EA045335B1 - NEW METHODS AND INTERMEDIATES FOR OBTAINING SOLUBLE GUANYL CYCLASE STIMULANTS - Google Patents

Description

Related applications

This application claims priority based on the filing date of U.S. Provisional Application No. 62/615678, filed January 10, 2018, and International Application No. PCT/CN2018/076982, filed February 2018. The entire contents of each of the foregoing applications are incorporated herein by reference. .

Field to which the invention relates

The present invention relates to new methods and intermediates for the preparation of compounds useful as soluble guanylate cyclase (sGC) stimulators. These methods provide stable 3-(2-pyrimidinyl)pyrazoles of formula II in high purity and yield. These methods have the added advantage of using convenient reaction conditions that can be easily scaled up for large-scale production.

BACKGROUND OF THE INVENTION sGC is the major receptor for NO in vivo. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine 5'-triphosphate (GTP) to the second messenger cGMP. Elevated cGMP levels, in turn, modulate the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs), and ion channels.

In the body, NO is synthesized from arginine and oxygen through the action of various nitric oxide synthase (NOS) enzymes and through the sequential reduction of inorganic nitrate. Experimental and clinical data indicate that decreased NO concentrations, decreased NO bioavailability, and/or decreased response to endogenously produced NO contribute to disease development.

sGC stimulators are NO-independent heme-dependent modulators of the sGC enzyme and demonstrate strong synergistic activation of the enzyme with NO. This clearly distinguishes them from NO-independent heme-independent sGC activators.

There is a need to develop new sGC stimulators as compounds that stimulate sGC in an NO-independent manner offer significant advantages over existing alternative therapies that target the aberrant NO pathway. As a result, there is also a need to develop efficient methods that are easily adaptable to large-scale production for the synthesis of these new sGC stimulators. There is a need for methods that are efficient and easily adaptable to large-scale production, which provide stable sGC stimulators with high purity and yields.

The essence of the invention

The present invention describes new methods for preparing compounds of formula II

In one aspect, the compounds of formula II and their pharmaceutically acceptable salts are sGC stimulants useful for treating diseases or disorders that benefit from sGC stimulation or increased concentrations of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP). In another aspect, the compounds of Formula II are useful intermediates in the preparation of said sGC stimulants.

For a compound of formula II, the following definitions apply:

R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O; And

R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or

6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, where indicated

A 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms, where each R ⁵ independently represents methyl or halogen.

In a first embodiment, the compound of formula II is a compound of formula V. In a second embodiment, the compound of formula II is a compound of formula VI.

In 1 specific embodiment, the present invention provides a process for preparing a compound of formula (4) comprising the following steps: i) coupling an amide of formula (1)

with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3)

and ii) reacting the mixture at pH>5 to obtain a compound of formula (4), wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl a ring optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O.

- 2 045335

In a 2nd specific embodiment, the present invention provides a process for preparing a compound of formula II comprising the following steps: i) coupling an amide of formula (1)

with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3)

iii) carrying out the condensation of a compound of formula (4) with a hydrazine of the formula R ² -CH ₂ -NH-NH ₂ or a salt thereof to obtain a compound of formula II, wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group, consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from a group consisting of N, S and O; And

R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or a 6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms, where each R ⁵ independently represents is methyl or halogen.

In a 3rd specific embodiment, the present invention provides a method for preparing a compound of formula II

including the following stages:

- 3 045335

i) amide combination of formula (1)

with a pyrimidine compound of formula (2)

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3)

ii) reacting the mixture at pH>5 to obtain a compound of formula (4)

ilia) carrying out the condensation of a compound of formula (4) with hydrazine to obtain a compound of formula (24)

and iiib) alkylation of the intermediate of formula (24) with an alkylating agent of formula (22) to obtain a compound of formula II

R ² -CH ₂ -X (22) where R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents , independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O; And

R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or a 6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms, where each R ⁵ independently represents a methyl or halogen;

X represents a leaving group selected from -Br, -I, -Cl, -F and a sulfonic acid ester.

In a 4th specific embodiment, the present invention provides a method according to the 2nd or 3rd embodiment, further comprising step iv) of demethylating a compound of formula II to obtain an alcohol compound (9)

- 4 045335

R ¹ / І on F Compound (θ)

In the 5th specific embodiment, the present invention provides the method of the 4th embodiment further comprising the step of v) chlorinating an alcohol compound of formula (9) with phosphoryl chloride to obtain a compound of formula III

R ¹ /-R ² η

Ν

Ci

F

Formula III

In a 6th specific embodiment, the present invention provides a process wherein R ¹ is a 5-membered heteroaryl ring or R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O.

In a 7th specific embodiment, the present invention provides a process wherein (i) R ² is phenyl substituted with up to two R ⁵ substituents;

(ii) R ² is phenyl substituted with one R ⁵ substituent;

(iii) R ² is represented by the formula

;

(iv) R ² is a 6-membered heteroaryl substituted with up to two R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms; and where (i) each R ⁵ independently represents methyl or halogen;

(ii) each R ⁵ is independently halogen; or (iii) each R ⁵ is fluorine.

In an 8th specific embodiment, the present invention provides a method wherein (i) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O;

R ² is phenyl, optionally substituted with one or two R ⁵ substituents;

each R ⁵ represents fluorine; or (ii) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O;

R ² represents

each R ⁵ represents fluorine.

In the 9th specific embodiment, the present invention provides a method for producing a compound of formula (4')

including the following stages:

- 5 045335

i) amide combination of formula (1')

with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3')

and ii) reacting the mixture at pH>5 to obtain a compound of formula (4').

In a 10th specific embodiment, the present invention provides a process for preparing a compound of formula V comprising the following steps: i) coupling an amide of formula (1')

with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3')

ii) reacting the mixture at pH>5 to obtain a compound of formula (4')

iii) effecting the condensation of a compound of formula (4') with hydrazine of formula

- 6 045335 or its salt to obtain a compound of formula V.

In an 11th specific embodiment, the present invention provides a method for preparing a compound of formula V

with a pyrimidine compound of formula (2) comprising the following steps: i) coupling of an amide of formula (1')

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3')

ii) reacting the mixture at pH>5 to obtain a compound of formula (4')

iiia) carrying out the condensation of a compound of formula (4') with hydrazine to obtain a compound of formula (24')

iiib) alkylation of the intermediate of formula (24') with an alkylating agent of formula (23A) to obtain a compound of formula V

- 7 045335

where X represents a leaving group selected from -Br, -I, -Cl, -F and a sulfonic acid ester.

In the 12th specific embodiment, the present invention provides a method according to embodiment 10 or 11, further comprising step iv) of demethylating a compound of formula V to obtain an alcohol compound (9')

In a 13th specific embodiment, the present invention provides the method of embodiment 12, further comprising the step of v) chlorinating an alcohol compound of formula (9') with phosphoryl chloride to obtain a compound of formula VI

Formula VI

In a 14th specific embodiment, the present invention provides a method wherein step ii) is carried out in the presence of added N,O-dimethylhydroxylamine or a salt thereof.

In a 15th specific embodiment, the present invention provides a method wherein the hydrazine in step iia) is hydrazine hydrate.

In a 16th specific embodiment, the present invention provides a method wherein X is a sulfonic acid ester selected from mesylate, tosylate and triflate.

In a 17th specific embodiment, the present invention provides a process wherein said phenyl or 5-6 membered heteroaryl ring represented by R ¹ is substituted with up to three substituents independently selected from the group consisting of halogen and methyl.

In the 18th specific embodiment, the present invention provides a method in which step iii) is carried out in the presence of a base.

In a 19th specific embodiment, the present invention provides a process wherein said phenyl or 6-membered heteroaryl represented by R ² is substituted with up to three R ⁵ substituents, wherein each R ⁵ independently represents methyl, methoxy or halogen.

In a 20th specific embodiment, the present invention provides a method wherein the base in step i) is n-butyllithium.

In a 21st specific embodiment, the present invention provides a method, where the method includes contacting the reaction product of the reaction between an amide of formula (1) or (1') and a pyrimidine compound of formula (2) with a solution comprising N,O-dimethylhydroxylamine or a salt thereof, and an acid to obtain a compound of formula (4) or (4').

In a 22nd specific embodiment, the present invention provides a method wherein the solution comprises N,O-dimethylhydroxylamine hydrochloride.

In the 23rd specific embodiment, the present invention provides a method wherein (i) the acid is an aqueous acid;

(ii) the acid is hydrochloric acid; or (iii) the acid is glacial acetic acid.

In the 24th specific embodiment, the present invention provides a method wherein X is -Br.

In the 25th specific embodiment, the present invention provides a connection of

- 8 045335 mules (3) or (4):

F

or wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5 or 6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O.

In a 26th specific embodiment, the present invention provides a compound wherein said phenyl or 5-6 membered heteroaryl ring represented by R ¹ is substituted with up to three substituents independently selected from the group consisting of halogen and methyl.

In a 27th specific embodiment, the present invention provides a compound wherein (i) R ¹ is a 5-membered heteroaryl ring; or (ii) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O.

In a 28th specific embodiment, the present invention provides a compound wherein the compound is represented by formula (3') or (4'):

F

; or

Description of drawings

Fig. 1 shows an X-ray powder diffraction pattern of crystalline form A of the compound of formula IA.

Fig. 2 shows the DSC profile of crystalline form A of the compound of formula IA.

Fig. 3A shows an X-ray powder diffraction pattern of crystalline form B of compound of formula ID in the 2Θ angle range of 5 to 45°.

Fig. 3B shows an X-ray powder diffraction pattern of crystalline Form B of compound of formula ID before and after storage for 14 months.

Fig. 3C shows an X-ray powder diffraction pattern of crystalline form B of compound of formula ID in the 2Θ angle range of 3 to 40°.

Detailed Description of the Invention

Certain embodiments of the invention will now be described in detail, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in connection with the listed embodiments, it should be understood that they are not intended to limit the invention. More precisely, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein, but includes any methods and materials similar or equivalent to those described herein that may be used in the practice of the present invention. In the event that one or more of the included literature references, patents or similar materials differ from or conflict with this application, including, but not limited to, certain terms, uses of terms, methods described, etc., this application controls.

Definitions and general terminology.

For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version and the Handbook of Chemistry and Physics, 75th ed. 1994. In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999; and March's Advanced Organic Chemistry, 5th ed., Smith, M.B. and March, J., eds., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entirety.

The term ring atom refers to an atom, such as C, N, O, or S, that is part of a ring (rings include, for example, a cycloaliphatic ring (e.g., a cycloalkyl ring), a heterocyclic ring, an aryl ring (e.g., a phenyl ring), or a heteroaryl ring ).

The ring atom being replaced is a carbon or nitrogen ring atom bonded

- 9 045335 with at least one hydrogen atom. Hydrogen may optionally be replaced by a suitable substituent group. The ring atom to be replaced does not include ring carbon or nitrogen atoms where the structure shows that they are already bonded to one or more groups or substituents other than hydrogen and there are no hydrogen atoms to substitute. When any ring is optionally substituted, it is understood that it may be substituted on one or more or all of its substituted ring atoms depending on the number of possible substituents.

Generally, the term substituted refers to the replacement of one or more hydrogen radicals of a given structure with another specified radical substituent other than hydrogen (some non-limiting examples include a hydroxy, phenyl or alkyl radical). If the structure or moiety is optionally substituted, it may be substituted or unsubstituted.

When one or more positions in a structure may be substituted by one or more substituents selected from a specified group or list, the substituent or substituents at each position may be independently selected to be equal or the same at each position and for each occurrence, unless otherwise indicated . For example, if phenyl is substituted with two R ¹⁰⁰ substituents, and each R ¹⁰⁰ is independently selected from halogen and methyl, this means that in each case R ¹⁰⁰ is separately selected from halogen or methyl; for example, one R ¹⁰⁰ may be fluorine and the other may be methyl, or both may be chlorine, etc. Likewise, if the atom being replaced is bonded to more than one hydrogen (eg, CH3 or NH2), the substituents may be independently selected to be equal or the same at each position and for each occurrence unless otherwise noted. For example, if a methyl (eg, CH3) is substituted with two R ¹⁰⁰ substituents, and each R ¹⁰⁰ is independently selected from halogen and methyl, this means that in each case R ¹⁰⁰ is separately selected from halogen or methyl; for example, one R ¹⁰⁰ could be fluorine and the other could be methyl (eg CHF(CH3), or both could be chlorine (eg CHCl2), etc.

The selection of substituents and combinations provided by the present invention includes only those that lead to the formation of stable or chemically possible compounds. Such choices and combinations will be apparent to those skilled in the art and can be determined without undue experimentation. The term stable, as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in some embodiments, their isolation, purification, and use for one or more of the purposes disclosed herein. invention. A chemically achievable compound is a compound that can be prepared by one skilled in the art based on the knowledge disclosed in the present invention, supplemented, if necessary, by relevant knowledge in the art.

The phrase up to, as used in the present invention, refers to zero or any integer that is equal to or less than the number following the phrase. For example, up to 3 means any of 0, 1, 2 or 3. As described in the present invention, the specified numerical range of atoms or substituents includes any integer within this range. For example, a group with 1-4 atoms may have 1, 2, 3 or 4 atoms. When any variable occurs more than once in any position, its definition in each case is independent of any other case. When a group is replaced by 0 by the amount of a certain variable, it means that the group is unsubstituted.

Unless one of the isomers is shown or specifically named, the structures provided herein are intended to include all stereoisomeric (eg, enantiomeric, diastereomeric, atropisomeric, and cis-trans-isomeric) forms of the structure; for example, R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans isomers. Therefore, individual stereochemical isomers, as well as racemates and mixtures of enantiomers, diastereomers and cis-trans isomers of the compounds of the invention are included within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are also included within the scope of the invention.

In one embodiment, the present invention may involve replacing hydrogen with deuterium (i.e., ^2H ), which may provide certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and therefore, may be preferable in some circumstances. The deuterium-labeled compounds of the present invention can generally be prepared by following procedures similar to those described in the Schemes and/or the Examples below by replacing a non-deuterated reagent with a deuterated reagent.

The term aliphatic (as in an aliphatic group or aliphatic chain) means a straight or branched hydrocarbon (formed only of carbon and hydrogen) chain that is fully saturated or contains one or more units of unsaturation. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl, acetylene, and the like. An aliphatic group will be represented by the term Cx-y aliphatic group, where x and y are the minimum and maximum number of carbon atoms forming the aliphatic chain. An aliphatic group will be represented by the term

C _x is an aliphatic group to indicate that it is formed by x number of carbon atoms.

The term alkyl (as, for example, an alkyl chain or an alkyl group) in the context of the present invention refers to a saturated straight (eg, linear) or branched monovalent hydrocarbon radical. C _x alkyl is an alkyl chain containing x carbon atoms, where x is an integer other than 0. C _x - _y alkyl, where x and y are two different integers both different from 0, is an alkyl chain , containing the number of carbon atoms between x and y inclusive. For example, _C1-6 alkyl is an alkyl as defined above containing any number of carbon atoms between 1 and 6. Examples of alkyl groups include, but are not limited to, methyl (i.e. C1 alkyl), ethyl (i.e. C2 alkyl), n-propyl ( _C3 alkyl), isopropyl (other _C3 alkyl), n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.

The term alkenyl (as in alkenyl chain or alkenyl group) refers to a straight (e.g., linear) or branched monovalent hydrocarbon radical with at least one unsaturation site that is a carbon-carbon, sp ² double bond, where the alkenyl radical includes radicals, having cis and trans orientations, or using alternative nomenclature, E and Z orientations. Examples of alkenyls include, but are not limited to, vinyl, allyl, and the like. C _x alkenyl is an alkenyl chain containing x carbon atoms, where x is an integer other than 0 or 1. Alternatively, an alkenyl group would be represented by the term C _xy alkenyl, where x and y denote the minimum and maximum number of carbon atoms forming the alkenyl group. chain.

The term alkynyl (as in an alkynyl chain or alkynyl group) refers to a straight-chain (eg, linear) or branched monovalent hydrocarbon radical with at least one unsaturation site that is a carbon-carbon sp triple bond. Examples include, but are not limited to, ethynyl, propynyl, and the like. C _x alkynyl is an alkynyl chain containing x carbon atoms, where x is an integer other than 0 or 1. Alternatively, an alkynyl group will be represented by the term C _x - _y alkynyl, where x and y represent the minimum and maximum number of carbon atoms, forming an alkynyl chain.

The term cycloaliphatic (as in cycloaliphatic ring or cycloaliphatic group) refers to a ring system formed only of carbon and hydrogen atoms that is fully saturated or contains one or more unsaturation units, but is not aromatic. A Cx cycloaliphatic group is a cycloaliphatic ring containing x carbon atoms, where x is an integer other than 0. Alternatively, a cycloaliphatic ring would be represented by the term C _x - _y cycloaliphatic group, where x and y are the minimum and maximum number of carbon atoms forming cycloaliphatic ring. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. The term cycloaliphatic also includes polycyclic ring systems (eg, bicyclic, tricyclic or tetracyclic). The polycyclic ring system may be a bridged, fused or spiro system.

Bridged ring systems include two rings that share two non-adjacent ring atoms.

Fused ring systems include two rings that share two adjacent ring atoms.

Spiro ring systems include two rings that share one boundary ring atom.

The term cycloalkyl (as in a cycloalkyl ring or cycloalkyl group) in the context of the present invention refers to a ring system formed only of carbon and hydrogen atoms that is fully saturated. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. A cycloalkyl ring will be represented by the term C _x - _y cycloalkyl, where x and y represent the minimum and maximum number of carbon atoms forming the cycloalkyl ring. The term cycloalkyl also includes polycyclic ring systems (eg, bicyclic, tricyclic or tetracyclic). The polycyclic ring system may be a bridged, fused or spiro system.

In the context of the present invention, the term aryl (as in an aryl ring or aryl group) refers to a ring system formed only of carbon atoms that is aromatic. The term also includes polycyclic ring systems (eg, bicyclic, tricyclic, tetracyclic, etc.). Examples of aryl rings include, but are not limited to, phenyl, naphthyl, indenyl, fluorenyl and anthracenyl.

The term heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon, including any oxidized form of nitrogen, sulfur, phosphorus or silicon and including the quaternized form of any basic nitrogen.

A ring that includes atoms other than carbon is called a heterocyclyl (or heterocycle or heterocyclic) (as in a heterocyclyl group or heterocyclyl ring) or heteroaryl (or heteroaromatic) (as in a heteroaryl group or heteroaryl ring). Heterocyclyl and heteroaryl rings include at least one ring atom other than the ring-forming carbon. The non-carbon ring atom can be any suitable atom, but is often selected from nitrogen, oxygen or sulfur. Heterocyclyl rings are fully saturated (eg piperidinyl) or contain one or more unsaturation units but are not aromatic (eg 1,2,3,4-tetrahydropyridinyl or 1,2-dihydropyridinyl). Heteroaryl rings are aromatic (eg pyridinyl). The terms heterocyclyl and heteroaryl also include polycyclic ring systems (eg, bicyclic, tricyclic or tetracyclic). The polycyclic ring system may be a bridged, fused or spiro system.

Heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4- thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiper azinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3- thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl and 5-imidazolidinyl. Examples of bicyclic heterocyclic ring systems include, but are not limited to, 2-oxa-bicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl.

Heteroaryl rings include, but are not limited to, the following monocycles, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl , 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3 -pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3 ,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl. Examples of bicyclic heteroaryl rings include, but are not limited to, indazole, pyrazolopyrimidine, imidazopyridine, etc.

In the context of the present invention, the term alkoxy refers to an alkyl group, as defined above, attached to the molecule through an oxygen atom. An alkoxy group can be represented as -O-(C _x-y alkyl), where x and y represent the minimum and maximum number of carbon atoms of the alkyl chain.

In the context of the present invention, the terms halogen or halo mean F, Cl, Br or I.

The terms haloalkyl, haloalkenyl, haloaliphatic and haloalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as appropriate, substituted with one or more halogen atoms. For example, C _1-3 haloalkyl can be, for example, -CFHCH2CHF2, and C _1-2 haloalkoxy can be, for example, -OC(Br)HCHF ₂ . This term includes perhalogenated alkyl groups such as -CCl ₃ and -CF ₂ CClF ₂ .

The term fluoroalkyl means alkyl substituted with one or more fluorine atoms. This term includes perfluorinated alkyl groups such as -CF ₃ and -CF ₂ CF ₃ .

In the context of the present invention, the term cyano refers to -CN or -C=N.

In the context of the present invention, the amino group refers to -NH2.

The term hydroxyl or hydroxy refers to -OH.

In the context of the present invention, carbonyl, used alone or in connection with another group, refers to -C(O)- or -C(=O)-.

In the context of the present invention, oxo refers to =O. When an oxo group is indicated as a possible substituent on a ring or other moiety or group (eg, an alkyl chain), it is understood that the bond between the oxygen on said oxo group and the ring or moiety or group to which the group is linked will be a double bond.

The compounds of the present invention are identified by their chemical structures and/or chemical names. When a compound is specified by presenting both its chemical structure and

- 12 045335 and its chemical name, and the chemical structure and the chemical name do not correspond to each other, the chemical structure is decisive for the identity of the compound.

Substituents, such as, for example, R ¹ , R ² and R ³ etc., are usually defined when they are introduced and remain so defined in the specification and in all independent claims unless otherwise indicated. In the context of the present invention, the term amide coupling agent or amide coupling reagent means a compound that reacts with the hydroxyl group of a carboxy group, thereby making it susceptible to nucleophilic attack. Examples of amide coupling reagents include DIC (diisopropylcarbodiimide), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), pyBOP ( benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), etc.

In the context of the present invention, the term solvent refers to a single solvent or mixture of solvents that results in the desired properties of the solvent mixture. For example, the aprotic organic solvent may be toluene or a mixture of toluene and another aprotic solvent such as DMF. Thus, in the context of the present invention, the term aprotic organic solvent can also cover a toluene/DMF mixture. As another example, the protic solvent may include water or a mixture of water and methanol.

In the context of the present invention, the term protic solvent is a solvent that has a hydrogen atom bonded to a polar group, such as oxygen (as in a hydroxyl group) or nitrogen (as in an amino group). In general terms, any solvent that contains labile H ⁺ is called a protic solvent. The molecules of such solvents easily donate protons (H ⁺ ) to the reagents. Conversely, aprotic solvents cannot readily give up hydrogen. Aprotic solvents are usually classified as polar aprotic or nonpolar (or apolar) aprotic, depending on the values of their dielectric constants. Protic solvents are typically polar protic solvents and have high dielectric constants and high polarity.

Some common characteristics of protic solvents are the ability to exhibit hydrogen bonding, having acidic hydrogens (although they can be very weakly acidic, such as ethanol), and that they are able to dissolve salts.

Examples include water, most alcohols, formic acid, hydrogen fluoride, nitromethane, acetic acid, and ammonia.

Some common characteristics of aprotic solvents are that they can accept hydrogen bonds, do not have acidic hydrogen, and are able to dissolve salts. These criteria are relative and very qualitative. For aprotic solvents, a range of acidities is known. Their ability to dissolve salts depends greatly on the nature of the salt.

Polar aprotic solvents are solvents that dissolve many salts. They do not contain acidic hydrogen. Therefore, they are not hydrogen bond donors. These solvents typically have intermediate dielectric constants and polarities. Although this discourages the use of the term polar aprotic, IUPAC describes such solvents as having both high dielectric constants and high dipole moments, an example being acetonitrile. Other solvents that meet IUPAC criteria include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), hexamethylphosphoramide (HMPA), tetrahydrofuran, ethyl acetate, acetone, acetonitrile (MeCN), and dimethyl sulfoxide (DMSO). Apolar or nonpolar aprotic solvents usually have small dielectric constants. Some examples of non-polar aprotic solvents are hexane and other alkanes, benzene, toluene, 1,4-dioxane, chloroform, ethers such as diethyl ether, dichloromethane, dichloroethane, etc.

The term equivalent used in the present invention when discussing the amount of reagent used refers to molar equivalent. For example, one equivalent of reactant A for every equivalent of reactant B means that the reaction uses one mole of reactant A for every mole of reactant B. A mole is defined as the amount obtained when the total mass of the substance used is divided by the molecular weight of the specified substance, with both masses are expressed in the same units (for example, grams).

The compounds of the present invention are identified by their chemical structures and/or chemical names. When a compound is specified by presenting both its chemical structure and its chemical name, and the chemical structure and chemical name do not correspond, the chemical structure is determinative of the identity of the compound.

Embodiments.

In a first embodiment, the compound of formula II is a compound of formula V. In a second embodiment, the compound of formula II is a compound of formula VI.

- 13 045335

In 1 specific embodiment, the present invention provides a method for producing a compound of formula (4)

comprising the following steps: i) coupling an amide of formula (1)

with a pyrimidine compound of formula (2)

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3)

and ii) reacting the mixture at pH>5 to obtain a compound of formula (4), wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl a ring optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O.

In a 2nd specific embodiment, the present invention provides a process for preparing a compound of formula II comprising the following steps: i) coupling an amide of formula (1)

- 14 045335 with a pyrimidine compound of formula (2)

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3)

ii) reacting the mixture at pH>5 to obtain a compound of formula (4)

and iii) carrying out the condensation of a compound of formula (4) with a hydrazine of the formula R ² -CH ₂ -NH-NH ₂ or a salt thereof to obtain a compound of formula II, wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O; And

R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or 6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms; wherein each R ⁵ independently represents methyl or halogen.

In a 3rd specific embodiment, the present invention provides a process for preparing a compound of formula II comprising the following steps: i) coupling an amide of formula (1)

with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3)

- 15 045335

ii) reacting the mixture at pH>5 to obtain a compound of formula (4)

iiia) carrying out the condensation of a compound of formula (4) with hydrazine to obtain a compound of formula (24)

and iiib) alkylation of the intermediate of formula (24) with an alkylating agent of formula (22) to obtain a compound of formula II

R ² -CH ₂ -X (22) where R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents , independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O; And

R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or 6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms; wherein each R ⁵ independently represents methyl or halogen;

X represents a leaving group selected from -Br, -I, -Cl, -F and a sulfonic acid ester.

In a 4th specific embodiment, the present invention provides a method according to the 2nd or 3rd embodiment, further comprising step iv) of demethylating a compound of formula II to obtain an alcohol compound (9)

R ¹ ^R ²

AND

N A

HE

F Connection (9)

In the 5th specific embodiment, the present invention provides the method of the 4th embodiment further comprising the step of v) chlorinating an alcohol compound of formula (9) with phosphoryl chloride to obtain a compound of formula III

In the 6th specific embodiment, the present invention provides a method wherein R ¹

- 16 045335 is a 5-membered heteroaryl ring or R ¹ is unsubstituted

A 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O.

In a 7th specific embodiment, the present invention provides a process wherein (i) R ² is phenyl substituted with up to two R ⁵ substituents;

(ii) R ² is phenyl substituted with one R ⁵ substituent;

(iii) R ² is represented by the formula

;

(iv) R ² is a 6-membered heteroaryl substituted with up to two R ⁵ substituents; and wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms, wherein (i) each R ⁵ independently represents methyl or halogen;

(ii) each R ⁵ is independently halogen; or (iii) each R ⁵ is fluorine.

In an 8th specific embodiment, the present invention provides a method wherein (i) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O;

R ² is phenyl, optionally substituted with one or two R ⁵ substituents;

each R ⁵ represents fluorine; or (ii) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O;

R ² represents

each R ⁵ represents fluorine.

In the 9th specific embodiment, the present invention provides a method for producing a compound of formula (4')

comprising the following steps: i) coupling an amide of formula (1')

with a pyrimidine compound of formula (2)

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3')

and ii) reacting the mixture at pH>5 to obtain a compound of formula (4').

In a 10th specific embodiment, the present invention provides a method for preparing a compound of formula V

- 17 045335 with a pyrimidine compound of formula (2) comprising the following steps: i) coupling of an amide of formula (1')

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3')

ii) reacting the mixture at pH>5 to obtain a compound of formula (4')

and iii) effecting the condensation of a compound of formula (4') with hydrazine of formula

or a salt thereof to obtain a compound of formula V.

In an 11th specific embodiment, the present invention provides a process for preparing a compound of formula V comprising the following steps: i) coupling an amide of formula (1')

- 18 045335 with a pyrimidine compound of formula (2)

in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3')

ii) reacting the mixture at pH>5 to obtain a compound of formula (4')

ilia) carrying out the condensation of a compound of formula (4') with hydrazine to obtain a compound of formula (24')

and iiib) alkylation of the intermediate of formula (24') with an alkylating agent of formula (23A) to obtain a compound of formula V

where X represents a leaving group selected from -Br, -I, -Cl, -F and a sulfonic acid ester.

In the 12th specific embodiment, the present invention provides a method according to embodiment 10 or 11, further comprising step iv) of demethylating a compound of formula V to obtain an alcohol compound (9')

In a 13th specific embodiment, the present invention provides the method of embodiment 12, further comprising the step of v) chlorinating an alcohol compound of formula (9') with phosphoryl chloride to obtain a compound of formula VI

- 19 045335

Formula VI

In a 14th specific embodiment, the present invention provides a method wherein step ii) is carried out in the presence of added N,O-dimethylhydroxylamine or a salt thereof.

In a 15th specific embodiment, the present invention provides a method wherein the hydrazine in step iia) is hydrazine hydrate.

In a 16th specific embodiment, the present invention provides a method wherein X is a sulfonic acid ester selected from mesylate, tosylate and triflate.

In a 17th specific embodiment, the present invention provides a process wherein said phenyl or 5-6 membered heteroaryl ring represented by R ¹ is substituted with up to three substituents independently selected from the group consisting of halogen and methyl.

In the 18th specific embodiment, the present invention provides a method in which step iii) is carried out in the presence of a base.

In a 19th specific embodiment, the present invention provides a process wherein said phenyl or 6-membered heteroaryl represented by R ² is substituted with up to three R ⁵ substituents, wherein each R ⁵ independently represents methyl, methoxy or halogen.

In a 20th specific embodiment, the present invention provides a method wherein the base in step i) is n-butyllithium.

In a 21st specific embodiment, the present invention provides a method, where the method includes contacting the reaction product of the reaction between an amide of formula (1) or (1') and a pyrimidine compound of formula (2) with a solution comprising N,O-dimethylhydroxylamine or a salt thereof, and an acid to obtain a compound of formula (4) or (4').

In a 22nd specific embodiment, the present invention provides a method wherein the solution comprises N,O-dimethylhydroxylamine hydrochloride.

In the 23rd specific embodiment, the present invention provides a method wherein (i) the acid is an aqueous acid;

(ii) the acid is hydrochloric acid; or (iii) the acid is glacial acetic acid.

In the 24th specific embodiment, the present invention provides a method wherein X is -Br.

In the 25th specific embodiment, the present invention provides a compound of formula (3) or (4):

wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5 or 6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O.

In a 26th specific embodiment, the present invention provides a compound wherein said phenyl or 5-6 membered heteroaryl ring represented by R ¹ is substituted with up to three substituents independently selected from the group consisting of halogen and methyl.

In a 27th specific embodiment, the present invention provides a compound wherein (i) R ¹ is a 5-membered heteroaryl ring; or (ii) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O.

- 20 045335

In a 28th specific embodiment, the present invention provides a compound wherein the compound is represented by formula (3') or (4'):

A suitable amount of amide intermediate (1') or amide intermediate (1) is at least one equivalent of amide (1) or amide (1') per equivalent of pyrimidine intermediate (2). In some embodiments, a suitable amount is between 0.95 and 1.2 equivalents of amide (1) or (1') per 1 equivalent of pyrimidine (2). In other embodiments, it is between 1 and 1.1 equivalents. In other embodiments, it is between 1 and 1.05 equivalents. In some other embodiments, one equals one equivalent. In still some embodiments, it is 1.05 equivalents.

A suitable aprotic organic solvent is an anhydrous organic solvent such as THF or hexane, or a mixture of THF and hexane. Other suitable aprotic organic solvents are, for example, 2-methyltetrahydrofuran or toluene.

Suitable temperature is below -40°C. In some embodiments, a suitable temperature is between -90 and -40°C. In some embodiments, a suitable temperature is between -90 and -45°C. In other embodiments, a suitable temperature is between -90 and -50°C. In some embodiments, a suitable temperature is between -90 and -60°C. In some embodiments, a suitable temperature is between -80 and -60°C. In some embodiments, a suitable temperature is between -78 and -60°C. In other embodiments, a suitable temperature is between -65 and -55°C. In some other embodiments, a suitable temperature is between -70 and -60°C. In still some embodiments, a suitable temperature is below -55°C.

A suitable base is, for example, n-butyllithium. Other suitable bases are bis(trimethylsilyl)amide (HMDS), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), sodium hydride (NaH), isopropyl magnesium chloride (iPrMgCl), methyl magnesium chloride (MeMgCl) and lithium diisopropylamide (LDA). Each of these bases is typically added to the reaction mixture in the form of a solution in an organic aprotic solvent. For example, n-butyllithium can be added as a solution in hexane.

A suitable amount of suitable base is between 0.90 and 1.2 equivalents for each equivalent of intermediate (2). In some embodiments, it is between 0.9 and 1.5 equivalents. In some embodiments, it is between 0.9 and 1.3 equivalents. In other embodiments, it is between 1.1 and 1.5 equivalents. In some other embodiments, it is between 1.1 and 1.4 equivalents. In still some embodiments, it is between 1.1 and 1.3 equivalents. In still some embodiments, it is 1 equivalent.

In some embodiments, the reaction of the amide intermediate (1) and pyrimidine (2) is quenched with an acid. In one embodiment, the acid is an aqueous acid, such as hydrochloric acid. In another embodiment, the acid is an anhydrous acid such as glacial acetic acid.

In some embodiments, a reaction mixture of amide intermediate (1) and pyrimidine (2), including intermediate (3), is used directly in step ii. In some embodiments, intermediate (3) is isolated prior to the reaction of step ii.

For step ii of any of the above-described methods for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and steps ii) in specific embodiments 1-38 described above.

In some embodiments, N,O-dimethylhydroxylamine is added as an HCl salt.

A suitable amount of N,O-dimethylhydroxylamine hydrochloride is between 0 and 1.5 equivalents of K,O-dimethylhydroxylamine hydrochloride per equivalent of pyrimidine intermediate (2). In some embodiments, a suitable amount is between 0 and 1.0 equivalent. In some embodiments, a suitable amount is between 0 and 1.4 equivalents. In some embodiments, a suitable amount is between 0 and 1.2 equivalents. In other embodiments, it is between 0.1 and 0.9. In still some embodiments, it is 0.6 or 0.5 equivalent. In other embodiments, no additional N,O-dimethylhydroxylamine is added in step ii).

A suitable solvent is a protic or non-protic solvent. Examples of protic solvents include, for example, water or an aqueous acid solution. A suitable solvent, which is an aqueous acid solution, is, for example, an HCl solution, an AcOH solution or an H2SO4 solution. In some embodiments, no added acid is required at this stage, and quenching occurs when at least 1 equivalent of N-O-dimethylhydroxylamine hydrochloride is used alone in the absence of added acid. In other embodiments, the acid quench is performed using one of the aqueous acid solutions noted above and in the absence of the addition of hydroxylamine hydrochloride. In some embodiments, the solvent is a mixture of an aqueous solution of an acidic solvent and an aprotic solvent. For example, the solvent may be a mixture of aqueous HCl and ethyl acetate. Other alternative solvents include, for example, 2-methylTHF, THF, MTBE, or mixtures of all of the above suitable solvents. In one embodiment, the solvent is an organic solvent or solvents such as ethyl acetate, 2-methylTHF, THF, MTBE, or a mixture thereof. In another embodiment, the solvent is an acidic anhydrous organic solvent such as glacial acetic acid. In another embodiment, the solvent is an organic solvent including an anhydrous acid such as glacial acetic acid.

A suitable temperature is between 0 and 30°C. In some embodiments, a suitable temperature is between 0 and 25°C. In other embodiments, it is between 0 and 5°C. In other embodiments, it is between 5 and 30°C. In other embodiments, it is between 5 and 25°C. In other embodiments, it is between 10 and 25°C. In other embodiments, it is between 15 and 25°C.

To achieve pH>5, the pH of the reaction mixture is adjusted after the solution obtained in step i) containing intermediate (3') is added to the acid reaction mixture optionally containing N,O-dimethylhydroxylamine hydrochloride. The reaction mixture may be acidic due to the presence of N,O-dimethylhydroxylamine hydrochloride or the presence of an added aqueous acid solution or both. Alternatively, the acid reaction mixture contains anhydrous acid in an organic solvent and optionally N,O-dimethylhydroxylamine hydrochloride. In one embodiment, the solution obtained in step i) is added to an acid reaction mixture containing glacial acetic acid and N,O-dimethylhydroxylamine hydrochloride in ethyl acetate. In some embodiments, the solution obtained in step i) containing intermediate (3') is added to the acid reaction mixture and, optionally, N,O-dimethylhydroxylamine or a salt thereof (eg, HCl salt) is added after the acid quench is performed. A suitable pH>5 can be obtained by adding an aqueous solution of a base, for example a saturated solution of sodium bicarbonate or a saturated solution of potassium bicarbonate or the like. In some embodiments, optionally added N,O-dimethylhydroxylamine or a salt thereof (eg, HCl salt) may be added after the base; in other embodiments, it may be added before the base. In some embodiments, a suitable pH achieved is any pH above 5 and below 9. In other embodiments, a suitable pH is above 6 and below 9. In some other embodiments, a suitable pH is above 7 and below 9. In others In some embodiments, a suitable pH is between 6.5 and 9. In some other embodiments, the pH of the mixture is adjusted to a pH between 7 and 8. In still some embodiments, a suitable pH is between 6.5 and 8.5. In still some embodiments, a suitable pH is between 6.75 and 8.25. In some other embodiments, a suitable pH is between 6.5 and 9.

For step iii) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and steps iii) in specific embodiments 2, 4, 6, 8, 10,11, 12, 14, 16, 18, 20, 22, 23, 24, 26, 28, 30, 32, 34, 36, 37 and 38 described above.

In some embodiments, hydrazine is used in salt form. In some embodiments, the salt is a hydrochloride salt.

A suitable amount of hydrazine of the formula R2-CH2-NH-NH2 or a salt thereof (eg HCl salt) is at least one equivalent of hydrazine for each equivalent of intermediate (4) or intermediate (4'). In some embodiments, the appropriate amount of hydrazine is between 1 equivalent and 2 equivalents. In other embodiments, it is between 1 and 1.5 equivalents. In some other embodiments, it is between 1 and 1.3 equivalents. In some other embodiments, it is between 1.1 and 1.4 equivalents. In still some embodiments, it is between 1.1 and 1.3 equivalents. In still some embodiments, it is 1.2 equivalents.

- 22 045335

An optional suitable base is, for example, potassium carbonate (K ₂ CO ₃ ). Other optionally suitable bases at this stage are, for example, sodium acetate (NaOAc), sodium carbonate (Na ₂ CO ₃ ), sodium hydrogen carbonate (NaHCO ₃ ) and potassium bicarbonate (KHCO 3 ).

A suitable amount of a suitable base is an amount that can partially or completely neutralize the acid from hydrazine hydrochloride when the hydrochloride form of hydrazine is used. For example, 0.5-1.1 equivalents of base for each equivalent of hydrazine hydrochloride. In other embodiments, a suitable amount is 0.5-0.9 equivalents. In some other embodiments, it is 0.65 equivalent. In still some embodiments, it is 0.6 equivalents. In still some embodiments, it is between 0.9 and 1.1 equivalents.

A suitable solvent is, for example, methanol, ethanol or isopropanol. Other solvents that can be used in this step are, for example, dichloromethane, THF, CH ₃ CN, DMSO, DMF, CHCl ₃ , dioxane and DMA. When an optional suitable base is used, the base should be dissolved or suspended in water before mixing it with hydrazine hydrochloride dissolved in a suitable protic or aprotic solvent. A mixture of hydrazine hydrochloride and an optional suitable base in a protic or aprotic solvent and water should then be mixed with a solution of intermediate (4) or (4') in a suitable protic or aprotic solvent. Therefore, the reaction in this case will be carried out in a mixture of a protic or aprotic solvent and water.

A suitable temperature is between 10 and 40°C. In other embodiments, a suitable temperature is between 15 and 30°C. In some embodiments, it is between 10 and 30°C. In other embodiments, it is between 15 and 30°C. In other embodiments, it is between 15 and 25°C. In some other embodiments, it is between 20 and 25°C.

For step iia) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and stage iia) in specific embodiments 3, 5, 7, 9, 10, 11, 12, 15, 17, 19, 21, 22, 23, 25, 27, 29, 31, 33, 35, 36, 37 and 38 described above.

A suitable amount of hydrazine (eg hydrazine hydrate) is at least one equivalent of hydrazine for each equivalent of intermediate (4) or intermediate (4'). In some embodiments, the suitable amount of hydrazine is between 1 equivalent and 5 equivalents. In other embodiments, it is between 1 equivalent and 2 equivalents. In other embodiments, it is between 1.5 and 1.8 equivalents. In some other embodiments, it is between 1.5 and 1.7 equivalents. In some other embodiments, it is between 1.55 and 1.65 equivalents. In still some embodiments, it is 1.6 equivalents.

In some embodiments, an optional suitable base is used in the reaction. An optional suitable base is, for example, potassium carbonate (K ₂ CO ₃ ). Other optionally suitable bases at this stage are, for example, sodium acetate (NaOAc), sodium carbonate (Na ₂ CO ₃ ), sodium hydrogen carbonate (NaHCO ₃ ) and potassium bicarbonate (KHCO ₃ ).

A suitable solvent is, for example, methanol, ethanol or isopropanol. Other protic or aprotic solvents that can be used in this step are, for example, dichloromethane, THF, dioxane, CH3CN, CHCl3, DMSO, DMF and DMA. In some embodiments, the reaction will be carried out in a mixture of a protic or aprotic solvent and water.

A suitable temperature is between 5 and 100°C. In other embodiments, a suitable temperature is between 10 and 80°C. In some embodiments, it is between 10 and 50°C. In other embodiments, it is between 15 and 30°C. In other embodiments, it is between 15 and 35°C. In some other embodiments, it is between 20 and 30°C. In still some embodiments, it is between 20 and 25°C.

For step iiib) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula III and stage iiib) in specific embodiments 3, 5, 7, 9, 10, 11, 12, 15, 17, 19, 21, 22, 23, 25, 27, 29, 31, 33, 35, 36, 37 and 38 described above.

A suitable amount of alkylating agent of formula (22) or (23A) is at least one equivalent of alkylating agent for each equivalent of intermediate (24) or intermediate (24'). In some embodiments, the suitable amount of alkylating agent is between 1 equivalent and 5 equivalents. In other embodiments, it is between 1 equivalent and 2 equivalents. In other embodiments, it is between 1 and 1.5 equivalents.

In some embodiments, the reaction is carried out in the presence of a suitable amount

- 23 045335 suitable base. A suitable base is, for example, an alkoxide (eg lithium t-butoxide (LTB), potassium t-butoxide (KTB), sodium t-butoxide (STB)), bis(trimethylsilyl)amine (HMDS), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), NaH or lithium diisopropylamide (LDA). A suitable amount of base is, for example, between 1 and 1.5 base equivalents.

A suitable solvent is, for example, ether, dioxane or THF. In some embodiments, the ether is dimethylethyl ether (DME). Other protic or aprotic solvents that can be used in this step are, for example, dichloromethane, CH ₃ CN, DMA, DMF, DMSO and CHCl ₃ . In some embodiments, the suitable solvent is selected from an ethereal solvent including an alkyl ether, dioxane, THF or DME. In other embodiments, it is selected from dichloromethane, CH3CN, DMA, DMSO and CHCl3.

A suitable temperature is between -10 and 50°C. In other embodiments, a suitable temperature is between -10 and 30°C. In some embodiments, it is between 0 and 30°C. In other embodiments, it is between 15 and 30°C. In other embodiments, it is between 15 and 25°C. In some other embodiments, it is between 20 and 25°C. In still some embodiments, it is between -10 and 0°C. In still some embodiments, it is between -10 and 5°C.

In some embodiments, for the alkylating agent of formula (22) or (23A), X is -F, -Cl, -Br, -II, mesylate (-OSO ₂ CH ₃ ), tosylate (-OSO ₂ PhCH ₃ ), or triflate (-OSO2CF3). In some embodiments, X is -Br.

For step a) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula III, and step a) to obtain the compound of formula (6) described in specific embodiments 10, 11, 12, 22, 23, 36, 37 and 38 described above.

A suitable methoxide salt is, for example, MeONa, MeOLi, MeOK, MeOCs or the like methoxides, and MeOH or a suitable aprotic solvent is used as the solvent. In other embodiments, a suitable base is, for example, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , KHCO ₃ or the like, and MeOH is used as the solvent. In one embodiment, the dibromopyrimidine compound of formula (5) is reacted with a methoxide salt (eg, MeONa) in methanol.

A suitable amount of suitable base is at least one equivalent of base for every equivalent of dibromopyrimidine (5). In other embodiments, it is between 0.9 and 1.2 equivalents. In other embodiments, it is between 1 and 1.1 equivalents. In other embodiments, it is 1.01 equivalents of base for each equivalent of dibromopyrimidine (5). In other embodiments, it is 1.02 equivalents of base for each equivalent of dibromopyrimidine (5).

A suitable aprotic solvent when MeOH is not a solvent is, for example, THF or a similar solvent.

A suitable temperature is between -25 and 15°C. In some embodiments, a suitable temperature is between -20 and 10°C. In other embodiments, it is between -15 and 5°C. In some other embodiments, it is between -15 and 0°C. In some other embodiments, it is between -20 and 5°C. In some other embodiments, it is between -15 and 5°C. In still some embodiments, it is between -15 and -5°C.

A suitable aprotic solvent in which the pyrimidine intermediate (6) is transferred to the next step is, for example, ether. In one embodiment, the ether is methyl tert-butyl ether. In other embodiments, a suitable aprotic solvent is, for example, CH ₂ Cl ₂ , EtOAc, THF, toluene, or a similar solvent.

For step b) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and step b) to obtain the compound of formula (7) described in specific embodiments 10, 11, 12, 22, 23, 36, 37 and 38 described above.

A suitable amount of ethynyltrimethylsilane is at least one equivalent of ethynyltrimethylsilane per equivalent of intermediate (6) formed in the previous step. In some embodiments, a suitable amount of ethynyltrimethylsilane is between 1.0 and 2.0. In other embodiments, it is between 1 and 1.8 equivalents. In other embodiments, it is between 1 and 1.6 equivalents. In still some embodiments, it is between 1 and 1.5 equivalents. In still some embodiments

- 24 045335 it is between 1 and 1.3 equivalents. In other embodiments, it is between

1.0 and 1.2 equivalents. In still some embodiments, it is 1.2 equivalents.

A suitable aprotic organic solvent is, for example, ether. In one embodiment, the ether is methyl tert-butyl ether. In other embodiments, a suitable aprotic solvent is, for example, EtOAc, THF, toluene, CH ₂ Cl ₂ or a similar solvent.

A suitable temperature is between 15 and 40°C. In one embodiment, a suitable temperature is between 15 and 35°C. In other embodiments, it is between 15 and 30°C. In other embodiments, it is between 18°C and 30°C. In some other embodiments, it is between 20 and 30°C. In still some embodiments, a suitable temperature is 25°C.

A suitable base is, for example, triethylamine, Hunig's base, Et ₂ NH, iPr ₂ NH, piperidine, pyrrolidine, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , K ₃ PO ₄ or the like.

A suitable amount of suitable base is at least 1 equivalent of suitable base for each equivalent of pyrimidine intermediate (6). In some embodiments, it is between 1 and 10 equivalents. In other embodiments, it is between 1 and 5 equivalents. In other embodiments, it is between 1 and 3 equivalents. In still some embodiments, it is between 1.5 and 2.5 equivalents. In some other embodiments, it is 2 equivalents. In still some embodiments, a suitable amount of a suitable base may be in large excess, for example, the base may be used as a solvent in the reaction.

Suitable optional Cu(I) salt is, for example, CuCl, CuBr, CuI or CuOTf. In some embodiments, the reaction can be carried out without a copper catalyst (copper-free conditions).

A suitable amount of Cu(I) salt is a catalytic amount. The catalytic amount may be any amount below 1 equivalent of Cu(I) salt for each equivalent of pyrimidine intermediate (6). In some embodiments, the catalytic amount is an amount greater than 0 and less than 1 equivalent. In other embodiments, the catalytic amount is an amount greater than 0 and less than 0.75 equivalent. In other embodiments, it is between 0 and 0.5 equivalents, or between 0 and 0.25 equivalents, or between 0 and 0.1 equivalents, or between 0 and 0.01 equivalents. In some other embodiments, the catalytic amount of Cu(I) salt is an amount of, for example, between 0.0025 and 0.006 equivalents of Cu(I) salt for each equivalent of pyrimidine intermediate (6). In some embodiments, the catalytic amount of Cu(I) salt is between 0.003 and 0.006 equivalents. In other embodiments, it is between 0.004 and 0.006 equivalents. In other embodiments, it is 0.005 equivalent.

A suitable Pd catalyst is, for example, PdCl ₂ (PPh ₃ ) ₂ . Other suitable Pd catalysts include Pd(OAc) ₂ , Pd(PPh ₃ ) ₄ , PdCl ₂ (dppf), Pd(dppe)Cl and Pd(dppp)Cl ₂ .

A suitable amount of a suitable Pd catalyst is a catalytic amount. The catalytic amount of Pd catalyst is an amount of, for example, between 0 and 0.2 equivalents of Pd for each equivalent of intermediate (6). In some embodiments, the catalytic amount is between 0 and 0.1 equivalents. In some other embodiments, it is between 0 and 0.01 equivalents. In some other embodiments, it is between 0.0010 and 0.0040 equivalents of Pd for each equivalent of pyrimidine intermediate (6). In another embodiment, the catalytic amount is between 0.0015 and 0.0030 equivalents. In other embodiments, it is between 0.0020 and 0.0030 equivalents. In some other embodiments, it is 0.0025 equivalent.

A suitable solvent in which the pyrimidine intermediate (7) is transferred to the next step is, for example, ether. In one embodiment, the ether is methyl tert-butyl ether. In other embodiments, a suitable solvent is, for example, Hunig's base, Et ₂ NH, iPr ₂ NH, piperidine, pyrrolidine, THF, toluene, CH ₂ Cl ₂ , CH3CN, DMF, DMSO or similar solvents.

In one embodiment, pyrimidine intermediate (6) is reacted with ethynyltrimethylsilane in methyl tert-butyl ether in the presence of trimethylamine, Pd(PPh3)2Cl2 catalyst and CuI.

For step c) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula III and step c) to obtain the compound of formula (2) described in specific embodiments 10, 11, 12, 22, 23, 36, 37 and 38 described above.

Desilylation can be accomplished using a suitable fluoride reagent, a suitable acid or a suitable base.

A suitable fluoride reagent is, for example, KF, TBAF, CsF or NaF, among others. In some embodiments, a suitable fluoride reagent is KF.

Suitable acid is, for example, HCl, HBr, MeSO ₃ H, HF or aqueous solutions of similar acids.

A suitable base is, _for example, MeONa, MeOK, MeOCs, _K2CO3 , _Na2CO3 , _Cs2CO3 or the like.

Desilylation reactions are widely known and many conditions can be found in the literature for carrying out the reaction. Therefore, many other fluoride reagents, acids and bases can be used.

A suitable amount of a suitable fluoride reactant, a suitable acid or a suitable base is the catalytic amount. The catalytic amount of a suitable fluoride reagent, a suitable acid or a suitable base is, for example, less than one equivalent of a suitable fluoride reagent, a suitable acid or a suitable base for each equivalent of intermediate (7). In one embodiment, the catalytic amount is between 0.01 and 1 equivalent. In other embodiments, it is between 0.01 and 0.75. In other embodiments, it is between 0.01 and 0.5. In other embodiments, it is between 0.01 and 0.25. In some other embodiments, it is between 0.01 and 0.1. In some other embodiments, it is between 0.01 and 0.05. In another embodiment, it is between 0.015 and 0.03. In some other embodiments, it is between 0.015 and 0.025. In other embodiments, it is 0.02 equivalent.

A suitable solvent is, for example, MeOH, THF, CH ₃ CN, EtOAc, CH ₂ Cl ₂ , CHCl ₃ or many others, depending on the fluoride reagent, acid or base used. In one embodiment, a suitable solvent is MeOH.

A suitable temperature is between 15 and 35°C. In one embodiment, a suitable temperature is between 15 and 30°C. In other embodiments, it is between 18 and 30°C.

For step d) any of the methods described above for the synthesis of a compound of formula II, a compound of formula III, a compound of formula IV, a compound of formula V, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and reaction step to produce the compound of formula (1) described in specific embodiments 11, 12, 23, 37 and 38.

A suitable oxalyl chloride equivalent reagent is, for example, thionyl chloride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC).

A suitable amount of oxalyl chloride or equivalent reagent is at least one equivalent of oxalyl chloride per equivalent of carboxylic acid (8) or (8'). In some embodiments, a suitable amount is between 1 and 3 equivalents. In other embodiments, a suitable amount is between 1 and 2 equivalents. In some other embodiments, a suitable amount is between 1 and 1.5 equivalents. In still some embodiments, a suitable amount is between 1.1 and 1.3 equivalents. In still some embodiments, a suitable amount is 1.1 equivalents or 1.2 equivalents.

A suitable aprotic organic solvent is, for example, toluene. Other suitable solvents are, for example, methylene chloride or tetrahydrofuran.

A suitable catalyst is DMF.

A suitable amount of a suitable catalyst is a catalytic amount, i.e. less than one equivalent of catalyst for each equivalent of starting material (8) or starting material (8'). In some embodiments, a suitable amount is between 0.01 and 0.09 equivalents. In other embodiments, it is between 0.01 and 0.07 equivalents. In some other embodiments, it is between 0.02 and 0.07 equivalents. In still some embodiments, it is between 0.04 and 0.06 equivalents. In still some embodiments, it is 0.05 equivalent.

A suitable temperature for the reaction of the starting material (8) or starting material (8') with oxalyl chloride or thionyl chloride is a temperature between 40 and 95°C. In some embodiments, it is between 40 and 80°C. In other embodiments, it is between 40 and 55°C. In some embodiments, a suitable temperature is between 45 and 55°C.

In other embodiments, the temperature is between 45 and 50°C. In other embodiments, the temperature is between 50 and 60°C.

A suitable temperature for reacting the starting material (8) or starting material (8') with EDAC is between -10 and 25°C. In some embodiments, a suitable temperature is between -10 and 20°C. In some embodiments, a suitable temperature is between -10 and 0°C. In some embodiments, a suitable temperature is between -10 and -5°C.

In some embodiments, N,O-dimethylhydroxylamine is used as the HCl or hydrochloride salt.

A suitable amount of N,O-dimethylhydroxylamine hydrochloride is at least one equivalent of N,O-dimethylhydroxylamine hydrochloride for each equivalent of starting material (8) or starting material (8'). In other embodiments, a suitable amount of N-O-dimethylhydroxylamine hydrochloride is between 1 equivalent and 2 equivalents for each equivalent of starting material (8) or starting material (8'). In other embodiments, it is between 1 and 1.5 equivalents. In other embodiments, it is between 1 and 1.2 equivalents. In other embodiments, it is between 1.1 and 1.2 equivalents.

A suitable base is, for example, K ₂ CO ₃ or NaOH. Other suitable bases are, for example, NaHCO ₃ , KHCO ₃ , Et ₃ N or Hunig's base.

A suitable excess of said suitable base is at least 2 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride used. In some embodiments, a suitable amount is between 2 and 5 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride. In other embodiments, it is 2-3 equivalents. In some other embodiments, it is between 2 and 4 equivalents.

A suitable solvent for the water/aprotic solvent mixture is, for example, dichloromethane (DCM). Other suitable solvents are, for example, ethyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran.

For step iv) of the synthesis of a compound of formula III, a compound of formula IV, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula IB, a compound of formula IC or a compound of formula ID and step iv) in specific embodiments 4-12 and 16- 38 described above.

The reaction can be carried out under suitable acidic, alkaline or neutral conditions.

A suitable aqueous acid solution is, for example, an HCl solution. Other acids that can be used include, for example, methylsulfonic acid (MeSO ₃ H) or HBr.

A suitable reagent that can be used under alkaline conditions is, for example, MeSNa.

A suitable reagent that can be used under neutral and anhydrous conditions is, for example, BBr3.

Demethylation reactions such as step iv) are typical reactions, and many different conditions can be found in the literature.

A suitable amount of acid is between 3 and 6 equivalents of acid per equivalent of a compound of Formula II or a compound of Formula V. In some embodiments, a suitable amount is between 4 and 6 equivalents. In other embodiments, it is between 4.5 and 6 equivalents. In some other embodiments, it is between 4.90 and 5 equivalents. HCl can be provided, for example, in the form of concentrated HCl (eg, 37 wt.% HCl).

A suitable protic solvent is, for example, MeOH. Other suitable protic solvents are EtOH and iPrOH.

A suitable aprotic solvent is, for example, ether or THF.

A suitable temperature is between 50 and 70°C. In some embodiments, a suitable temperature is between 55 and 65°C. In some other embodiments, a suitable temperature is between 60 and 65°C. In some other embodiments, a suitable temperature is between 62 and 65°C.

For step v) of the synthesis of a compound of formula III, a compound of formula IV, a compound of formula VI, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and step v) in specific embodiments 6-12 and 18- 38 described above.

A suitable amount of POCl ₃ is at least two equivalents of POCl ₃ for each equivalent of intermediate (9) or intermediate (9') used. In some embodiments, a suitable amount of POCl ₃ is at least 4 equivalents. In some embodiments, a suitable amount is at least 3 equivalents. In some embodiments, a suitable amount is at least 2 equivalents. In some embodiments, a suitable amount is at least 1 equivalent. In some other embodiments, a suitable amount is between 1 and 4 equivalents of POCl3 for each equivalent of intermediate (9) or intermediate (9').

A suitable temperature is between 50 and 90°C. In some embodiments, a suitable temperature is between 60 and 90°C. In some embodiments, a suitable

- 27 045335 temperature is between 65 and 90°C. In other embodiments, a suitable temperature is between 70 and 90°C. In some other embodiments, a suitable temperature is between 75 and 90°C. In still some embodiments, a suitable temperature is between 75 and 85°C. In other embodiments, a suitable temperature is between and 80°C.

A suitable aprotic organic solvent is, for example, acetonitrile (CNMe). The reaction can also be carried out in pure POCl ₃ , in the absence of any solvents.

A suitable optional base is, for example, N,N-dimethylaniline. The reaction can also be carried out in the absence of a base.

A suitable amount of suitable base, when used, is between 0.2 and 2 equivalents of base for each equivalent of intermediate (9) or intermediate (9') used. In some embodiments, a suitable amount of base is between 1.3 and 1.6 equivalents. In some embodiments, a suitable amount of base is between 1.2 and 1.8 equivalents. In other embodiments, it is 1 equivalent.

For step vi) of the synthesis of a compound of formula IV, a compound of formula VII, a compound of formula IA, a compound of formula III, a compound of formula IC or a compound of formula ID and step vi) in specific embodiments 8-12 and 20-38 described above.

Suitable amount of amine (10), or amine (13), or amine salt with malic acid (14), or amine salt with malic acid (18), or amine (15A), or its corresponding HCl salt (15), or amine (19A), or its corresponding HCl salt (19) is at least one equivalent of an amine or HCl salt or malic acid for each equivalent of a compound of formula VI or a compound of formula III. In some embodiments, an excess amount of amine may be used. In some embodiments, an amount of between 1 and 5 amine equivalents may be used. In other embodiments, a suitable amount is between 1 and 4 equivalents. In other embodiments, it is between 1 and 3 equivalents. In some other embodiments, it is between 1 and 2 equivalents. In still some embodiments, it is between 1.1 and 1.5 equivalents. In still some embodiments, it is 1.1-1.3 equivalents.

A suitable optional base is, for example, a Hunig base. Other suitable optional bases are, for example, Et ₃ N, NaHCO ₃ and KHCO3. A suitable amount of amine (10) or amine (13) or amine (15A) or amine (19A) itself can also be used as a base when the amine is used in excess.

A suitable amount of a suitable optional base is at least one equivalent of an optional base for each equivalent of a Formula VI intermediate or a Formula III intermediate. In some embodiments, a suitable amount is 2 equivalents.

A suitable solvent is dimethyl sulfoxide (DMSO). Other suitable solvents are, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) and tert-butanol (t-BuOH).

A suitable temperature is between 90 and 135°C. In some embodiments, a suitable temperature is between 120 and 130°C. In other embodiments, a suitable temperature is between 125 and 130°C. In other embodiments, a suitable temperature is between 90 and 105°C. In some other embodiments, it is between 95 and 104°C.

New intermediates are also disclosed that are useful in the methods described in the present invention.

In one embodiment, the present invention is directed to a compound of formula (3) or (4). In one embodiment, for a compound of formula (3) or (4), R ¹ is a 5-membered heteroaryl ring. In another embodiment, for a compound of formula (3) or (4), R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O.

In yet another embodiment, the present invention is directed to a compound of formula (3') or (4').

In yet another embodiment, the present invention is directed to a compound of formula (14), (18), (15), (19), (20) or (21).

In one aspect, the present invention provides crystalline Form A of the compound of formula IA. Form A can be prepared in accordance with the method described in the present invention, for example the method of specific embodiment 13, the first, second, third, fourth, fifth or sixth method for preparing the compound of formula IA described above.

Form A is characterized by an X-ray powder diffraction (XRPD) pattern. In one embodiment, Form A of a compound of Formula IA has an X-ray powder diffraction pattern, according to

- 28 045335 essentially similar to the one shown in FIG. 1. In one embodiment, Form A has the X-ray powder diffraction pattern shown in FIG. 1. In another embodiment, Form A has the XRPD peaks shown in the table below.

Corner d-value and intensity relative intensity 4.218° 20.92949 A 1531 34.8% 9.082° 9.72888 A 2846 64.7% 9.787° 9.02964 A 3669 83.4% 10.885° 8.12181 A 14.8 0.3% 12.198° 7.24980 A 65.7 1.5% 13.758° 6.43115 A 288 6.5% 15.443° 5.73323 A 379 8.6% 16.880° 5.24808 A 568 12.9% 17.222° 5.14486 A 750 17.0% 17.743° 4.99495 A 4401 100.0% 18.213° 4.86700 A 1862 42.3% 18.923° 4.68599 A 277 6.3% 19.646° 4.51517 A 282 6.4% 20.726° 4.28219 A 34.1 0.8% 20.969° 4.23314 A 16.4 0.4% 21.816° 4.07062 A 54.8 1.2% 23.126° 3.84299 A 106 2.4% 24.585° 3.61801 A 185 4.2% 25.495° 3.49102 A 114 2.6% 26.106° 3.41067 A 99.3 2.3% 27.050° 3.29372 A 112 2.5% 27.499° 3.24097 A 734 16.7% 28.082° 3.17498 A 233 5.3% 28.827° 3.09457 A 85.8 2.0% 29.767° 2.99895 A 243 5.5% 30.683° 2.91146 A 55.1 1.3% 31.156° 2.86841 A 113 2.6% 31.871° 2.80565 A 60.0 1.4% 32.981° 2.71369 A 138 3.1% 35.312° 2.53969 A 44.2 1.0% 36.005° 2.49240 A 1225 27.8% 39.044° 2.30515 A 270 6.1%

In yet another embodiment, Form A is characterized by having one, two, three, four, five, six, seven, or eight major peaks in the X-ray powder diffraction pattern selected from 4.2, 9.1, 9.8, 17. 2, 17.7, 18.2, 27.5 and 36.0° angle 2θ. In one embodiment, Form A is characterized as having one, two, three, four or five major XRPD peaks selected from 4.2, 9.1, 9.8, 17.7, 18.2 and 36.0° angle 2θ. In another embodiment, Form A has major XRPD peaks at 9.1, 9.8, 17.7 and 18.2° 2θ. In yet another embodiment, Form A has major XRPD peaks at 4.2, 9.1, 9.8, 17.7, 18.2 and 36.0° 2θ. In another embodiment, Form A has major XRPD peaks at 4.2, 9.1, 9.8, 17.2, 17.7, 18.2, 27.5 and 36.0° 2θ. It should be understood that the specified angle of 2Θ means the specified value of ±0.1°.

In the context of the present invention, the term major peaks refers to an XRPD peak with a relative intensity greater than 10%. Relative intensity is calculated as the ratio of the intensity of the peak of interest to the intensity of the largest peak.

Form A can also be characterized by differential scanning calorimetry (DSC). In one embodiment, Form A has an endothermic onset (i.e., melting point) at a temperature between 140 and 180°C, between 155 and 170°C, between 160 and 170°C, between 160 and 165°C, between 162 and 164°C or between 162.5 and 163.5°C. In one embodiment, the onset of the endothermic transition occurs at 163.1°C. It should be understood that the temperature indicated means the indicated value is ±0.5°C.

In some embodiments, Form A has a purity of at least 70, 80, 90, 95, 98,

- 29 045335

99, 99.5 or 99.9%. The purity of Form A is determined by dividing the weight of Form A of the compound of Formula IA in the composition comprising the compound of Formula IA by the total weight of the compound of Formula IA in the composition.

In some embodiments, the composition of a compound of Formula IA contains at least 70, 80, 90, 95, 98, 99, 99.5, or 99.9% by weight of a compound that is crystalline Form A of the compound.

The terminology used in the present invention is intended to describe specific embodiments only and is not intended to limit the invention. As used herein, the singular forms are intended to also include plural forms unless the context clearly indicates otherwise. It should also be clear that the terms include (and any form of include, such as includes and including), have (and any form of have, such as has and having), include (and any form of include, such as includes in itself and including), contain (and any form of contain, such as contains and containing) and any other grammatical variations are non-restrictive verbs. As a result, a method that includes, has includes, or contains one or more steps has such one or more steps, but is not limited to having only those one or more steps. Likewise, a method step that includes, has includes, or contains one or more features has those one or more features, but is not limited to having only those one or more features.

All publications cited herein are incorporated herein by reference as if each individual publication were specifically and individually designated for inclusion herein by reference as if set forth in their entirety.

When one or more ranges are specified herein, each range is intended to be a shortened format for presenting information, where a range is meant to cover each discrete point within the range as if those points were fully described herein.

Examples

The following production examples are presented in order to better understand the present invention. These examples are presented for purposes of illustration only and should not be construed as limiting in any way the scope of the invention.

Methods of control during the technological process.

HPLC analysis, method A (TFA-modified mobile phase).

Equipment.

A. HPLC analyzes were performed using an Agilent 1100/1200 series HPLC system consisting of a pump, ChemStation UV VWD or DAD detector, autosampler, and column heater or equivalent. ChemStation software installed on GX270 or equivalent. The column was a HALO C18 150x4.6 mm.

B. Column: HALO C18 150x4.6mm 2.7 micron or equivalent.

C. Autodispenser bottles, silicone/teflon gaskets, 12x32mm.

D. 100 mL Class A volumetric flasks.

E. Measuring funnels.

F. Spatulas.

G. Disposable glass Pasteur pipettes.

H. A scale capable of accurately weighing 0.01 mg.

I. 2x2 liter solvent reservoir.

Reagents.

A. HPLC grade water or equivalent.

B. HPLC grade Acetonitrile (ACN) or equivalent.

C. HPLC grade trifluoroacetic acid (TFA) or equivalent.

D. Test sample of the intermediate.

E. Authentic intermediates or reference standard, if available.

Solvent and thinner.

A. Solvent A: 0.1% TFA in water (i.e. 1 ml in 1 liter of water).

B. Solvent B: 0.1% TFA in acetonitrile (i.e. 1 ml in 1 L ACN).

C. Diluent: acetonitrile/water.

Flow rate: 1.0 ml/min.

Column temperature: 40°C.

Time table

Time (minutes) % Solvent A % Solvent B 0 85 15

- 30 045335

10 5 95 15 5 95

Retention time of selected compounds

Compound Approximate retention time (min) (8') 1.8 Piper idynamide 4.9 (G) h,o (5) 7.0 (6) 6.5 (7) 9.5 (2) 5.4 Formula V 8.7 (9') 6.9 Formula VI 9.3 Formula IA 8.8 Formula ID 6.9

HPLC analysis, method B (neutral mobile phase).

Equipment.

A. HPLC analyzes were performed using an Agilent 1100/1200 series HPLC system consisting of a pump, ChemStation UV VWD or DAD detector, autosampler, and column heater or equivalent. ChemStation software installed on GX270 or equivalent. The column was a HALO C18 150x4.6 mm.

B. Column: HALO C18 150x4.6mm 2.7 micron or equivalent.

C. Autodispenser bottles, silicone/teflon gaskets, 12x32mm.

D. 100 mL Class A volumetric flasks.

E. Measuring funnels.

F. Spatulas.

G. Disposable glass Pasteur pipettes.

H. A scale capable of accurately weighing 0.01 mg.

I. 2x2L solvent tank

Reagents.

A. HPLC grade water or equivalent.

B. HPLC grade Acetonitrile (ACN) or equivalent.

C. Test sample of the intermediate.

D. Authentic intermediates or reference standard, if available.

Solvent and thinner.

A. Solvent A: water.

B. Solvent B: acetonitrile

C. Diluent: acetonitrile/water.

Flow rate: 1.0 ml/min.

Column temperature: 40°C.

Time table

Time (minutes) % Solvent A % Solvent B 0 85 15 10 5 95 15 5 95

- 31 045335

Nuclear magnetic resonance spectroscopy.

1H NMR spectra of all compounds were recorded on a BRUKER NMR spectrometer operating at 500 MHz at room temperature. Samples dissolved in CDCl ₃ were referenced to the residual solvent peak at 7.27 ppm. Samples dissolved in DMSO-d ₆ were referenced to the residual solvent peak at 2.50 ppm. The resulting FIDs were transferred to a PC and processed using the ACD/Labs NMR data processing program.

X-ray structural analysis (XRPD).

X-ray powder diffraction patterns were obtained using a D8 Advance, Bruker using one of two methods:

scan 5-45° 2-theta, step size 0.02°, 1 s per step; or 3-40° scan 2-theta, 0.037° step size, 1.5 sec per step

Example 1. Preparation of compounds of formula VI.

Step d: coupling compound (8') and N,O-dimethylhydroxylamine to give N-methoxy-Nmethylisoxazole-3-carboxamide (1').

c ₄ h ₃ no ₃ c ₆ h ₈ n ₂ o ₃ mol. mass: 113.07 ^{mol mass} : 156.14 (8') (G)

Isooxazole-3-carboxylic acid ((8'), 92 wt.%, by ¹ H-NMR, 3.86 kg, 34.1 mol, 1.0 eq.), toluene (19.3 L) and DMF (0.131 L, 1.69 mol, 0.05 eq.) was mixed in a 30 L jacketed reaction vessel equipped with a nitrogen inlet/outlet, a top drive stirrer, a thermocouple and a dropping funnel. The resulting suspension was heated to 45-55°C. Oxalyl chloride (4.80 kg, 37.8 mol, 1.11 eq.) was charged through the addition funnel over 4 hours 30 minutes while maintaining the reaction temperature between 45-55°C. Strong gas evolution was observed. After addition, a brown mixture was obtained. The brown mixture was kept at 45-55°C for 30 minutes, then heated to 85-95°C and stirred at 85-95°C for 1 hour. During the heating process, the brown mixture turned into a black mixture. The black mixture was cooled to 20-25°C over 4 hours and kept at 20-25°C for a minimum of 16 hours. The reaction was monitored by quenching a portion of the reaction mixture in piperidine and monitoring the formation of piperidinamide using HPLC ((8'):piperidinamide area:area%<1.9). Once the reaction was complete by HPLC, the dark mixture was filtered through an in-line gas dispersion tube (large frit) into a 20-L rotary evaporator flask. Toluene (3.9 L) was used to wash the reactor and the wash solution was filtered through an inline filter into a 20 L rotary evaporator flask. The filtered reaction mixture was concentrated under reduced pressure until separation of distillate was no longer observed.

Separately, potassium carbonate (7.06 kg, 51.1 mol, 1.5 eq.) and water (31 L) were mixed in a 100 L jacketed reactor. The reaction solution was cooled to -10-10°C. The reactor was charged with X,O-dimethylhydroxylamine hydrochloride (3.93 kg, 40.3 mol, 1.18 eq.), then dichloromethane (39 L). The reaction mixture was cooled to -10-0°C. The acyl chloride intermediate formed as described above (4.4 kg) was charged into a 100 liter jacketed reactor containing X,O-dimethylhydroxylamine in dichloromethane with stirring speed set at 210 rpm while maintaining the reaction temperature between -10-0°C, for 30 minutes. The addition was slightly exothermic and a brown mixture was obtained upon addition. The reaction mixture was stirred at -10-0°C for 20 minutes, then heated to 15-25°C and stirred for 10 minutes at this temperature. The layers were separated. The lower organic layer was collected and the upper aqueous layer was extracted with dichloromethane (7.7 L). The combined organic layers were transferred to a 100 L jacketed reactor and washed with 15 wt% aqueous sodium chloride solution (11.6 L). The layers were separated. The lower organic layer was collected and the upper aqueous layer was extracted with dichloromethane (3.9 L). The combined organic layers were concentrated under reduced pressure until no more distillate separated. Tetrahydrofuran (7.7 L) was added to this dark oil and the resulting mixture was concentrated under reduced pressure to give intermediate

- 32 045335 compound (1') in the form of a dark oil (4.6 kg, yield 83% corrected for THF, THF content 4 wt.%, according to ¹ H-NMR, water content 0.01 wt.%, determined according to the Karl Fischer (KF) method, purity according to HPLC 98.9%).

1H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.48 (s, 1H); 6.71(s, 1H); 3.78 (s, 3H); 3.38 (s, 3H).

Step a: replacement of compound (5) with methoxide to obtain 2-bromo-5-fluoro-4methoxypyrimidine (6).

O-

MeONa N-/

---------- Br—c y ^- F MeOH N=/

C ₅ H ₄ BrFN ₂ O mol.wt: 207 _f 00 (6)

2,4-Dibromo-5-fluoropyrimidine ((5), 6.42 kg, 25.1 mol, 1.0 eq.) and methanol (35.3 L) were mixed in a 30 L jacketed reaction vessel equipped with an opening for nitrogen input/output, top drive stirrer, thermocouple and dropping funnel. The reaction solution was cooled to -15-(-5)°C and a suspension was obtained. Sodium methoxide, 5.4 M solution in methanol (4.75 L, 25.7 mol, 1.02 eq.), was charged over 3 hours through a dropping funnel while maintaining the reaction temperature at -15-(-5) °C. After addition, the mixture was stirred at -15-(-5)°C for 30 minutes. According to HPLC method A, the reaction was complete ((5):(6) area:area %=not determined). 2 N HCl (0.26 L, 0.52 mol, 0.02 eq.) was charged over 2 minutes while maintaining the temperature at -15-(-5)°C. Then water (12.8 L) was charged for 2 minutes, while maintaining the temperature at -15-25°C. The pH of the reaction mixture was ~3-4, determined using indicator paper. The reaction mixture was concentrated under reduced pressure until most of the methanol was distilled off.

Methyl tert-butyl ether (51.4 L) was added to the concentrated reaction mixture and the layers were allowed to separate for 1 hour. The organic layer was filtered through a gas dispersion tube (coarse frit) and concentrated under reduced pressure to a volume of 19.3 L. Water was removed by azeotropic distillation under reduced pressure by continuously feeding methyl tert-butyl ether (24.0 L). The final volume was 18.0 L, and azeotropic water removal was completed according to Karl Fischer analysis (water content 0.24 wt.%, acceptance criteria: water content <0.4 wt.%). Intermediate (6) in methyl tert-butyl ether was obtained as a light brown solution and used directly in the next step.

1H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.08 (s, 1H); 4.04 (s, 3H).

Step b: coupling compound (6) and ethynyltrimethylsilane to give 5-fluoro-4-methoxy-2((trimethylsilyl)ethynyl)pyrimidine (7).

The resulting solution of intermediate (6) in methyl t-butyl ether (18.0 L, 25.1 mol, 1.0 eq.) was charged to a 100 L jacketed reaction vessel and methyl t-butyl ether (16.0 L) was added. to bring the volume to 34.0 l. Triethylamine (5.1 kg, 50.4 mol, 2.0 eq.) was then charged into a 100 L jacketed reaction vessel. The reaction mixture was deoxygenated through 4-5 vacuum/nitrogen cycles at 15-30°C (400 mbar for 5 min followed by nitrogen filling). The reaction mixture was charged with copper iodide (24.0 g, 0.126 mol, 0.005 eq.) and bis(triphenylphosphine) palladium(II) dichloride (44.2 g, 0.063 mol, 0.0025 eq.). The reaction mixture was deoxygenated by 2-3 vacuum/nitrogen cycles at 15-30°C (400 mbar for 5 min followed by nitrogen filling). Ethynyltrimethylsilane (3.0 kg, 30.5 mol, 1.2 eq.) was charged through the addition funnel over 2.5 h while maintaining the reaction temperature between 18-30°C. The reaction mixture was stirred at 20-30°C for 16 hours and a suspension was obtained. According to HPLC method A, the reaction was complete ((6):(7) area:area %=not determined).

The reaction mixture was cooled to 5-15°C. 2 N HCl (16.0 L, 32.0 mol, 1.3 eq.) was then charged over 4 min while maintaining the reaction temperature below 25°C (batch temperature increased from 6 to 22°C). The layers were allowed to separate for 20 minutes. The pH of the aqueous layer, determined using indicator paper, was ~1-2, and the layer was drained. SiliaMetS dimercaptotriazine (411 g, 0.21 mol, 0.008 eq.) was loaded into the reaction mixture. The reaction mixture was heated to 45-55°C and kept for 2 hours at 45-55°C, then cooled to 20-25°C. The reaction mixture was filtered through Hyflo SuperCel (0.66 kg)

- 33 045335 and methyl tert-butyl ether (12.9 L) was used to wash a 100 L jacketed reaction vessel and the wash solution was transferred to a cake wash filter. The filtrate was concentrated under reduced pressure to a volume of 19.2 L. The solvent was exchanged from methyl tert-butyl ether to methanol under reduced pressure by continuously feeding methanol (25.6 L), and the final volume after solvent exchange was 19.2 L. Intermediate (7) in methanol was obtained as a light brown solution and used directly in the next step.

¹ H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.09 (s, 1H); 3.94 (s, 3H); 0.12 (s, 9H).

Step c: desilylation of compound (7) to obtain 2-ethynyl-5-fluoro-4-methoxypyrimidine (2).

The resulting solution of intermediate (7) in methanol (19.2 L, 25.1 mol, 1.0 eq.) was charged into a 100 L jacketed reaction vessel and methanol (9.0 L) was added to bring the volume to 28. 2 l. Potassium fluoride (29.5 g, 0.508 mol, 0.02 eq.) was charged into the reaction mixture. The reaction mixture was stirred at 18-30°C for 1 hour, after which the reaction was complete according to HPLC method A ((7):(2) area/area %=not determined). Then water (22.5 L) was charged into the reaction mixture over 10 minutes, while maintaining the temperature at 15-30°C. The reaction mixture was concentrated under reduced pressure until most of the methanol was distilled off to obtain a suspension in water.

Methyl tert-butyl ether (32.1 L) was added to the suspension and the layers were allowed to separate for 30 minutes. The upper organic layer was collected and the lower aqueous layer was extracted with methyl t-butyl ether (12.8 L). The combined organic layers were concentrated under reduced pressure to a volume of 19.3 L. The concentrate was filtered through a pad of silica (960 g) and the silica layer was washed with additional methyl t-butyl ether (12.8 L). The filtrate was collected and concentrated under reduced pressure to a volume of 19.3 L. The solvent was exchanged from methyl tert-butyl ether to heptane under reduced pressure by continuously feeding heptane (33.4 L). The final volume after solvent exchange was 22.5 L. The resulting suspension was cooled to 0-5°C for 30 minutes and kept at 0-5°C for 1 hour. The suspension was filtered and the filter cake was washed with heptane (6.4 L). The wet cake was dried under vacuum at 20-25°C for 4 hours to constant weight to give intermediate (2) as a light brown solid (3.33 kg, 88% yield from (5) for 3 steps).

¹ H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.28 (d, J=2.44 Hz, 1 N,); 4.11 (s, 3H); 3.06 (s, 1H).

Steps i and ii: coupling compounds (2) and (1') to obtain (E)-3-(5-fluoro-4-methoxypyrimidin-2yl)-1 -(isoxazol-3 -yl)-3 -(methoxy( methyl)amino)prop-2-en-1-one (4').

Compound (2) (1.826 kg, 12.0 mol, 1.0 eq.) and anhydrous THF (11.0 L) were mixed in a 50-L round bottom flask equipped with a mechanical stirrer and thermocouple. The reaction solution was cooled to -78-(-60)°C. Load n-butyllithium, 2.5 M solution in hexane (4.8 L, 12.0 mol, 1.0 eq.), over 1 hour 30 minutes through the cannula, while maintaining the reaction temperature at -78-(- 60)°C and a brown suspension was obtained. After addition, the suspension was stirred at a temperature below -60°C for 30 minutes. Compound (1') (2.06 kg, 95 wt%, 12.6 mol, 1.05 eq.) was then charged over 40 min while maintaining the reaction temperature below -55°C (batch temperature increased from - 73 to -60°С). The reaction mixture was stirred at -65-(-55)°C for 1 hour and then heated to -50-(-45)°C and kept at -50-(-45)°C for 30 minutes to obtain a dark solution.

Separately, N-O-Dimethylhydroxylamine hydrochloride (0.586 kg, 6.0 mol, 0.5 eq.) and 1 N HCl (9.6 L, 9.6 mol, 0.8 eq.) were mixed in a 100 liter jacketed a reaction vessel equipped with a nitrogen inlet/outlet, a top-drive stirrer and a thermocouple. The reaction solution was cooled to 0-5°C. The resulting dark reaction solution from a 50 L round bottom flask

- 34 045335 was transferred into a 100 liter jacketed reaction vessel for 15 minutes with vigorous stirring. Ethyl acetate (18.3 L) was used to wash a 50 L round bottom flask and the wash solution was transferred to a 100 L jacketed reaction vessel. A 100 L jacketed reaction vessel was charged with saturated sodium bicarbonate solution (9.2 L) to adjust the pH of the batch to ~7-8. After stirring for 2 hours at 15-25°C, the reaction was completed by HPLC method B ((3'):(4') area:area %=not determined). The upper ethyl acetate layer was collected and washed with 10 wt.% sodium chloride solution (11.0 L). The organic layer was filtered through a gas dispersion tube (coarse frit) and concentrated under reduced pressure to a volume of 9.1 L. Ethyl acetate was removed by azeotropic distillation under reduced pressure by continuously feeding methanol (18.3 L). The final volume after solvent exchange was 9.1 L and a suspension was obtained. The resulting suspension was cooled to 0-5°C and stirred at 0-5°C for 30 minutes. The resulting suspension was filtered and the filter cake was washed with pre-cooled 0-5°C methanol (2.7 L). The filter cake was dried under high vacuum at 35-45°C for 8 hours to constant weight to give (4') as a light brown solid (2.73 kg, 74% yield, 99% purity by HPLC) .

¹ H-NMR (500 MHz, CD3OD) δ ppm 8.68 (d, J=1.53 Hz, 1H); 8.50 (d, J=3.05 Hz, 1H); 6.61 (d, J=1.68 Hz, 1H); 6.44 (s, 1H); 4.08 (s, 3H); 3.82 (s, 3H); 3.14 (s, 3H).

Step iii: cyclization of compound (4') and 2-fluorobeuylhydrazine to give 3-(3-(5-fluoro-4methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole ( formula V).

2-Fluorobenzylhydrazine hydrochloride (3.37 kg, 19.1 mol, 1.2 eq.) and methanol (9.8 L) were mixed in a 50-L round bottom flask equipped with an overhead stirrer and thermocouple. The reaction mixture was stirred at 10-25°C until most of the solids had dissolved. Separately, potassium carbonate (1.32 kg, 9.6 mol, 0.6 eq.) was charged into a suitable reaction vessel and dissolved in water (3.4 L). The potassium carbonate solution was charged into a 50 liter round bottom flask containing a solution of 2-fluorobenzylhydrazine hydrochloride at a temperature between 10-25°C for 5 minutes to obtain a suspension.

Separately, compound (4') (4.89 kg, 15.9 mol, 1.0 eq.) and methanol (24.5 L) were mixed in a 100 L jacketed reaction vessel equipped with a nitrogen inlet/outlet, stirrer with top drive, thermocouple and dropping funnel. The resulting suspension of 2-fluorobenzylhydrazine in methanol was transferred to the reaction mixture in a 100 liter jacketed reaction vessel for 5 minutes while maintaining the temperature at 15-30°C. After stirring for 10 hours at 20-25°C, a suspension was obtained. The reaction was completed by HPLC method B ((4'): formula V area: area %=not determined). The reaction mixture was charged with concentrated hydrochloric acid (1.31 L, 37 wt%, 15.9 mol, 1.0 eq.) over 2 min, and the batch temperature was raised from 21 to 29°C. The mixture was cooled to 20-25°C over 30 minutes and stirred at 20-25°C for 1 hour. Water (24.5 L) was added through a dropping funnel over 30 minutes, while maintaining the temperature at 20-25° WITH. The resulting suspension was stirred at 20-25°C for 30 minutes and filtered. The filter cake was washed with a mixture of methanol (14.7 L) and water (14.7 L). The filter cake was dried under high vacuum at 45-55°C for 16 hours until constant weight, yielding Formula V as an off-white solid (5.83 kg, 99% yield, 99% purity by HPLC).

1I-NMR (500 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=1.68 Hz, 1H); 8.41 (d, J=2.59 Hz, 1H); 7.36 (s, 1H); 7.17-7.24 (m, 1H); 6.95-7.07 (m, 2H); 6.83-6.90 (m, 1H); 6.60 (d, J=1.68 Hz, 1H); 5.99 (s, 2H); 4.19 (s, 3H).

- 35 045335

Step iia: formation of pure pyrazole.

Compound (4') (50.16 g, 163 mmol) was charged into a 3 L 4 neck flask equipped with an overhead stirrer and thermocouple. Methanol (750 ml) and water (250 ml) were added and the mixture was cooled to 10°C. Hydrazine hydrate (55 wt%, in water) (23.7 g, 260 mmol, 1.6 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. Another 250 ml of water was added dropwise and the resulting solids were isolated by filtration and washed with the mixture

2x250 ml 3:1 MeOH:water. The solids were partially dried under vacuum on a filter and then in an oven at 35° C. under vacuum/nitrogen flow overnight to give compound (24') as a pale yellow solid, 38.50 g, 91%.

Step nib: alkylation of pure pyrazole.

Compound (24') (3.5 g, 13.4 mmol) was dissolved in DME (130 ml) at room temperature and lithium tert-butoxide (2.14 g, 26.8 mmol) was added. After stirring for 15 minutes, benzyl bromide (4.58 g, 26.8 mmol) was added and the mixture was heated at 60°C for 16 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (45 ml) and then washed with water (3x10 ml). The organic layer was dried over magnesium sulfate and concentrated. The resulting oil was purified by silica gel chromatography to give the desired compound (2.29 g, 46%).

Step iv: demethylation of formula V to give 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3yl)-1H-pyrazol-3-yl)pyrimidin-4-ol (9').

Formula V (5.76 kg, 15.6 mol, 1.0 eq), methanol (46.1 L) and concentrated hydrochloric acid (3.90 L, 37 wt%, 47.4 mol, 3.0 eq.) was loaded into a 100-L jacketed reaction vessel equipped with a nitrogen inlet/outlet, thermocouple, condenser, and top-drive stirrer. The mixture was heated to 63-65°C and stirred at 63-65°C for at least 24 hours to obtain a suspension. According to HPLC method A, the reaction was completed (formula V: (9') area: area % = 0.8). The suspension was cooled to 20-25°C for 1 hour and kept at 20-25°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with methanol (17.3 L). The wet cake was dried under high vacuum at 35-45°C for 16 hours to constant weight to give (9') as an off-white solid (5.35 kg, 97% yield, 99% purity by HPLC) .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.90-13.61 (br.s, 1H); 9.11 (d, J=1.68 Hz, 1H); 8.16 (s, 1H);

- 36 045335

7.64 (s, 1H); 7.29-7.42 (m, 1H); 7.17-7.28 (m, 2H); 7.08-7.15 (m, 1H); 6.97 (s, 1H); 5.91 (s, 3H).

Step v: chlorination of compound (9') to obtain 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2fluorobeyyl)-1H-pyrazol-5-yl)isoxazole (formula VI).

Intermediate (9') (3.975 kg, 11.2 mol, 1.0 eq), acetonitrile (35.8 L) and N,N-dimethylaniline (0.28 L, 0.27 kg, 2.23 mol , 0.2 eq.) were mixed in a 100-liter jacketed reaction vessel with a nitrogen inlet, thermocouple, dropping funnel, condenser, and top-drive stirrer. The suspension was heated to 70-80°C. Phosphorus oxychloride (1.55 L, 2.55 kg, 16.6 mol, 1.5 eq.) was then charged through the addition funnel over 1 hour while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80°C for at least 4 hours to obtain a green solution. According to HPLC, method A, the reaction was completed ((9'): formula VI area: area % = 0.4). The mixture was then cooled to -5-5°C over 1 hour. Water (17.9 L) was charged over 40 minutes through a dropping funnel while maintaining the reaction temperature at -5-5°C. The resulting suspension was stirred at 0-5°C for 30 minutes and filtered. The filter cake was washed with a mixture of acetonitrile (8.0 L) and water (8.0 L) and then with water (8.0 L). The filter cake was dried under high vacuum at 35-45°C for 16 hours until constant weight, yielding Formula VI as an off-white solid (4.04 kg, 97% yield, 99% purity by HPLC).

¹ H NMR (500 MHz, CDCl3) δ ppm 8.65 (s, 1H); 8.48 (d, J=1.68 Hz, 1H); 7.44 (s, 1H); 7.21-7.25 (m, 1H); 6.97-7.06 (m, 2H); 6.83-6.87 (m, 1H); 6.61 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

Example 2: Preparation of Formula IA.

Step I: amination of compound (16) to obtain 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan2-ol (17).

About NH ₄ OH, TVME _{u Μ} χχ.ΟΗ

CF ₃ ^{ό 3} c ₄ h ₂ f ₆ oc ₄ h ₅ f ₆ no mol. mass: 180.05 ^{mol mass: 1} 97.08 (16) < ¹⁷ )

Ammonium hydroxide (28-30% (as NH ₃ ) solution in water, 1.75 L, 26.8 mol, 9.6 eq.) and methyl tert-butyl ether (1.75 L) were charged into a 10-L jacketed a reaction vessel equipped with a nitrogen inlet/outlet, a thermocouple, a condenser, and a top-drive stirrer (note: the condenser temperature was set at -20°C to minimize evaporation losses of both ammonia gas and (16)). 2,2-bis(trifluoromethyl)oxirane ((16), 500 g, 2.78 mol, 1.0 eq.) was charged into the vigorously stirred reaction mixture (300 rpm) for 40 min while maintaining the reaction temperature at 20-30°C. The mixture was stirred at 20-30°C for 3 hours after addition. The mixture was left to separate the layers and the lower aqueous layer was extracted with methyl t-butyl ether 4 times (4 x 1.75 L). The combined organic layers were concentrated under reduced pressure (jacket temperature no more than 20°C and vacuum 100 Torr) to bring the volume to 1.5 L. N-heptane (1.8 L) was added and the mixture was concentrated under reduced pressure (jacket temperature less than 20°C and vacuum 100 torr) to bring the volume to 1.5 L.

The suspension was cooled to 0-5°C and stirred at 0-5°C for 30 minutes. The resulting suspension was filtered and the filter cake was washed with n-heptane (500 ml). The solid was air-dried in a hood at 20-25°C for 10 hours until constant weight, yielding intermediate (17) as a white solid (383 g, 70% yield, 99% purity by GC).

1H NMR (500 MHz, MeOD) δ ppm 3.09 (s, 2H).

- 37 045335

Step vi: coupling formula VI and compound (17) to obtain 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro2-(1-(2-fluorobenzyl)-5-(isoxazol- 3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (formula IA).

Intermediates formula VI (2.80 kg, 7.49 mol, 1.0 eq.) and (17) (1.76 kg, 8.93 mol, 1.2 eq.), dimethyl sulfoxide (5.6 L) and Hunig's base (1.3 L, 7.46 mol, 1.0 eq.) was charged into a 30 L jacketed reaction vessel equipped with a nitrogen inlet/outlet, thermocouple, condenser, and top drive stirrer. The reaction mixture was heated to 125-130°C and maintained at 125-130°C for a minimum of 4 hours. The reaction was completed by HPLC (formula VI:formula IA area:area %=1.7). The reaction mixture was cooled to 15-25°C.

The resulting reaction mixture was transferred to a 100 L jacketed reaction vessel equipped with a nitrogen inlet/outlet, thermocouple, condenser and top drive stirrer. Toluene (11.2 L), n-heptane (22.4 L), and Hunig's base (0.64 L, 3.68 mol, 0.5 eq.) were then added to the reaction mixture. The reaction mixture was heated to 40-50°C. Water (4.2 L) was added to the vigorously stirred reaction mixture (300 rpm) at 40-50°C for 2 hours, and the reaction mixture was stirred at 40-50°C for 30 minutes to obtain a seed layer. Water (7.0 l) was again added to the intensively stirred suspension (300 rpm) at 40-50°C for 2 hours. The suspension was cooled to 20-25°C for 1 hour and stirred at 20-25°C within 20 min. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of n-heptane and toluene (5.6/2.8 L), then with a pre-mixed solution of water and methanol (5.6 L/2.8 L). The filter cake was then dried in vacuo at 35-45°C for 16 hours until constant weight yielding Formula IA as an off-white solid (4.05 kg, mixed with 7 wt.% DMSO by NMR, refined by analysis yield 94%, purity 98% by HPLC).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.11 (d, J=1.96 Hz, 1H); 8.66 (s, 1H); 8.37 (d, J=3.13 Hz, 1H); 8.11 (t, J=5.87 Hz, 1H); 7.48 (s, 1H); 7.30-7.37 (m, 1H); 7.17-7.24 (m, 1H); 7.21 (d, J=1.7 Hz, 1H); 7.06-7.13 (m, 1H); 7.00-7.06 (m, 1H); 5.87 (s, 2H); 4.11 (d, J=5.87 Hz, 2H).

Step II: recrystallization of the compound of formula IA to obtain a purer compound of formula IA (corresponding to steps A', B', C', D' and E' in the method for preparing the compound of formula IA or in specific embodiment 13 described above).

The compound of Formula IA obtained above (1st part, 4.76 kg, 8.91 mol) and methanol (19.0 L) were charged into a 30 L jacketed reaction vessel. The reaction mixture was stirred at low speed and heated to 40-50°C until most of the solids had dissolved. The solution in the 30 liter jacketed reaction vessel was filtered through an in-line gas dispersion tube (coarse frit) into a 100 liter jacketed reaction vessel. Methanol (4.8 L) was used to wash the 30 L jacketed reaction vessel, and the wash solution was transferred to the 100 L jacketed reaction vessel.

The compound of formula IA obtained above (2nd part, 4.96 kg, 9.28 mol) and methanol (19.9 L) were charged into a 30 L jacketed reaction vessel. The reaction mixture was stirred at low speed and heated to 40-50°C until most of the solids had dissolved. The solution in the 30 liter jacketed reaction vessel was filtered through an in-line gas dispersion tube (large frit) into a 100 liter jacketed reaction vessel. Methanol (5.0 L) was used to wash the 30 L jacketed reaction vessel, and the wash solution was transferred to the 100 L jacketed reaction vessel.

Methanol (12.0 L) was added to a 100 L jacketed reaction vessel to bring the volume to 68.0 L. The reaction mixture was then heated to 55-65°C and water (29.2 L) was charged over 1 hour 30 minutes while maintaining the batch temperature at 50-60°C. The resulting suspension was cooled to 20-25°C for 2 hours and kept at 20-25°C for 1 hour. The suspension was filtered and the filter cake was washed with a pre-mixed solution of methanol and water (19.5/19.5 l). The filter cake was then dried in vacuo at 40-50°C for 24 hours to obtain the compound of formula IA as a white solid (8.93 kg, 92% yield, 99% purity by HPLC).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.11 (d, J=1.96 Hz, 1H); 8.66 (s, 1H); 8.37 (d, J=3.13 Hz, 1H); 8.11 (t, J=5.87 Hz, 1H); 7.48 (s, 1H); 7.30-7.37 (m, 1H); 7.17-7.24 (m, 1H); 7.21 (d, J=1.7 Hz, 1H); 7.06-7.13 (m, 1H); 7.00-7.06 (m, 1H); 5.87 (s, 2H); 4.11 (d, J=5.87 Hz, 2H).

Determination of the characteristics of crystalline form A of the compound of formula IA.

The crystallinity of the compound of formula IA, obtained in accordance with the procedure described above, was determined by XRPD. The X-ray powder diffraction pattern is shown in Fig. 1.

The melting range was also determined by differential scanning calorimetry (DSC). DSC analysis was carried out in a hermetically sealed bowl with the temperature increasing at a rate of 10°C/min to 300°C. The DSC profile is shown in Fig. 2 and it shows a melting point of 163.1°C.

Example 3. Preparation of the compound of formula ID.

Step A: cyanidation of compound (10) to obtain a racemic mixture of 2-(bromomethyl)-3,3,3trifluoro-2-((trimethylsilyl)oxy)propanenitrile (11).

C ₃ H ₂ BrF ₃ O CyHnBrFaNOSi molecular weight: 190.95 molecular weight: 290.16 (10) (11)

Trimethylsilanecarbonitrile (3.41 kg, 34.4 mmol, 0.97 eq.) and triethylamine (0.100 L, 0.073 kg, 0.72 mol, 0.02 eq.) were mixed in a 30 L jacketed reactor. The mixture was cooled to 10-15°C. Charge 3-bromo-1,1,1-trifluoropropan-2-one ((10), 6.74 kg, 35.3 mol, 1.0 eq.) through a dropping funnel over 1 hour 40 minutes while maintaining reaction temperature between 0-20°C. The reaction mixture was stirred at 20-25°C for 1 hour. ¹ H-NMR of the sample indicated that the reaction was complete ((10):(11) area:area %=<1) to give intermediate (11) as a thick oils This intermediate (11) (racemic mixture) was used directly in the next step.

¹ H-NMR (500 MHz, CDCl ₃ ) δ ppm 3.68 (d, J=11.14 Hz, 1H); 3.57 (d, J=11.14 Hz, 1H); 0.34-0.37 (m, 9H).

Step B: Convert the racemic nitrile (11) to the amide to give the racemic 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (12).

F

CyH^BrFaNOSi C ₄ H ₅ BrF ₃ NO2 mol. weight: 290.16 mol. weight: 235.99 (11) (12)

Concentrated sulfuric acid (8.6 L, 158 mol, 4.5 eq.) was stirred in a 100 L jacketed reactor. Sulfuric acid was heated to 40-45°C, then the resulting intermediate (11) (racemic) was added through a dropping funnel over 1 hour while maintaining the temperature below 75°C. The reaction mixture was stirred at 65-75°C for 2 hours and then allowed to cool to 20-25°C. The reaction mixture was further cooled to -15-(-5)°C and diluted with ethyl acetate (40.4 L) through a dropping funnel over 2 hours (highly exothermic reaction), while maintaining the temperature between -15 and -5°C. Water (33.7 L) was added via a dropping funnel over 1 hour 30 minutes (highly exothermic reaction), while maintaining the temperature between -15 and -5°C. The reaction mixture was heated and kept at 0-5°C. The layers were separated and 15% aqueous sodium chloride (20 L) followed by 20% aqueous sodium bicarbonate (20 L) was added to the organic layer while maintaining the temperature between 5 and 20°C for 5 minutes. The mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with 15% aqueous sodium chloride solution (20 L). Organic

- 39 045335 the layer was transferred through an inline filter through a gas dispersion tube (large frit) into a 20 liter rotary evaporator and concentrated under reduced pressure until no more distillate was observed, yielding 10.0 kg of crude intermediate (12) (racemic) as a light yellow oil which contained 77% by weight of intermediate (12) (racemic) as determined by ¹ H-NMR analysis. This oil was dissolved in methanol (6.7 L) and concentrated to give 9.13 kg of intermediate (12) (racemic) (7.73 kg adjusted weight). This oil was used directly in the next step.

¹ H-NMR (500 MHz, CDCl ₃ ) δ 6.61-6.94 (m, 1H); 5.92-6.26 (m, 1H); 3.93-4.00 (m, 1H); 3.68 (d, J=11.14 Hz, 1H).

Step C: amination of the racemic mixture (12) to obtain the racemic mixture of 2-(aminomethyl)3,3,3-trifluoro-2-hydroxypropanamide (13).

Vg

1MM ₂ F mn ₃

MeOH

c ₄ h ₇ f ₃ n ₂ o ₂ molecular weight: 1 72.11 (13)

C ₄ H ₅ BrF ₃ NO ₂ molecular weight: 235.99 (12)

N solution of ammonia in methanol (57.5 L, 403 mol, 12.3 eq.) was stirred in a 100 L reactor. The solution was cooled to -10-10°C. The resulting intermediate (12) (racemic, 7.73 kg, 32.8 mol, 1.0 eq.) was then added via addition funnel over 3 min. The reaction mixture was heated to 20-30°C for 1 hour and maintained at this temperature for 16 hours. The reaction mixture was cooled to 0-10°C and sodium methoxide (5.8 L, 5.4 M, 31.3 mol, 0.95 eq.) for 2 min. The reaction mixture was then divided into 4 equal parts and processed. Each portion was concentrated under reduced pressure to a volume of 7.7 L, and ethyl acetate (11.6 L) was continuously charged, performing azeotropic distillation to remove methanol to a volume of 7.7 L as a slurry. This method was repeated for the remaining three parts. The entire 4-part ethyl acetate slurry was transferred to a 100 L jacketed reactor and ethyl acetate was added again to bring the volume to 74 L. Water (7.7 L) was added and the reaction mixture was stirred vigorously for 20-30 minutes and then left to separate for at least 12 hours.

The ethyl acetate layer was then divided into 4 equal parts and processed. Each portion was concentrated under reduced pressure to a volume of 7.7 L. This method was repeated for the remaining three parts. All 4 parts were transferred to a 100 L jacketed reactor and ethyl acetate was added to bring the volume to 46.4 L. The reaction mixture was heated to 55-60°C and heptane (38.7 L) was added over 50 minutes while maintaining the temperature above 50°C. The resulting suspension was cooled to 20-25°C for 2 hours, then kept at 20-25°C for 1 hour 30 minutes and filtered onto an 18-inch Buchner funnel. Ethyl acetate (3.9 L) and heptane (7.7 L) were charged into the reactor, the mixture was stirred for 2 minutes and transferred to a filter to wash the cake. The wet cake was filter dried for 2 hours and then vacuum dried at 25-30°C for 36 hours until constant weight, yielding intermediate (13) (racemic) as an off-white solid (3.21 kg , yield 53%).

¹ H-NMR (500 MHz, MeOH-d ₄ ) δ ppm 2.94 (d, J=13.73 Hz, 1H); 3.24 (d, J=13.58 Hz, 1H).

Step D: chiral resolution of the racemic mixture (13) as D-malic acid salt (14) (R)-2,2-dimethyl-5-(trifluoromethyl)oxazolidine-5-carboxamide (20).

O ^Η θγ^Α _ΟΗ o (20)

O OH o C ₄ H ₆ O ₅ \-0 ^CF 3

I, mi mol.mass: 134.09I Q

P2 N Ν p 2 ►

HO CF ₃ acetoneNO

ABOUT HE

C ₄ H ₇ F ₃ N ₂ O ₂ ScH^^Oy mol. mass: 1 72.11 ^mol mass: 346.26 (13)<

Intermediate (13) (racemic) (2.0 kg, 11.6 mol, 1.0 eq) and acetone (10.0 L) were mixed in a 22 L round bottom flask equipped with a mechanical stirrer, dropping funnel and digital thermometer . The reaction mixture was stirred at low speed at 20-25°C to obtain

solution.

Separately, (D)-(+)-malic acid (1.56 kg, 11.6 mol, 1.0 eq.) and acetone (30 L) were stirred in a 100 L jacketed reactor. The reaction solution was heated to 33-38°C. 20% of the resulting solution of intermediate (13) in acetone was then charged into a 100 liter jacketed reactor in one portion, then a suspension of intermediate (14) (0.52 g) was charged into

- 40 045335 acetone (20 ml) as seed crystals. The remaining 80% (13) acetone solution was then charged into a 100 L jacketed reactor for a minimum of 1 hour while maintaining the reaction temperature between 33 and 38°C. The reaction mixture was cooled to 28-32°C gradually over a minimum of 2 hours and stirred at 28-32°C for a minimum of 12 hours. The resulting suspension was filtered at 28-32°C and the filter cake was washed with acetone (16.0 L) ( Note: Care was taken to ensure that the filter cake was not dry at the start of filtration). The filter cake was then dried under vacuum at 30°C for 8 hours to constant weight to give salt (14) as an off-white solid (1.53 kg, 38% yield, RR:SR=97:3 according to chiral GC).

¹ H-NMR (500 MHz, D2O) δ ppm 4.33 (br.s, 1H); 3.61 (lat, J=13.58 Hz, 1H); 3.40-3.47 (m, 1H); 2.76 (lat, J=15.87 Hz, 1H); 2.53-2.63 (m, 1H); 2.16 (br.s, 4H).

Step E: combination of formula VI and malic acid salt (14) to give (R)-3,3,3-trifluoro-2(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole -3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2hydroxypropanamide (formula ID).

(D)-Malic acid salt (14) (0.81 kg, 2.34 mol, 1.25 eq.) and water (0.98 L) were charged into a 30 L jacketed reaction vessel. The reaction mixture was stirred at low speed and the jacket was heated to 65-70°C and maintained at this temperature for 30 minutes. The acetone formed during the reaction was removed by applying a weak vacuum. The reaction mixture was cooled to 20-40°C and charged with Formula VI (0.70 kg, 1.87 mol, 1.0 eq), DMSO (9.8 L) and Hunig's base (0.82 L, 4.71 mol, 2.5 eq.). The reaction mixture was heated to 88-93°C for 2 hours and maintained at 88-93°C for 20 hours. The reaction was complete as shown by HPLC analysis (formula VI:formula ID area:area %=0.5). Then the mixture was cooled to 50-60°C. Another portion of Hunig's base (1.96 L, 11.3 mol, 6.0 eq.) was added, followed by water (4.9 L) for 15 minutes at 50-60°C. The reaction mixture was stirred for 15 minutes at 50-60°C to obtain a seed layer. Water (7.0 L) was added through a dropping funnel at 50-60°C for 30 minutes and the mixture was kept at 50-60°C for 30 minutes. The resulting suspension was filtered at 50-60°C and the filter cake was washed with a pre-mixed solution of methanol and water (3.5/3.5 l). The filter cake was then dried in vacuo at 50°C for 16 hours until constant weight, yielding Formula ID as an off-white solid (0.83 kg, 87% yield).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, br, 1H); 7.90 (s, 1H); 7.78 (s, br, 1H); 7.69 (s, br, 1H); 7.52 (s, 1H); 7.33 (sq., J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1 N); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

Step F: hydrolysis of oxazolidine salt of malic acid (14) to obtain HCl salt (15) (R)-2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (15A). ABOUT

HN nh ₂

END BUT γ γ he oh he

THF

BUT h ₂ n^4 but' ^νη ₂ (15A)

CF ₃

C11H17F3N2O7 molecular weight: 346.26 (14)

Malic acid salt (14)

C ₄ H ₈ OF ₃ N ₂ O ₂ mol.wt: 208.57 (15) (1.53 kg, 4.42 mol, 1.0 eq.) and THF (12.3 L) were stirred in

100 liter jacketed reactor. The suspension was stirred at 20-25°C for 5 minutes. A 100 L jacketed reactor was charged with concentrated HCl (37 wt%, 0.41 L, 4.92 mol, 1.1 eq.) in one portion. The reaction mixture was stirred at 20-30°C for a minimum of 1 hour. The suspension was cooled to 0-5°C for 1 hour and kept at 0-5°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with THF (3.1 l). The wet cake was dried under high vacuum at 45-55°C for 16 hours until constant weight, yielding HCl salt (15) as an off-white solid (0.83 kg, 90% yield, R:S=97, 7:2,3, by

- 41 045335 chiral GC data).

1H-NMR (500 MHz, D2O) δ ppm 3.50 (d, J=13.73 Hz, 1H); 3.67 (d, J=13.73 Hz, 1H).

Large scale step vi: coupling of formula VI and HCl salt (15) to give (R)-3,3,3trifluoro-2-(((5-fluoro-2-( 1 -(2-fluorobeyyl)-5 -( isoxazol-3 -yl)-1 H-pyrazol-3 -yl)pyrimidin-4yl)amino)methyl)-2-hydroxypropanamide (formula ID).

Formula VI (1.02 kg, 2.73 mol, 1.0 eq), salt (15) (0.685 kg, 3.28 mol, 1.2 eq), dimethyl sulfoxide (4.1 L) and Hunig's base (1.29 L, 7.41 mol, 2.7 eq.) was charged into a 30 L jacketed reaction vessel equipped with a nitrogen inlet/outlet, thermocouple, condenser and top drive stirrer. The reaction mixture was heated to 99-103°C and maintained at 99-103°C for a minimum of 4 hours. According to HPLC method A, the reaction was complete (formula VI:formula ID area:area %=0.6). The reaction mixture was cooled to 50-55°C and then methanol (4.1 L) was charged in one portion. Water (2.7 L) was added to the reaction mixture at 50-55°C over 30 minutes, and the reaction mixture was stirred at 50-55°C for 15 minutes to obtain a seed layer. Water (5.5 L) was added again at 50-55°C for 30 minutes and the suspension was kept at 50-55°C for 30 minutes. The suspension was then cooled to 20-25°C for 1 hour and stirred at 20-25°C for 1 hour. The suspension was filtered and the filter cake was washed with a pre-mixed solution of methanol and water (10.2/10.2 L). The filter cake was then dried in vacuo at 45-55°C for 16 hours until constant weight yielded compound of formula ID as an off-white solid (1.29 kg, 93% yield, 100% purity by HPLC, R :S=99.2:0.8 according to chiral HPLC).

1H-NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, br, 1H); 7.90 (s, 1H); 7.78 (s, br, 1H); 7.69 (s, br, 1H); 7.52 (s, 1H); 7.33 (sq., J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1 N); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

Step vi on kg scale: coupling formula VI and HCl salt (15) to give (R)-3,3,3-trifluoro-2(((5-fluoro-2-(1-(2-fluorobenzyl)-5- (isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2hydroxypropanamide (formula ID).

Formula VI (53.5 mmol, 1.0 eq), (15) (12.3 g, 59.0 mmol, 1.1 eq), dimethyl sulfoxide (40.0 ml) and Hunig's base (21.4 g, 166 mmol, 3.1 eq.) was charged into a 500 mL jacketed reaction vessel equipped with a nitrogen inlet/outlet, thermocouple, condenser, and top drive stirrer. The reaction mixture was heated to 100-105°C and kept at 100-105°C for at least 4 hours. According to HPLC method A, the reaction was complete (formula VI:formula ID area:area %=1.0). The reaction mixture was cooled to 58-63°C and then methanol (160 ml) was charged into the reaction mixture in one portion. Water (60 ml) was added to the reaction mixture at 58-63°C over 30 minutes, and the reaction mixture was stirred at 58-63°C for 15 minutes to obtain a seed layer. Water (140 ml) was added again at 58-63°C for 30 minutes and the suspension was kept at 5863°C for 30 minutes. The suspension was then cooled to 30-35°C for 2 hours and stirred at 3035°C for 1 hour. The suspension was filtered and the filter cake was washed with a premixed solution of methanol and water (100/100 ml). The filter cake was then vacuum dried at 70-80°C for 16 hours until constant weight yielded Formula ID as an off-white solid (26.3 g, 96% yield, 99.3% purity by HPLC) .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, br, 1H); 7.90 (s, 1H); 7.78 (s, br, 1H); 7.69 (s, br, 1H); 7.52 (s, 1H); 7.33 (sq., J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1 N); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

- 42 045335

Step G: recrystallization of the compound of formula ID to obtain polymorph Form B of the compound of formula ID (corresponding to steps A, B, C, D and E in the method for preparing the compound of formula ID or in specific embodiment 18).

Formula ID (25.7 g, 50.5 mmol) obtained above, acetonitrile (386 ml) and water (68 ml) were charged into a 1 liter jacketed reaction vessel. The reaction mixture was stirred at low speed and heated to 70-75°C until most of the solids had dissolved. The solution in the 1 L jacketed reaction vessel was filtered through an in-line gas dispersion tube (coarse frit) into another 1 L jacketed reaction vessel. The reaction mixture was then heated to 70-75°C to form a solution and water (318 ml) was charged while maintaining the batch temperature above 65°C for 30 minutes. The resulting suspension was stirred at 65-72°C for 1 hour and cooled to 0-5°C for at least 2 hours and kept at 0-5°C for at least 1 hour. The suspension was filtered and the filter cake was washed with a pre-mixed acetonitrile solution and water (125/125 ml). The filter cake was then dried under vacuum at 80-95°C for a minimum of 20 hours to obtain Formula ID, Form B as a white solid (22.7 g, 88% yield).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, br, 1H); 7.90 (s, 1H); 7.78 (s, br, 1H); 7.69 (s, br, 1H); 7.52 (s, 1H); 7.33 (sq., J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1 N); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

Determination of the characteristics of crystalline form B of the compound of formula ID.

The crystallinity of Form B of Formula III was analyzed by XRPD. Form B is characterized by the X-ray powder diffraction pattern shown in FIG. 3A, 3B and 3C.

In one embodiment, Form B is characterized by one or more peaks in the XRPD spectrum at 18.8-19.1° 2θ.

In yet another embodiment, Form B is characterized by one or more peaks in the XRPD spectrum selected from 8.8, 16.4, 17.2, 18.8-19.1, 20.1 and 21.1-21.6° 2θ.

In yet another embodiment, Form B is characterized by one or more peaks in the XRPD spectrum selected from 8.8, 10.6, 12.6-13.0, 14.6, 16.4, 17.2, 18.8- 19.1, 20.1, 21.1-21.6, 24.5, 25.3, 27.0-27.5, 28.9, 29.8 and 30.5° 2θ.

In some embodiments, Form B exhibits an XRPD spectrum substantially similar to that shown in FIG. 3C.

In other embodiments, Form B is characterized by one or more peaks in the XRPD spectrum selected from 8.9 (76.55% rel.int.), 17.4 (57.67%), 19.1 (100.00%) and 25.5 (52.26)° 2θ.

In other embodiments, Form B is characterized by one or more peaks in the XRPD spectrum selected from 7.0 (44.44% rel.int.), 8.9 (76.55%), 17.4 (57.67%) , 19.1 (100.00%), 20.3 (49.78%), 21.8 (36.16%) and 25.5 (52.26)° 2θ.

In other embodiments, Form B is characterized in that it exhibits a substantially unchanged X-ray powder diffraction pattern when stored for 14 months under stable conditions of 40° C. and 75% relative humidity. X-ray powder diffraction patterns for Form B before and after storage under these conditions are shown in FIG. 3B.

- 43 045335

Example 4 Large scale synthesis of compound (4').

Reagents and conditions.

(a) NaOMe, MeOH, -15-(-5)°C, 1-2 hours;

(b) CuI, PdCl ₂ (PPh3)2, TMS-Acetylene, EtsN, 20-30°C, 15-20 h;

(c) KF, MeOH, 20-30°C, 1-2 h, yield 75-84% (in three stages);

(d) n-BuLi, THF, (1'), -78°C, 1-3 h;

(f) NH(MeO)Me-HCl, 20-30°C, 0.5-1 h, EA, CH3COOH, yield 75-84% (in two stages).

2-bromo-5-fluoro-4-methoxypyrimidine (6).

2,4-Dibromo-5-fluoropyrimidine (5) (44.9 kg, 175.4 mol, 1.0 eq.) and methanol (199 kg) were added to the reactor at 20-30°C under N ₂ atmosphere. The mixture was stirred at 20-30°C for 0.5-1 hour until compound (5) was completely dissolved, then cooled to -15-(-5)°C (note: compound (5) can precipitate at temperatures below 5° WITH). A solution of sodium methoxide (35.0 kg, 192.9 mol, 1.1 eq.) was added dropwise to the reaction mixture over 7 hours while maintaining the internal temperature between -15 and -10°C. (Note: The reaction is exothermic. Temperature should be maintained below -10°C to minimize bismethoxy by-product.) The addition was followed by a wash with methanol (22.6 kg). The mixture was then stirred at -15-(-5)°C for 1 to 2 hours until the reaction was complete (note: temperature should be maintained below -10°C during the IPC procedure). The reaction mixture was quenched by adding a solution of 2 M HCl (10 kg) for 10 min at -15-(-5)°C (note: pH should be adjusted to 3-4). Water (130 kg) (pH ~6) was added to the reaction mixture and then the solution was stirred for 10-30 min at -15-(-5)°C and then heated to 20-30°C. The reaction solution was concentrated in vacuo to remove most of the methanol (note: jacket temperature was kept below 30°C). The resulting residue was extracted with methyl tert-butyl ether (MTBE) (350 kg), precipitated, separated and the aqueous layer was removed. The organic layer was then washed twice with water (2x200 kg) to adjust the pH of the aqueous layer to ~7. The remaining organic layer (MTBE) was concentrated in vacuum to 5-6 volumes at a temperature below 30°C. Additional MTBE (150 kg) was added and then distilled to 5-6 volumes to control the water content (Karl Fischer method) of the compound (6)/MTBE solution below 0.5%. (note: shirt temperature was kept below 30°C). The resulting solution was directly transferred to the next stage without further purification.

5-fluoro-4-methoxy-2-((trimethylsilyl)ethynyl)pyrimidine (7).

Triethylamine (35.2 kg, 347.8 mol, 1.98 eq.) was added to the solution of compound (6)/MTBE and then the mixed solution was degassed by sparging with nitrogen for 0.5-1 hour at 20-30°C. Pd(PPh ₃ ) ₂ Cl ₂ (0.32 kg, 0.455 mol, 0.0025 eq.) and copper(I) iodide (CuI) (0.17 kg, 0.892 mol, 0.005 eq.) were added to the mixture under atmosphere N ₂ and then stirred for 30 minutes. Ethynyltrimethylsilane (21.0 kg, 213.8 mol, 1.2 eq.) was slowly added to the reaction mixture over 3-4 hours while maintaining the internal temperature at 20-30°C. (Note: the reaction is slightly exothermic.) The mixture was stirred at 20-30°C for 15-20 hours until the reaction was complete (note: IPC control: less than 0.5% of compound (6) remains). The reaction mixture was quenched by adding 2M HCl solution (126 kg) for 10 min at 20-25°C (note: pH should be adjusted to 1-2). The reaction solution was stirred for 30 minutes, precipitated, separated, and the aqueous layer was removed. The organic layer was first washed with water (1x202 kg), then with 10% N-acetyl-cysteine (1x258 kg), 7% aqueous NaHCO ₃ (1x248 kg) and finally with 10% aqueous Na ₂ SO ₄ ( 1x178 kg). The organic layer was treated with circulating CUNO (with a 3M CUNO carbon filtration system) for 18 hours to remove palladium impurities, followed by washing with MTBE (150 kg). The remaining organic layer (MTBE) was concentrated in vacuum to 3-4 volumes at a temperature below 30°C. Methanol (280 kg) was added and then distilled to 3-4 volumes at a temperature below 30°C. The resulting solution was directly used in the next step without further purification.

2-ethynyl-5-fluoro-4-methoxypyrimidine (2).

Potassium fluoride (244 g, 4.2 mol, 0.023 eq.) was added to the solution of compound (7)/methanol under N ₂ atmosphere and then the mixture was stirred for 1-2 hours at 20-30° C. until the reaction was complete (note: IPC

-

Claims (28)

control: less than 0.5% of compound (7) remains). The reaction mixture was quenched by adding water (180 kg) for 10 min at 20-30°C (note: quenching is slightly exothermic). The reaction mixture was concentrated in vacuo to 3-5 volumes until most of the methanol was distilled off (note: jacket temperature should be maintained below 30°C). Then MTBE (250 kg) was added to the mixture, the mixture was stirred for 1 hour, precipitated, and separated. The organic layer was retained and the aqueous layer was re-extracted with MTBE (80 kg), precipitated, separated and the aqueous layer was discarded. The combined organic layer was washed with water (1x100 kg) and then the resulting organic layer was concentrated in vacuo to 3-4 volume (note: jacket temperature should be kept below 30°C). Methylcyclohexane (200 kg) was added and then distilled to 3-4 volumes at a temperature below 30°C. The resulting solution was cooled to 0-5°C and stirred for 3 hours. The reaction suspension was filtered and the filter cake was washed with pre-cooled methylcyclohexane (60 kg). The isolated wet cake was dried under vacuum at 20-30°C for 24-48 hours to obtain the title compound as an off-white solid (20.1 kg, 83% yield, HPLC purity=99.8% , analysis=97.8%). 1H NMR (400 MHz, chloroform-d) δ ppm 3.00 (d, J=0.86 Hz, 1H), 4.04 (s, 3H), 8.22 (d, J=2.69 Hz, 1H). (E)-3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(isoxazol-3-yl)-3-(methoxy(methyl)amino)prop-2-en-1one (4') . Compound (2) (20.0 kg, 128.6 mol, 1.0 eq.) and tetrahydrofuran (THF, 108 kg) were added to reactor (R1) at 20-30° C. under N2 atmosphere. The mixture was stirred at 20-30°C for 0.5-1 hour until compound (2) was completely dissolved, then cooled to -90-(-75)°C (note: compound (2) may precipitate at low temperatures). A solution of n-butyllithium, 2.5 M in hexane (39.0 kg, 139.2 mol, 1.08 eq.) was added dropwise to the reaction mixture over 11 hours while maintaining the internal temperature below -85°C. (Note: The reaction is exothermic. Temperature should be kept below -75°C to minimize polymerization by-product. An off-white viscous suspension was observed during the addition.) The addition was followed by a rinse with THF (18 kg). The mixture was then stirred at -85°C for 2 hours. N-Methoxy-N-methylisoxazole-3-carboxamide (5) (22.8 kg, 146.0 mol, 1.1 eq.) was added to the reaction suspension via a dropwise funnel for 3 hours while maintaining the internal temperature below -80°C. (Note: The reaction is slightly exothermic and the off-white slurry gradually turned to a brown slurry.) The addition was followed by a rinse with THF (18 kg). The mixture was then heated to -70-(-60)°C for 1 hour and then stirred at -70-(-60)°C for 1.5 hours. At this time, N,O-dimethylhydroxyamine hydrochloride (3.9 kg, 39.9 mol, 0.3 eq), glacial acetic acid (8.0 kg, 133.2 mol, 1.03 eq) and ethyl acetate (EtOAc) (190 kg) were added to another reactor (R2) . The reaction mixture was stirred at 20-30°C for 0.5-1 hour to obtain a solution and cooled to 0-5°C and then stirred at 0-5°C for 0.5-6 hours. The reaction mixture was transferred from R1 into a vigorously stirred acid solution in R2 for 10-60 minutes, while maintaining the internal temperature below 10°C. The transfer was followed by a run of EtOAc (92 kg) to wash R1 and the mixture was combined into R2. 7% sodium bicarbonate solution (120 kg) was then added to the reaction mixture in R2 and the mixture was heated to 20-30°C and then stirred at 20-30°C for 0.5-1 hour (note: the reaction was controlled by quenching the reaction mixture in acetonitrile/water and reported IPC data). The two layers were separated and the aqueous layer was drained. The organic layer was washed twice with 10% sodium sulfate solution (2x130 kg) and then filtered through celite, followed by a run-through wash with EtOAc (57 kg). The combined filtrate was concentrated in vacuo to 3-4 volumes (note: jacket temperature should be kept below 40°C). Methanol (170 kg) was added and then distilled to 3-5 volumes at a temperature below 40°C. The resulting solution was heated to 60-70°C and stirred for 0.5-1 hour and then gradually cooled to 0-5°C over 8-9 hours. The reaction suspension was stirred at 0-5°C for another 5- 8 hours and then filtered, the filter cake was washed with pre-cooled methanol. The isolated cake was dried under vacuum at 30-40°C for 24-48 hours to obtain the title compound as an off-white solid (28.95 kg, 73% yield, HPLC purity=99.5%, analysis=98.7%). ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.03 (s, 3H), 3.71 (s, 3H), 3.99 (s, 3H), 6.46 (s, 1H), 6.55 (d, J=1.71 Hz, 1H ), 8.30 (d, J=1.71 Hz, 1H), 8.34 (d, J=2.69 Hz, 1H). CLAIM 1. Method for preparing the compound of formula (4) - 45 045335 comprising the following steps: i) coupling of an amide of formula (1) with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3) and ii) reacting the mixture at pH>5 to obtain a compound of formula (4), wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl a ring optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O. 2. A process for preparing a compound of formula II comprising the following steps: i) coupling of an amide of formula (1) with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3) ii) reacting the mixture at pH>5 to obtain a compound of formula (4) - 46 045335 and iii) carrying out the condensation of a compound of formula (4) with a hydrazine of the formula R ² -CH ₂ -NH-NH ₂ or a salt thereof to obtain a compound of formula II, wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O; And R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or a 6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms, where each R ⁵ independently represents is methyl or halogen. 3. A process for preparing a compound of formula II comprising the following steps: i) coupling of an amide of formula (1) with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3) C> > = r ¹ Ν=ς o— (3) ii) carrying out the reaction of the mixture at pH>5 to obtain a compound of formula (4) iiia) carrying out the condensation of a compound of formula (4) with hydrazine to obtain a compound of formula (24) - 47 045335 and iiib) alkylation of the intermediate of formula (24) with an alkylating agent of formula (22) to obtain a compound of formula II IR ² -CH ₂ -X (22) where R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents , independently selected from the group consisting of halogen or methyl, wherein said 5-6 membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O; And R ² is phenyl, optionally substituted with up to three R ⁵ substituents, or a 6-membered heteroaryl, optionally substituted with up to three R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms, where each R ⁵ independently represents a methyl or halogen; X represents a leaving group selected from -Br, -I, -Cl, -F and a sulfonic acid ester. 4. Method according to claim 2 or 3, further comprising step iv) demethylating a compound of formula II to obtain an alcohol compound (9) R ¹ ^R ² η He F Connection (θ) 5. The method according to claim 4, further comprising the step of v) chlorinating the alcohol compound of formula (9) with phosphoryl chloride to obtain a compound of formula III 01 d2 TO Ν ^Χ Ν CI F Formula III 6. Method according to any one of claims 1 to 5, where R ¹ represents a 5-membered heteroaryl ring or R ¹ represents an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O. 7. Method according to any one of claims 2 to 6, where (i) R ² represents phenyl substituted with up to two R ⁵ substituents; (ii) R ² is phenyl substituted with one R ⁵ substituent; (iii) R ² is represented by the formula ; (iv) R ² is a 6-membered heteroaryl substituted with up to two R ⁵ substituents, wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms; and where (i) each R ⁵ independently represents methyl or halogen; (ii) each R ⁵ is independently halogen; or - 48 045335 (iii) each R ⁵ is fluorine. 8. The method according to any one of claims 1 to 5, where (i) R ¹ represents an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O; R ² is phenyl, optionally substituted with one or two R ⁵ substituents; each R ⁵ represents fluorine; or (ii) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O; R ² represents the following steps: i) coupling of an amide of formula (1') each R ⁵ represents fluorine. 9. A method for preparing a compound of formula (4') with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, an intermediate compound of formula (3') and ii) reacting the mixture at pH>5 to obtain a compound of formula (4'). 10. Method for preparing the compound of formula V comprising the following steps: i) coupling an amide of formula (1') - 49 045335 with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3') ii) reacting the mixture at pH>5 to obtain a compound of formula (4') and iii) effecting the condensation of a compound of formula (4') with hydrazine of formula or a salt thereof to obtain a compound of formula V. 11. A process for preparing a compound of formula V comprising the following steps: i) coupling of an amide of formula (1') with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base to obtain, after quenching with acid, the intermediate compound of formula (3') - 50 045335 ii) reacting the mixture at pH>5 to obtain a compound of formula (4') iiia) carrying out the condensation of a compound of formula (4') with hydrazine to obtain a compound of formula (24') and iiib) alkylation of the intermediate of formula (24') with an alkylating agent of formula (23A) to obtain a compound of formula V where X represents a leaving group selected from -Br, -I, -Cl, -F and a sulfonic acid ester. 12. The method according to claim 10 or 11, further comprising step iv) demethylating a compound of formula V to obtain an alcohol compound (9') 13. The method according to claim 12, further comprising the step of v) chlorinating the alcohol compound of formula (9') with phosphoryl chloride to obtain a compound of formula VI 14. Method according to any one of claims 1-3 and 9-11, where step ii) is carried out in the presence of added N,O-dimethylhydroxylamine or a salt thereof. - 51 045335 15. Method according to any one of claims 3-8 and 11-14, wherein the hydrazine in step iia) is hydrazine hydrate. 16. Method according to any one of claims 3-8 and 11-15, where X is a sulfonic acid ester selected from mesylate, tosylate and triflate. 17. The method according to any one of claims 1 to 3, wherein said phenyl or 5-6 membered heteroaryl ring represented by R ¹ is substituted with up to three substituents independently selected from the group consisting of halogen and methyl. 18. Method according to claim 2 or 10, wherein step iii) is carried out in the presence of a base. 19. The method according to claim 2 or 3, characterized in that said phenyl or 6-membered heteroaryl represented by R ² is substituted with up to three R ⁵ substituents, where each R ⁵ independently represents methyl, methoxy or halogen. 20. Method according to any one of claims 1 to 19, wherein the base in step i) is n-butyllithium. 21. The method according to any one of claims 1 to 20, where the method includes contacting the reaction product of the reaction between an amide of formula (1) or (1') and a pyrimidine compound of formula (2) with a solution comprising N,O-dimethylhydroxylamine or a salt thereof, and an acid to obtain a compound of formula (4) or (4'). 22. The method according to claim 21, where the solution includes N,O-dimethylhydroxylamine hydrochloride. 23. The method according to claim 21 or 22, where (i) the acid is an aqueous acid; (ii) the acid is hydrochloric acid; or (iii) the acid is glacial acetic acid. 24. Method according to any one of claims 3, 13, 20-23, where X represents -Br. 25. Compound of formula (3) or (4): wherein R ¹ is phenyl, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, or a 5-6 membered heteroaryl ring, optionally substituted with up to three substituents independently selected from the group consisting of halogen or methyl, wherein said 5- or 6-membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S and O. 26. A compound according to claim 25, wherein said phenyl or 5-6 membered heteroaryl ring represented by R ¹ is substituted with up to three substituents independently selected from the group consisting of halogen and methyl. 27. The compound according to claim 25, where (i) R ¹ represents a 5-membered heteroaryl ring; or (ii) R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O. 28. A compound according to claim 27, where the compound is represented by formula (3') or (4'): F or -