography (DCM in MeOH 0~5%) and preparative HPLC ([Phenomenex Gemini-NX 80x30 mmx3 mm, A=H2O (10 mM NH ₄ HCO ₃ ) and B=CH ₃ CN; 41-71 % in 9.5 minutes] to obtain the product (7.27 mg, 0.0185 mmol, 10% yield) as an oil 1H NMR (400 MHz, CDCl ₃ ) δ 9.52 (s, 1H), 8. 24 (s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 3.95 (s, 3H), 2.40 (s, 3H) LCMS Rt=1.95 min. during chromatography 3.0 min, 10-80CD, MS ESI calculated for C ₁₅ HnF ₆ N ₄ O ₂ [M+H]+393.1 determined 393.1.

Example 41: Synthesis of compound 41-3-(1-ethoxy-1-methylethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

^Cl V ^N N ₂ H ₄ .H ₂ O °' ^ΗΟ Αθ^ ^Cl VN h \ / ^N< ^CI EtOH, 90°C, 12 h ^NH 2 PyBOP, DIEA, DCM ^Ν ^ ^χΧ Ν' ^Ν γ ^Χ 'Ο '^' ^H 25°C,2h ^H O

AY0 A101

dioxane/H ₂ O ^A102 90°C, 3 hours ⁴¹

A100: (5-chloropyrazin-2-yl)hydrazine.

A mixture of N2H4-H2O (50.34 g, 1 mol) and 2,5-dichloropyrazine (30 g, 201.37 mmol) in ethanol (150 ml) was stirred at 90°C for 12 hours. After cooling to RT, water (500 ml) was added and the aqueous layer was stirred for 1 hour. The aqueous layer was filtered and the filter cake was dried to give the product (22 g, 152.19 mmol, 75% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δκ 8.05-8.03 (m, 2H), 6.00 (brs, 1H), 3.84 (brs, 2H).

A101: Na-(5-chloropyrazin-2-yl)-2-ethoxy-2-methylpropanhydrazide.

To a mixture of 2-ethoxy-2-methylpropanoic acid (2 g, 15.13 mmol), PyBOP (11.81 g, 22.7 mmol) and DIPEA (5.27 ml, 30.27 mmol) in DCM (25 ml ) (5-chloropyrazin-2-yl)hydrazine (2.2 g, 15.22 mmol) was added. The mixture was stirred at 25°C for 2 hours. Water (100 ml) was added and the mixture was extracted with EtOAc (100 mlx2). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 15% to 30%) to give the product (3.9 g, 15.08 mmol, 99% yield) as an oil. 1H NMR (400 MHz, CDC13) δκ 8.70 (d, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.36 (s, 1H), 3.55 (q , 2H), 1.45 (s, 6H), 1.25 (t, 3H).

A102: 6-chloro-3-(1-ethoxy-1-methylethyl)-[1,2,4]triazolo[4,3-a]pyrazine.

To a solution of N-(5-chloropyrazin-2-yl)-2-ethoxy-2-methylpropanehydrazide (3.9 g, 15.08 mmol) in DCM (40 ml) was added 2-methoxypyridine (3.17 ml, 30. 15 mmol) and then Tf ₂ O (3.06 ml, 18.09 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. Water (100 ml) was added and the mixture was extracted with EtOAc (100 mlx2). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 15% to 30%) to give product (1.1 g). The product (1.1 g) was further purified using preparative HPLC (Xtimate C18 (150 mm x 40 mm, 5 mm) A=H ₂ O (0.1% TFA) and B=CH ₃ CN; 26% B for 8 minutes) with receiving the product. (350 mg, 1.45 mmol, 9% yield) as a solid. LCMS R _t =2.17 min at 4.0 min chromatography, 0-60AV, MS ESI calc. for C ₁₀ H ₁₄ ClN ₄ O [M+H] ⁺ 241.1, determined 241.1.

Compound 41: 3-(1-ethoxy-1-methylethyl)-6-[2-methyl-4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3a]pyrazine.

Mixture of 6-chloro-3-(1-ethoxy-1-methylethyl)-[1,2,4]triazolo[4,3-a]pyrazine (350 mg, 1.45 mmol), 4,4,5,5tetramethyl -2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (439.3 mg, 1.45 mmol), Cs ₂ CO ₃ (947.53 mg, 2.91 mmol) and then Pd(dppf)Cl ₂ (159.6 mg, 0.22 mmol) in 1,4-dioxane (5 ml) and water (0.5 ml) was stirred at 90° C. under N ₂ atmosphere for 3 hours . After cooling to RT, water (50 ml) and EtOAc (50 ml) were added and the mixture was filtered through celite. After separation of the layers, the aqueous phase was extracted with EtOAc (50 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Kromasil (150 mm x 25 mm, 10 mm) A=H ₂ O (0.05% NH4OH) and B=CH ₃ CN; 50-80% B in 8 minutes) to obtain the product (103 .24 mg, 270.9 mmol, yield 18%) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δκ 9.42 (d, 1H), 8.51 (s, 1H), 7.45 (d, 1H), 7.23-7.16 (m, 2H), 3.28 (q, 2H), 2.45 (s, 3H), 1.84 (s, 6H), 1.17 (t, 3H). LCMS R _t =1.22 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C18H20F3N4O2 [M+H] ⁺ 381.1, determined 381.1.

- 57 046421

Example 42: Synthesis of 42-3-[difluoro(methoxy)methyl]-6-[2-fluoro-5-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a] pyrazine

I tribromide

BUT tetrabutylammonium γ ³ DCM/MeOH, 25°C, 3 h

F but

Br F

A103

BnBr, K ₂ CO ₃ BnO,

DCM, 25°C, 16 h _o

Br

F

A104

Pd ₂ dba ₃ , XPhos

COAc, dioxane, 95°C, 6 h

BnO

R'°

F OY

N^ _C|

BnO

Pd(dppf)CI ₂ Cs ₂ CO ₃

1,4-dioxane/ _H2O , 55°C, 3 h

And vpo

E H ₂ N-NH ₂ ..H ₂ O

N AON, 100°С, 6 h*

FN _C|

A106

T Ύ N

FN,Y. _K1 ,NH ₂

Ν ^ζ

Η

A107° _F (COCI) ₂ DMF° _F

OFF-------'----“GI F

Br THF, 25 C, 1 h Br

THF, 25°C, 2 h

A105

BnO

H V

A108

TsOH

Br

BnO toluene, 125°C, 16 h

MeOH, 60°C, 8 h

A10E

Br AgBF ₄

BnO

A110

HBg/NOAc 25°C, 2 hours

HO

AgOTf, selective F, CsF, 2-fluoropyridine, TMSCF3 glovebox, toluene, 25°C, 16 h

F

A111

A103: 4-bromo-5-fluoro-2-methylphenol.

Tetrabutylammonium tribromide (76.46 g, 158.57 mmol) was added to a solution of 5-fluoro-2-methylphenol (20 g, 158.57 mmol) in DCM (1.2 L) and methanol (800 mL). The mixture was stirred at 25°C for 3 hours. The solution was concentrated to give a residue, and the residue was redissolved in petroleum ether:EtOAc=5:1 (2 L) and filtered through 300-400 mesh silica gel. The silica precipitate was washed with petroleum ether: EtOAc=5:1 (5 L) and concentrated to give the product (23 g, 112.18 mmol, 70% yield) as an oil. ^1H NMR (400 MHz, CDCI3) δκ 7.25 (d, 1H), 6.63 (d, 1H), 5.93 (brs, 1H), 2.18 (s, 3H).

A104: 1-benzyloxy-4-bromo-5-fluoro-2-methylbenzene.

To a mixture of 4-bromo-5-fluoro-2-methylphenol (23 g, 112.18 mmol) and K2CO3 (23.25 g, 168.28 mmol) in MeCN (200 ml) was added bromomethylbenzene (13.32 ml, 112 .18 mmol). The mixture was stirred at 25°C for 16 hours. The mixture was filtered with celite. The filter cake was washed with EtOAc (50 mlx2). The combined organic phase was concentrated to give the crude product (32 g, 108.42 mmol) as an oil. 1H NMR (400 MHz, CDCI3) δκ 7.27-7.11 (m, 6H), 6.54 (d, 1H), 4.89 (s, 2H), 2.07 (s, 3H).

A105: 2-(4-benzyloxy-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

To a mixture of 1-benzyloxy-4-bromo-5-fluoro-2-methylbenzene (32 g, 108.42 mmol) 4,4,5,5-tetramethyl-2(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (30.29 g, 119.26 mmol), KOAc (21.28 g, 216.84 mmol), XPhos (5.17 g, 10.84 mmol) in 1,4-dioxane (200 ml) was added Pd ₂ (dba) ₃ (4.96 g, 5.42 mmol). The mixture was stirred at 95°C for 6 hours under N2 atmosphere. After cooling to RT, the mixture was filtered through celite. The filter cake was washed with EtOAc (50 mlx2). The combined organic phase was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0~2%) to give the product (33 g, 96.43 mmol, 88% yield) as an oil. 1H NMR (400 MHz, CDC13) δ _κ 7.51 (d, 1H), 7.45-7.35 (m, 5H), 6.60 (d, 1H), 5.08 (s, 2H), 2.23 (s, 3H), 1.36 (s, 12H).

A106: 2-(4-benzyloxy-2-fluoro-5-methylphenyl)-5-chloropyrazine.

Mixture of 2-(4-benzyloxy-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 g, 96.43 mmol), 2-bromo-5- chloropyrazine (15.5 g, 80.13 mmol), Cs ₂ CO ₃ (52.21 g, 160.26 mmol) and then Pd(dppf)Cl ₂ (2.93 g, 4.01 mmol) in 1, 4-dioxane (350 ml) and water (35 ml) were stirred at 55°C under N ₂ atmosphere for 3 hours. After cooling to RT, the mixture was concentrated under reduced pressure. Water (500 ml) and EtOAc (500 ml) were added and the mixture was filtered through celite. After phase separation, the aqueous phase was extracted with EtOAc (250 mlx2). The combined organic phase was washed with brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 10% to 20%) to give the product (24 g, 73 mmol, 91% yield) as a solid. LCMS R _t =1.44 min with chromatography 2.0 min, 10-80АВ, MS ESI calc. for C ₁₈ H ₁₅ ClFN ₂ O [M+H]+ 329.1, determined 329.1.

A107: [5-(4-benzyloxy-2-fluoro-5-methylphenyl)pyrazin-2-yl]hydrazine.

- 58 046421

A mixture of 2-(4-benzyloxy-2-fluoro-5-methylphenyl)-5-chloropyrazine (24 g, 73 mmol) and hydrazine hydrate (36.54 g, 730 mmol) in MeCN (300 ml) was stirred at 100 °C in within 6 hours. After cooling to RT, the mixture was poured into water (500 ml). The mixture was extracted with EtOAc (500 mlx2). The combined organic phase was washed with brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 30% to 50%) to give the product (7.2 g, 22.20 mmol, 30% yield) as a solid. 1H NMR (400 MHz, DMSO^ ₆ ) _δH 8.31 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7, 51-7.47 (m, 2H), 7.42 (t, 2H), 7.37-7.32 (m, 1H), 7.01 (d, 1H), 5.19 (s, 2H) , 4.33 (brs, 2H), 2.21 (s, 3H).

A108: X[5-(4-benzyloxy-2-fluoro-5-methylphenyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (6.5 g, 37.16 mmol) in THF (100 ml) was added one drop of DMF, followed by oxalyl dichloride (3.77 ml, 44.59 mmol) at 0 °C. The resulting mixture was stirred at 25°C for 1 hour. [5-(4-Benzyloxy-2-fluoro-5-methylphenyl)pyrazin-2yl]hydrazine (6 g, 18.5 mmol) was added to the mixture, and the mixture was stirred at 25° C. for 2 hours. The mixture was concentrated to give the crude product (8.9 g, 18.49 mmol) as a solid. LCMS R _t =1.35 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₂₀ Hi ₇ BrF ₃ N ₄ O ₂ [M+H]+ 481.0, determined 480.9.

A109: 6-(4-benzyloxy-2-fluoro-5-methylphenyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

A mixture of X[5-(4-benzyloxy-2-fluoro-5-methylphenyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetohydrazide (9.9 g, 20.57 mmol) and TsOH (1, 06 g, 6.17 mmol) in toluene (100 ml) was stirred at 125°C for 16 hours. After cooling to RT, the mixture was concentrated under reduced pressure. Water (200 ml) was added and the aqueous layer was extracted with EtOAc (200 mlx3). The combined organic layer was washed with brine (300 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 40% to 80%) and then recrystallized from MeOH (30 ml) to give the product (6.6 g, 14.25 mmol, 69% yield ) in the form of a solid. LCMS R _t =4.10 min with chromatography 7.0 min, 10-80AV, MS ESI calc. for C ₂₀ H ₁₅ BrF ₃ N ₄ O [M+H]+ 463.0, determined 463.2.

A110: 6-(4-benzyloxy-2-fluoro-5-methylphenyl)-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-α]pyrazine.

Mixture of 6-(4-benzyloxy-2-fluoro-5-methylphenyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.6 g, 5 .61 mmol), Na ₂ CO ₃ (1.19 g, 11.23 mmol) and AgBF ₄ (2.18 g, 11.23 mmol) in methanol (25 ml) were stirred at 60 ° C in the dark for 8 hours. After cooling to RT, brine (100 ml) and EtOAc (100 ml) were added and the mixture was filtered through celite. After phase separation, the organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 50% to 80%) and then by preparative-HPLC (Phenomenex luna C18 (250 mm x 50 mm, 10 mm) A=H ₂ O ( 0.1% TFA) and B=CH ₃ CN; 50-80% B in 8 minutes) to obtain the product (310 mg, 748.1 mmol, 13% yield) as a solid. LCMS R _t =3.85 min with chromatography 7.0 min, 10-80AV, MS ESI calc. for C ₂₁ H ₁₈ F ₃ N ₄ O ₂ [M+H]+ 415.1, determined 415.3.

A111: 4-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]-5-fluoro-2-methylphenol.

A solution of 6-(4-benzyloxy-2-fluoro-5-methylphenyl)-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3a]pyrazine (310 mg 0.75 mmol) in HBr/AcOH (5 ml, 33% in HOAc) was stirred at 25°C for 2 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (30 mlx2). The combined organic phase was washed with saturated aqueous NaHCO ₃ (30 mlx2) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 50% to 100%) to give the product (130 mg, 0.4 mmol, 53% yield) as a solid. 1H NMR (400 MHz, DMSOO δn 10.33 (s, 1H), 9.66 (s, 1H), 8.58 (s, 1H), 7.84 (d, 1H), 6.74 (d, 1H), 3.88 (s, 3H), _2.17 (s, 3H). LCMS R _t =2.35 min with chromatography 7.0 min, 10-80AB, MS ESI calc _{. 3} N ₄ O ₂ [M+H]+ 325.1, determined 325.1.

Compound 42: 3-[difluoro(methoxy)methyl]-6-[2-fluoro-5-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

AgOTf (400 mg, 1.54 mmol) was placed in a three-neck flask and dried at 200°C in vacuum for 20 minutes. 4-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]-5-fluoro-2-methylphenol (100 mg, 0.31 mmol ), selective F (546.26 mg, 1.54 mmol), CsF (281.07 mg, 1.85 mmol), toluene (10 ml), 2-fluoropyridine (149.73 mg, 1.54 mmol) and TMSCF3 (219.25 mg, 1.54 mmol) was added in a glovebox. The mixture was stirred at 25°C for 16 hours. The mixture was filtered through celite and the filter cake was eluted with DCM (20 mlx2). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0% to 4% to 8%) and then by preparative HPLC [Phenomenex Gemini-NX 80x30 mmx3 mm, A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 47-77% in 8 minutes] with obtaining the product

- 59 046421 (12.11 mg, 30.3 mmol, yield 9%) as a solid. 1H NMR (400 MHz, CDCl ₃ ) δ _δ 9.53 (s, 1H), 8.75 (s, 1H), 8.16 (d, 1H), 7.15 (d, 1H), 3.97 (s, 3H), 2.39 (s, 3H). LCMS Rt=1.35 min with chromatography 2.0 min, 10-80АВ, MS ESI calc. for C ₁₅ H _n F ₆ N ₄ O ₂ [M+H]+ 393.1, determined 393.0.

Example 43: Synthesis of compound 43-3-[difluoro(methoxy)methyl]-6-[2-fluoro-6-methyl-4(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-a] pyrazine

But

F tetrabutylammonium tribromide

DCM/MeOH, 25°С, 2 h

TBSCI, imidazole

TBSO

DCM, 25°С, 3 h

A113

Pd ₂ dba ₃ , XPhos

COAc, dioxane, 100°C, 12 h

A112

A112: 4-bromo-3-fluoro-5-methylphenol.

To a solution of 3-fluoro-5-methylphenol (30.0 g, 237.85 mmol) in DCM (1.8 L) and methanol (1.2 L) was added dropwise tetrabutylammonium tribromide (114.69 g, 237.85 mmol) with stirring at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated. Water (500 ml) was added and the aqueous layer was extracted with DCM (500 mlx3). The combined organic layers were washed with brine (1 L), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 15%) to give the product (25.0 g, 121.94 mmol) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ _6.56-6.49 (m, 2H), 2.37 (s, 1H).

A113: (4-bromo-3-fluoro-5-methylphenoxy)-tert-butyldimethylsilane.

To a solution of 4-bromo-3-fluoro-5-methylphenol (8.0 g, 39.02 mmol) in DCM (100 ml) was added t-butylchlorodimethylsilane (8.82 g, 58.53 mmol) and imidazole. (5.3 g, 78.04 mmol). The mixture was stirred at 25°C for 3 hours. After cooling to 25°C, water (200 ml) was added to the mixture and the aqueous layer was extracted with EtOAc (100 mlx3). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (petroleum ether) to give the product (10.0 g, 31.32 mmol, 80% yield) as an oil. 1H NMR (400 MHz, CDC13) _δΗ 6.55 (s, 1H), 6.48 (dd, 1H), 2.37 (s, 3H), 0.98 (s, 9H), 0.22 ( s, 6H).

A114: tert-butyl-[3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]dimethylsilane.

To a mixture of (4-bromo-3-fluoro-5-methylphenoxy)-tert-butyldimethylsilane (5.0 g, 15.66 mmol) in 1,4dioxane (50 ml) was added 4,4,5,5-tetramethyl-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2dioxaborolane (4.8 g, 18.79 mmol) and KOAc (3.07 g, 31 .32 mmol). Pd ₂ (dba) ₃ (1.43 g, 1.57 mmol) and XPhos (1.49 g, 3.13 mmol) were then added to the mixture. The mixture was stirred at 100°C under N2 atmosphere for 12 hours. After cooling to room temperature, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to remove 1,4-dioxane. Water (50 ml) was added and the aqueous layer was extracted with EtOAc (100 mlx3). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 20%) to give the product (4.0 g, 8.73 mmol) as an oil. 1H NMR (400 MHz, CDC13) δκ 6.45 (s, 1H), 6.33 (dd, 1H), 2.41 (s, 3H), 1.37 (s, 12H), 0.97 (s , 9H), 0.19 (s, 6H).

- 60 046421

A115: tert-butyl-[4-(5-chloropyrazin-2-yl)-3-fluoro-5-methylphenoxy]dimethylsilane.

A mixture of 2-bromo-5-chloropyrazine (1.86 g, 9.61 mmol), tert-butyl-[3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl1,3,2- dioxaborolan-2-yl)phenoxy]dimethylsilane (4 g, 8.73 mmol), Cs ₂ CO ₃ (5.69 g, 17.47 mmol) and Pd(dppf)Cl ₂ (639 mg, 0.87 mmol) in 1,4-dioxane (40 ml) and water (4 ml) was stirred at 55°C for 4 hours under N2 atmosphere. After cooling to 25°C, water (50 ml) was added. The aqueous layer was extracted with EtOAc (30 mlx2). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to leave a residue. The residue was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0~5%) to give the product (2 g, 5.67 mmol, 65% yield) as an oil. ^1H NMR (400 MHz, CDCl ₃ ) δн 8.70 (s 1H), 8.44 (s, 1H), 6.61 (s, 1H), 6.52 (d, 1H), 2.22 ( s, 3H), 1.00 (s, 9H), 0.25 (s, 6H). LCMS R _t =1.13 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₇ H ₂₃ ClFN ₂ OSi [M+H]+ 353.1, determined 353.3.

A116: 4-(5-chloropyrazin-2-yl)-3-fluoro-5-methylphenol.

To a solution of tert-butyl-[4-(5-chloropyrazin-2-yl)-3-fluoro-5-methylphenoxy]dimethylsilane (2 g, 5.67 mmol) in methanol (30 ml) was added. NH4HF2 (1.62 g, 28.34 mmol) at 25°C. The mixture was stirred at 60°C for 12 hours. After cooling to RT, the mixture was concentrated and purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 30%) to give (900 mg, 3.77 mmol, 66% yield) as a solid. ^1H NMR (400 MHz, _CDCl3 ) _δH 8.70 (s, 1H), 8.44 (s, 1H), 6.59 (s, 1H), 6.53 (d, 1H), 5, 62 (brs, 1H), 2.22 (s, 3H). LCMS R _t =0.80 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₁ H ₉ ClFN ₂ O [M+H]+ 239.0 determined to be 238.9.

A117: 2-(4-benzyloxy-2-fluoro-6-methylphenyl)-5-chloropyrazine.

To a solution of 4-(5-chloropyrazin-2-yl)-3-fluoro-5-methylphenol (900 mg, 3.77 mmol) in MeCN (10 ml) was added K ₂ CO ₃ (729.55 mg, 5.28 mmol). Bromomethylbenzene (644.99 mg, 3.77 mmol) was then added dropwise to the mixture. The mixture was stirred at 25°C for 16 hours under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 15%) to give the product (1 g, 3.04 mmol, 80% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) _δH 8.70 (s, 1H), 8.44 (s, 1H), 7.47-7.32 (m, 5H), 6.76 (s, 1H) , 6.66 (d, 1H), 5.10 (s, 2H), 2.25 (s, 3H). LCMS R _t =1.01 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₈ H ₁₅ ClFN ₂ O [M+H]+ 329.1 determined to be 328.9.

A118: [5-(4-benzyloxy-2-fluoro-6-methylphenyl)pyrazin-2-yl]hydrazine.

To a solution of 2-(4-benzyloxy-2-fluoro-6-methylphenyl)-5-chloropyrazine (1 g, 3.04 mmol) in MeCN (10 ml) was added N2H4H2O (1.52 g, 30.42 mmol) at 25°C. The mixture was stirred at 100°C for 16 hours. After cooling to 25°C, water (20 ml) was added to the mixture. After separation of the layers, the aqueous layer was extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (980 mg, 3.02 mmol) as a solid. 1H NMR (400 MHz, DMSO-de) δн 8.19 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.49-7.30 (m, 5H), 6 .87-6.77 (m, 2H), 5.14 (s, 2H), 4.31 (brs, 2H), 2.14 (s, 3H). LCMS R _t =0.77 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₁₈ H ₁₈ FN ₄ O [M+H]+325.1, determined to be 325.3.

A119: Na-[5-(4-benzyloxy-2-fluoro-6-methylphenyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetohydrazide.

To a solution of 2-bromo-2,2-difluoroacetic acid (205 mg, 1.17 mmol) in THF (2 ml) was added a drop of DMF and (COCl) ₂ (0.12 ml, 1.41 mmol). The resulting mixture was stirred at 25°C for 30 minutes. [5-(4-Benzyloxy-2-fluoro-6-methylphenyl)pyrazin-2-yl]hydrazine (250 mg, 0.77 mmol) was added to the mixture. The mixture was stirred at 25°C for 18 hours. Water (20 ml) was added and the aqueous layer was extracted with EtOAc (20 mlx2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 40% to 100%) to give the product (270 mg, 0.56 mmol, 72% yield) as a solid. 1H NMR (400 MHz, DMSO-de) δн 11.35 (br s, 1H), 9.46 (s, 1H), 8.15 (s, 2H), 7.49-7.31 (m, 5H ), 6.89-6.81 (m, 2H), 5.16 (s, 2H), 2.15 (s, 3H). LCMS R _t =1.01 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₂₀ H ₁₇ BrF ₃ N ₄ O ₂ [M+H]+ 481.0, determined 482.8.

A120: 6-(4-benzyloxy-2-fluoro-6-methylphenyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3a]pyrazine.

To a solution of Na-[5-(4-benzyloxy-2-fluoro-6-methylphenyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetohydrazide (390 mg, 0.81 mmol) in toluene (5 ml ) TsOH (41.86 mg, 0.24 mmol) was added. The mixture was stirred at 130°C for 12 hours. Water (30 ml) was added and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 30% to 40%) to give the product (210 mg, 0.45 mmol, 55% yield) as a solid. 1H NMR (400 MHz, CDCl ₃ ) _δH 9.58 (s, 1H), 8.21 (s, 1H), 7.51-7.30 (m, 5H), 6.80 (s, 1H) , 6.69 (dd, 1H), 5.12 (s, 2H), 2.31 (s, 3H). LCMS R _t =1.05 min with chromatography 1.5 min, 5-95АВ, MS ESI calc. for C ₂₀ H ₁₅ BrF ₃ N ₄ O

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[M+H]+ 463.0, determined 464.8.

A121: 6-(4-benzyloxy-2-fluoro-6-methylphenyl)-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine.

To a solution of 6-(4-benzyloxy-2-fluoro-6-methylphenyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3a]pyrazine (210 mg, 0.45 mmol ) in methanol (2 ml), AgBF4 (175.89 mg, 0.91 mmol) and Na ₂ CO ₃ (96.09 mg, 0.91 mmol) were added at 28°C. The mixture was stirred at 70°C for 3 hours. Brine (20 ml) was added and the mixture was filtered through celite. The filter cake was washed with EtOAc (10 mlx2). The filtrate was separated and the aqueous layer was extracted with EtOAc (30 mlx2). The combined organic layer was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether=0% to 15% to 30%) to give the product (130 mg, 0.31 mmol, 69% yield) as a solid. The product (50 mg, 0.12 mmol) was dried in vacuo to give the product (43.8 mg, 105.7 μmol, 87% yield) as a solid. ^1H NMR (400 MHz, CDCl ₃ ) δκ 9.52 (s, 1H), 8.21 (s, 1H), 7.50-7.34 (m, 5H), 6.79 (s, 1H) , 6.68 (dd, 1H), 5.12 (s, 2H), 3.93 (s, 3H), 2.28 (s, 3H). LCMS R _t =1.21 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C ₂₁ H ₁₈ F ₃ N ₄ O ₂ [M+H] ⁺ 415.1, determined 415.2.

A122: 4-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]-3-fluoro-5-methylphenol.

A mixture of 6-(4-benzyloxy-2-fluoro-6-methylphenyl)-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3a]pyrazine (80 mg 0.19 mmol) in HBr/HOAc (1 ml, 33% in HOAc) was stirred at 25°C for 2 hours. Water (10 ml) was added and the mixture was extracted with EtOAc (15 ml x 3). The combined organic phase was washed with saturated aqueous NaHCO ₃ (20 mlx1) and brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by silica gel flash chromatography (EtOAc in petroleum ether=0% to 20% to 50%) and preparative HPLC [YMC Triart C18 (150x25mmx5cm). A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 36-66% B in 9.5 minutes) to give the product (6.71 mg, 20.7 μmol, 10% yield) as a solid. 1H NMR (400 MHz, CDCI3) δκ 9.52 (d, 1H), 8.21 (s, 1H), 6.65 (s, 1H), 6.58-6.57 (m, 1H), 5 .80 (s, 1H), 3.93 (s, 3H), 2.26 (s, 3H). LCMS R _t =1.20 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C14H11F3N4O2 [M+H] ⁺ 325.1, determined 325.1.

Compound 43: 3-[difluoro(methoxy)methyl]-6-[2-fluoro-6-methyl-4-(trifluoromethoxy)phenyl][1,2,4]triazolo[4,3-a]pyrazine.

AgOTf (435.81 mg, 1.7 mmol) was placed in a three-neck flask and dried at 200°C (heat gun) in vacuum for 20 minutes. 4-[3-[difluoro(methoxy)methyl][1,2,4]triazolo[4,3-a]pyrazin-6-yl]-3-fluoro-5-methylphenol (110 mg, 0.34 mmol), selective F (600.89 mg, 1.7 mmol), CsF (309.18 mg, 2.04 mmol), then toluene (3 ml), 2-fluoropyridine (164.7 mg, 1 .7 mmol) and TMSCF ₃ (241.18 mg, 1.7 mmol) to obtain a mixture. The mixture was stirred at 28°C for 16 hours. The mixture was filtered through celite and the filter cake was eluted with DCM (20 mlx2). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0% to 10%) and preparative HPLC [Phenomenex Gemini-NX8 80x30 mmx3 cm, A=H ₂ O (10 mM NH4HCO3) and B=CH ₃ CN; 40-70% in 9.5 minutes] to obtain the product (8.85 mg, 22.4 μmol, 6% yield) as a solid. 1H NMR (400 MHz, CDC13) δΗ 9.54 (s, 1H), 8.26 (s, 1H), 7.05 (s, 1H), 6.98 (d, 1H), 3.94 (s , 3H), 2.34 (s, 3H). LCMS R _t =1.17 min with chromatography 2.0 min, 10-80AV, MS ESI calc. for C15H11F6N4O2 [M+H] ⁺ 393.1, determined 393.0.

Example 44: Synthesis of A12-6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine.

A18 A12

To a solution of (6-chloropyridazin-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (80 ml) 2-methoxyacetyl chloride (2.48 g, 22.83 mmol) was added dropwise at 25°C. The solution was stirred at 25°C for 30 minutes and refluxed at 120°C for 24 hours. After cooling to room temperature, the mixture was diluted with H ₂ O (40 ml) and extracted with ethyl acetate (40 ml x 2). The combined organic phase was washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was triturated with i-Pr ₂ O (10 ml) to obtain the product (1500 mg, 7.31 mmol, 35% yield) as a solid. LCMS R _t =0.43 min with chromatography 1.5 min, 5-95AV, MS ESI calc. for C ₇ H ₈ ClN ₄ O [M+H] ⁺ 198.0, determined 199.0.

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Example 45: Synthesis of A32-6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine.

A123: 2-chloro-N-(5-chloropyrazin-2-yl)-2,2-difluoroacetohydrazide.

To a stirred solution of 2-chloro-5-hydrazinylpyrazine (5.0 g, 33.99 mmol) in toluene (50 ml) was added chlorodifluoroacetic anhydride (6.54 ml, 37.39 mmol) at 0°C. The reaction mixture was heated at 110°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to give a residue. The residue was treated with water (50 ml) and extracted with ethyl acetate (2x50 ml). The organic layer was washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated to a solid (6 g). It was used for the next step without further purification.

A32: 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine.

To a stirred solution of 2-chloro-N-(5-chloropyrazin-2-yl)-2,2-difluoroacetohydrazide (6.0 mg, 23.34 mmol) in DCM (120 ml) was added trifluoromethanesulfonic acid anhydride (4.73 ml , 28.01 mmol) and 2-methoxypridine (4.91 ml, 46.69 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (2x50 ml). The organic layer was washed with brine (50 ml), dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by 15% EtOAc/PE silica gel column chromatography to give the product (4.0 g, 16.5 mmol, 71% yield) as a solid. LCMS: 239.0 (M+H), Rt 1.66 min. Column: ZORBAX XDB C-18 (50x4.6 mm), 3.5 µm Mobile phase: A: 0.1% HCOOH in water: AFM (95:5), B: ACN; Flow rate: 1.5 ml/min.

Example 46: Efficacy of Exemplary Compounds in Modulating Late Sodium Current (INaL).

Functional characterization of exemplary compounds for modulation of INaL expressed by the voltage-gated sodium channel NaV1,6 was performed using the PatchXpress™ high-throughput electrophysiology platform (Molecular Devices, Sunnyvale, CA). HEK-293 cells expressing recombinant human NaV1.6 (hNaV1.6) were grown in DMEM/c high-glucose Dulbecco's modified medium, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES, and 400 μg/ml G418. Before harvesting, cells were grown to 50–80% confluency. Trypsinized cells were washed, allowed to recover for 1 hour and then resuspended in extracellular recording solution at a concentration of 1x106 cells/ml. The PatchXpress in-line liquid handling system was used to dispense cells and apply test formulations. Late NaV currents were induced by application of 300 nM ATX-II. INaL was induced by depolarizing pulses to 0 mV for 200 ms from a noninactivating holding potential (eg, −120 mV) at a frequency of 0.1 Hz. The amplitude and stability of INaL were determined by analyzing the average current amplitude over the last 20 ms of the test pulse. After steady state blockade with exemplary compounds (eg, as described herein), a Na + -free solution containing an impermeable cation (eg, choline or NDMG) was added to confirm the sodium current determination. The percentage of sustained inhibition of INaL was calculated as: [(INaL_compound)/(INaL_control)]*100, where INaL_compound and INaL_control represent INaL recorded in the presence or absence of compound, respectively.

The results of this assay regarding the percentage of INaL inhibition by hNaV1.6 (measured using a procedure similar to that described above but using HEK-293 cells expressing recombinant human NaV 1.6 (hNaV 1.6) at 1 μM are summarized in the table below. B In this table, A means less than 30% inhibition; B means about 30% to about 70% inhibition; and C means more than 70% inhibition;

No. NaV 1.6 analysis data 1 WITH 2 WITH 3 A

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4 WITH 5 IN 6 With 7 V 8 V 9 V 10 V AND A 12 IN 13 A 14 IN 15 A 16 IN 17 A 18 WITH 19 WITH 20 IN 21 V 22 V 23 V 24 With 25 With 26 With 27 V 28 V 29 With thirty V 31 A 32 A 33 WITH 34 With 35 V 36 V 37 With 38 With 39 V 40 With 41 A 42 WITH 43 V

Although we have described a number of embodiments, it is apparent that our basic examples may be modified to provide other embodiments employing the compounds and methods of this invention. It is therefore to be understood that the scope of the present invention is to be determined by the appended claims and not by the specific embodiments which have been presented by way of example.

The contents of all references (including references to literature, issued patents, published patent applications and pending patent applications) cited in this application are hereby incorporated herein in their entirety by reference. Unless otherwise specified, all technical and scientific terms used herein have the meaning known to one skilled in the art.

Claims (20)

1. A compound having formula I or a pharmaceutically acceptable salt thereof, wherein X represents CR ^d ; Y represents N; %< ^r2 R ¹ is ^RR ' CF ₃ , monocyclic C ₃ . ₆ cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more R ^a ; R ² represents hydrogen, C1. ₄ haloalkyl or monocyclic _C3 . ₆ cycloalkyl, optionally substituted with one or more R ^b ; R ³ represents hydrogen, C1. ₄ alkyl or C1. ₄ haloalkyl; R ⁴ represents hydrogen or C1. ₄ alkyl; R ⁵ represents halogen, C ₃ . ₆ cycloalkyl or C1. ₄ alkyl, optionally substituted with O-C1. ₄ alkyl or O-C ₃ . ₆ cycloalkyl; R ⁶ represents C1. ₄ alkyl or C1. ₄ haloalkyl, where each is C1. ₄ alkyl or C1. ₄ haloalkyl is substituted with OR ^c ; t is 1 or 2; R ^a and R ^b are each independently selected from halogen, C1. ₄ alkyl, C1. ₄ haloalkyl, C1. ₄ alkoxy and C1. ₄ haloalkoxy; R ^c represents C1. ₄ alkyl, optionally substituted with C ₃ . ₆ cycloalkyl or phenyl, or is preferably C ₃ - ₆ cycloalkyl; and R ^d represents hydrogen or C _1-4 alkyl, where the heterocyclyl has 1 ta, oxygen and sulfur in the ring system. 2. A compound having formula II with up to 4 heteroatoms independently selected from azo- or a pharmaceutically acceptable salt thereof, where <^ ^r2 R ¹ is ^RR ' CF3, monocyclic C3. ₆ cycloalkyl or 4-7 membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more R ^a ; R ² represents hydrogen, C1. ₄ haloalkyl or monocyclic C3. ₆ cycloalkyl, optionally substituted with one or more R ^b ; R3 represents hydrogen, C1. ₄ alkyl or C1. ₄ haloalkyl; R ⁴ represents hydrogen or C1. ₄ alkyl; R ⁵ represents halogen, C3. ₆ cycloalkyl or C1. ₄ alkyl, optionally substituted with O-C1. ₄ alkyl or O-C ₃ . ₆ cycloalkyl; R ⁶ represents C1. ₄ alkyl or C1. ₄ haloalkyl, where each indicated is C1. ₄ alkyl or C1. ₄ haloalkyl is substituted with OR ^c ; t is 1 or 2; R ^a and R ^b are each independently selected from halogen, C1. ₄ alkyl, C1. ₄ haloalkyl, C1. ₄ alkoxy and C1. ₄ haloalkoxy; And R ^c represents C1. ₄ alkyl, optionally substituted with C3. ₆ cycloalkyl or phenyl, or is preferably C3. ₆ cycloalkyl, where the heterocyclyl has from 1 to 4 heteroatoms in the ring system, independently selected from nitrogen, oxygen and sulfur. 3. The connection according to any one of claims 1-2, where R ¹ represents - 65 046421 x^r ² is a) ^RR ' b) cyclobutyl, optionally substituted with one or more R ^a or c) CF3. 4. A compound according to any one of claims 1 to 3, wherein R ² represents a C _1-4 haloalkyl, and preferably R ² represents CF3. 5. A compound according to any one of claims 1 to 3, where R ² represents hydrogen. 6. A compound according to any one of claims 1 to 3, where a) R ³ represents C1-4 alkyl and R ⁴ represents hydrogen or C1-4 alkyl, preferably R ³ represents methyl and R ⁴ represents hydrogen; b) R ³ and R ⁴ are each C _1-4 alkyl, preferably R ³ and R ⁴ are each methyl, or c) R ³ and R ⁴ are each hydrogen. 7. A compound according to any one of claims 1 to 6, where R ⁶ represents i) CF2-OR ^c , and optionally R ^c represents a) C1-4 alkyl, optionally substituted with cyclopropyl or b) cyclopropyl; or ii) R ⁶ is CF2OCH3, CF2OCH2CH3, CFzOCH^b, or CF2OCH2C3H5; or iii) R ⁶ represents CH2-OR ^c , and optionally R ^c represents a) C1-4 alkyl, optionally substituted with cyclopropyl or phenyl; or b) cyclopropyl; or iv) R ⁶ is CH2OCH3, CH2OCH2CH3, CH2OCH2C3H5, CH2OCH2CH(CH3)2, or CH2OCH2C6H5; or v) R ⁶ represents C(CH3)2-OR ^c , where optionally R ^c represents C1-4 alkyl; or vi) R ⁶ is C(CH3AOCH2CH3. 8. A compound according to any one of claims 1 to 7, where R ^a represents fluorine. 9. Connection according to any one of claims 1-8, where t is 1 or 2. 10. A compound according to any one of claims 1 to 9, where R ⁵ represents a) halogen or C1-4 alkyl, optionally substituted by OCH3 or OCH3H5; b) R ⁵ represents fluorine; c) R ⁵ is methyl or d) R ⁵ is fluorine, _CH3 , _CH2CH3 , CH2OCH3, _CH ( _CH3 ) _OCH3 , or _CH2OC3H5 . 11. Connection according to any one of paragraphs. 1 and 3-10, where R ^d represents hydrogen. 12. The connection according to claim 1, characterized in that the connection is - 66 046421 - 67 046421 or a pharmaceutically acceptable salt of any of the above. 13. The connection according to claim 4, characterized in that the connection is or a pharmaceutically acceptable salt of any of the above. 14. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier. 15. A method of treating a condition associated with aberrant sodium ion channel function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14. 16. The method according to claim 15, characterized in that the condition is a) a neurological or mental disorder; b) epilepsy or epileptic syndrome; c) genetic epilepsy or genetic epileptic syndrome; d) childhood epilepsy or childhood epileptic syndrome; or e) epileptic encephalopathy. 17. The method according to claim 16, characterized in that the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms or Lennox-Gastaut syndrome. 18. The method according to claim 16, characterized in that the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, incurable childhood epilepsy with generalized tonic-clonic seizures, infantile seizures, benign familial neonatal-infantile seizures, epileptic encephalopathy with SCN2A mutation, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, epileptic encephalopathy with mutation SCN8A, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), epileptic encephalopathy KCNQ2 and epileptic encephalopathy KCNT1. 19. A method of treating a neurological disorder or mental disorder, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14. 20. A method of treating pain, the method comprising administering to a subject in need thereof a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14.