1h-pyrazolo[4,3-d]pyrimidine derivatives

Abstract

The present invention relates to PERK inhibiting compounds and pharmaceutical compositions comprising the same. The present invention further relates to the treatment of disorders using the PERK inhibiting compounds and pharmaceutical compositions of the invention.

Description

[0001] 1H-PYRAZOLO[4,3-D]PYRIMIDINE DERIVATIVES The present invention relates to inhibitors of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and pharmaceutical compositions comprising the same. The present invention further relates to the treatment of disorders using the PERK inhibiting compounds and pharmaceutical compositions of the invention. Background to the invention The endoplasmic reticulum (ER) represents the main subcellular compartment involved in folding and maturation of proteins destined for organelles and the extracellular space. Several kinds of stresses can alter the function of the ER, including hypoxia, alteration of protein glycosylation, depletion of luminal ER calcium, and changes in ER redox status. These conditions provoke the accumulation of unfolded or misfolded proteins inside the ER, which culminates in the activation of a series of adaptive mechanisms referred to as the Unfolded Protein Response (UPR) and that are aimed at restoring protein-folding homeostasis. However, if cell damage is sufficiently severe or prolonged, UPR signalling results in cell death by apoptosis. The UPR is associated with the maintenance of cellular homeostasis in specialized secretory cells, such as pancreatic beta cells, salivary glands and plasma B cells, where the high demand for protein synthesis and secretion requires an efficient and tightly controlled protein homeostasis. More widely, however, UPR is involved in many other physiological processes, including lipid and cholesterol metabolism, energy control, inflammation and cell differentiation. The large number of activities mediated by UPR reflects the role of ER stress in the progression of diseases such as cancer, neurodegenerative disorders and diabetes. PERK is one of three classes of sensors of ER stress (alongside IRE1 and ATF6). The activation of PERK involves dimerization, trans-autophosphorylation and the formation of large clusters. Upon activation, PERK phosphorylates eukaryotic translation initiator factor 2^ (elF2^), which leads to the inhibition of protein synthesis, thus reducing the number of nascent proteins that enter the ER. This has an important pro-survival effect on the cell, but also allows the translation of mRNAs such as that of the activating transcription factor 4 (ATF4), which controls the expression of genes that encode proteins involved in redox processes and amino acid metabolism. ATF4 also regulates the expression of important genes involved in apoptosis, including the transcription factor C / EBP-homologous protein (CHOP) and growth arrest and DNA damage-inducible 34 (GADD34), which participates in a feedback loop to dephosphorylate elF2^, restoring protein synthesis. Tumour cells are likely to be dependent on active UPR signalling, as during their growth they are often hypoxic and deprived of nutrients due to insufficient blood supply and abnormal blood vessel function. Human tumours, including those derived from cervical carcinomas, glioblastomas, hepatocellular carcinomas, pancreatic cancers, and breast cancers, show levels of proteins involved in UPR higher than in normal tissues, suggesting a stronger dependence of cancer cells on protein homeostasis and functional ER in order to survive. Hence, PERK is a target of significant interest in cancer therapy. Aberrant activation of the UPR is also implicated in a wide variety of other pathologies, such as ocular diseases, obesity, diabetes (e.g. type 1 diabetes), stroke, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, viral infections, inflammatory diseases, and neurodegenerative diseases (such as prion-related diseases, amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and Parkinson’s disease). PERK has therefore become a therapeutic target of significant interest, on the basis that inhibition of PERK may in turn achieve inhibition of the UPR in a manner having clinical utility in a range of pathological conditions. To this end, a wide range of companies have described PERK inhibiting compounds, such as in WO 2011 / 119663 and WO 2015 / 056180 (both GlaxoSmithKline), J. Med. Chem.2015, 58, 3, 1426–1441 (Amgen), WO 2017 / 220477 (Nerviano), WO 2018 / 194885 (Eli Lilly), and WO 2021 / 041970, WO 2021 / 041973, WO 2021 / 041975 and WO 2021 / 041976 (all Hibercell). In particular, the compound HC-5404, of structure , is under development by Hibercell and is the subject of a phase 1 clinical trial for solid tumours (NCT04834778). A compound having this chemical structure is also disclosed in WO 2018 / 194885 (Eli Lilly). In Pharmaceutics 2022, 14, 2233, 1-20, Hibercell also published a study entitled “Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors” and reporting the “identification of lead molecule 26” of structure: . The compounds of WO 2017 / 220477 (Nerviano) are N-(substituted-phenyl)- sulfonamide derivatives, represented, for instance, by a compound of structure: . In ACS Med. Chem. Lett.2013, 4, 10, 964–968, GlaxoSmithKline published a study entitled “Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development” and disclosing the compound GSK2656157 of structure . There exists a need for safe, alternative, and / or improved methods and compositions containing PERK inhibitors and potentially applicable to treatment of conditions in pathologies involving aberrant activation of the UPR. For instance, there exists a need for new methods and compositions containing PERK inhibitors that have favourable pharmacokinetic profiles, and / or that can be administered in lower doses, and / or that have improved safety profiles, and / or that have favourable selectivity for PERK and hence lower risk of undesirable side effects (for example, lack of inhibition of CYP450 enzymes, favourable kinome selectivity, and / or lack of inhibition of the hERG channel). Summary of the invention The present invention provides compounds (‘compounds of the invention’). Such compounds in particular include compounds of formula (I), as defined herein, as well as tautomers, N-oxides, pharmaceutically acceptable salts, and solvates thereof. Such compounds of the invention include those defined in the appended set of claims. The present invention also provides a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carriers. The present invention also provides a compound of the invention, or a pharmaceutical composition of the invention, for use as a medicament, and particularly for use in a method for treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity. The present invention also provides the use of a compound of the invention, or the pharmaceutical composition of the invention, for the manufacture of a medicament, and particularly a medicament for use in a method for treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity. The present invention also provides a method of treatment, and particularly a method for treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity in a patient in need thereof, the method comprising administering a compound of the invention, or the pharmaceutical composition of the invention, to the patient. Definitions Compounds of the present invention have at least one asymmetric centre. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Hence, the compounds of the present invention include all possible chiral, diastereomeric and racemic forms thereof and all possible geometric isomers thereof. When no specific mention is made of the configuration (cis, trans, R, S, etc.) of a compound (or of an asymmetric carbon), then any one of the isomers or a mixture of more than one isomer is intended. Limitation to a particular asymmetric form of a compound is only intended where expressly indicated. The processes for preparation can use racemates, enantiomers, or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatographic or fractional crystallization. The prepared compounds may be in the free or hydrate form. Compounds of the present invention encompass both compounds in which: (a) all contained atoms are in their natural isotopic form (“natural isotopic form of the compound”); and (b) compounds in which one or more contained atoms are in a non- natural isotopic form (“unnatural variant isotopic form of the compound”), for instance compounds comprising isotopic replacement, enrichment, or depletion. An unnatural variant isotopic form of the compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36Cl), chlorine-37 (37Cl), and fluorine-18 (18F) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms. Unnatural variant isotopic forms of the compound comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half- life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated. The term “substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound (for instance, avoiding unstable acetals, or similar groups). Thus, when a designated moiety is substituted at each designated atom with one or more hydroxy and / or methoxy groups, then that designated atom will not be substituted with more than one methoxy or hydroxy in order to avoid an unstable acetal. Similarly, carbon atoms which are adjacent to a heteroatom that is not part of an aromatic structure will typically not be substituted with additional heteroatoms, and in particular will not be substituted with hydroxy, methoxy or F. When a substituent is oxo (i.e., =O), then 2 hydrogens on the atom are replaced. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with an oxo group, it is intended that the carbon atom of the oxo group be part of (i.e., within) the ring. When a carbon atom is substituted with at least one F, then 1, 2 or 3 hydrogens may be replaced by F. In instances where a designated group is indicated as “optionally substituted with at least one” designated substituent group, then the designated group is either unsubstituted or substituted with a number of the designated substituted groups that is up to but not exceeding the number of hydrogen atoms available on the designated group. Preferably, “at least one” is not more than 7, more preferably not more than 3 (in other words, “optionally substituted with at least one” preferably means “unsubstituted or substituted with up to 7” and more preferably means “unsubstituted or substituted with up to 3”). When any variable (e.g., R2a, R2b, etc.) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence unless otherwise stated. Thus, for example, if a group is substituted with multiple R2agroups, then each R2agroup is selected independently from the definition of R2a. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. "C1- C3alkyl" is intended to include C1, C2and C3alkyl groups (specifically methyl, ethyl, n- propyl and i-propyl). Additionally, for example, "C1-C6 alkyl" denotes alkyl having 1 to 6 carbon atoms (excluding any substituent that may be present). "C1-C3 alkyl" denotes alkyl having 1 to 3 carbon atoms (excluding any substituent that may be present). For avoidance of doubt, a “hydroxy-alkyl” group is a group in which an alkyl group, as herein defined, carries a hydroxy substituent (for instance, -CH2-OH). "Alkoxy" or "alkyloxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C1-C3alkoxy" (or alkyloxy), is intended to include C1, C2 and C3 alkoxy groups (and can also be written equivalently as –O-C1-3 alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy and i-propoxy. The term "cycloalkyl" in general refers to a monocyclic ring or polycyclic (e.g., bicyclic or tricyclic) ring system whose ring atoms consist of carbon atoms, in which all ring bonds between adjacent carbon atoms are single bonds (i.e. a saturated ring system). A polycyclic cycloalkyl may comprise fused rings (where a first ring and a second ring share two adjacent ring carbon atoms), bridged rings (where two non-adjacent ring carbon atoms of a first ring are shared with a second ring) and / or spirocyclic rings (where a first ring shares only a single ring carbon atom with a second ring). A tricyclic or higher order polycyclic cycloalkyl may comprise a mixture of fused, bridged and spirocyclic relationships between its constituent rings. A bicyclic cycloalkyl is one of fused, bridged and spirocyclic. A typical cycloalkyl (or cycloalkylene) is C3-C6cycloalkyl, which is intended to include C3, C4, C5 and C6 cycloalkyl groups. A C5-C6 cycloalkyl is intended to include C5 and C6cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.0]pentyl and the like. As used herein, "heterocyclyl”, “heterocycle” or "heterocyclic” in general refers to a monocyclic ring or polycyclic (e.g., bicyclic or tricyclic) ring system whose ring atoms consist of carbon atoms and at least one heteroatom. A polycyclic heterocyclyl may comprise fused rings (where a first ring and a second ring share two adjacent ring atoms), bridged rings (where two non-adjacent ring atoms of a first ring are shared with a second ring) and / or spirocyclic rings (where a first ring shares only a single ring atom with a second ring). A tricyclic or higher order polycyclic heterocycle may comprise a mixture of fused, bridged and spirocyclic relationships between its constituent rings. A bicyclic heterocycle is one of fused, bridged and spirocyclic. The heterocycle may be saturated or partially unsaturated. Aromatic heterocycles are referred to herein as “heteroaryl”. The term "heterocycle" also includes cycloheteroalkyl. The heterocycle contains at least one heteroatom ring atom. Typically, heteroatoms are selected from N, NR, O, S and SO2, where R is defined appropriately herein. Such heteroatoms may also be referred to as “heteroatomic moieties”. Where a heterocycle (or heteroaryl) is said to include a heteroatom (or heteroatomic moiety) NR, then the nitrogen atom in said NR is to be understood as being part of the ring system, with the -R group not part of the ring system. Similarly, where a heterocycle (or heteroaryl) is said to include a heteroatom (or heteroatomic moiety) SO2, then the sulfur atom in said SO2is to be understood as being part of the ring system, with the two =O groups not part of the ring system. The at least one heteroatom is commonly 1-3 heteroatoms, for instance 1-2 heteroatoms or 1 heteroatom. Preferably, the at least one heteroatom ring atom is selected from N, NR, O and S. More preferably, the at least one heteroatom ring atom is N or NR. Typically the heterocycle contains, in addition to heteroatom ring atoms, at least 1 carbon ring atom, preferably at least two carbon ring atoms. In polycyclic heterocycles, typically each ring contains at least 1 carbon atom. In polycyclic heterocycles at least one ring of the polycyclic ring system contains at least one heteroatom ring atom (for avoidance of doubt, it is not necessary for each ring of a polycyclic heterocycles to contain at least one heteroatom). One or more carbon atoms in any given heterocycle may be substituted with an oxo group. Preferably, one carbon in any given heterocycle may be substituted with an oxo group. Typically, a carbon atom that is adjacent to a nitrogen atom in the heterocycle is substituted with an oxo group. Typical examples of heterocycles include 4- to 7-membered heterocycles, wherein “X-membered” means that the total number of ring atoms possessed by the heterocycle is X. Preferred heterocycles are 4- to 6-membered heterocycles and, particularly preferred are 5- to 6-membered heterocycles. Examples of (cycloheteroalkyl) heterocycles include, but are not limited to, azetidinyl, 1,3-diazetinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolindinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, thianyl, 1,3-dithianyl, 1,4-dithianyl, morpholinyl and thiomorpholinyl. Typical examples of heteroaryl (or “heteroarylene”) groups include 5-membered heteroaryls and 6-membered heteroaryls. 5-membered heteroaryl groups include, without limitation, furanyl, thiophenyl, imidazolyl, thiazolyl, isothiazolyl, indolyl, pyrrolyl (pyrryl), oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and tetrazolyl. 6-membered heteroaryl groups include, without limitation, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and the like. 6-membered heteroaryl groups containing one or two N atoms include pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, especially human beings, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The compounds of the present invention encompass pharmaceutically acceptable salts (in particular, pharmaceutically acceptable salts of compounds of formula (I), as well as solvates, N-oxides and tautomers thereof). As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound (e.g., of formula (I)) is modified by making pharmaceutically acceptable acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (e.g., of formula (I)) which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418, the disclosure of which is hereby incorporated by reference. Non-pharmaceutically acceptable salt forms of the compounds of the invention may be of use during the preparation of non-salt or pharmaceutically acceptable salt forms. Consequently, the disclosure also includes a non-pharmaceutically acceptable salt of a compound of formula (I). The compounds of the present invention encompass solvates (in particular, solvates of compounds of formula (I), as well as salts, N-oxides and tautomers thereof). Solvates include, and preferably are, hydrates. Methods of solvation are generally known in the art. The compounds of the present invention encompass tautomers (in particular, tautomers of compounds of formula (I), as well as salts, solvates and N-oxides thereof). Some compounds of the invention may exist in a plurality of tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are encompassed by the compounds of the present invention. In cases where there are nitrogen atoms (e.g., amines) on compounds of the present invention (e.g. of formula (I)), these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative. The compounds of the present invention encompass N-oxides (in particular, N-oxides of compounds of formula (I), as well as salts, solvates and tautomers thereof). For avoidance of doubt, many compounds of the invention can exist simultaneously in the form of two or more of a tautomer, N-oxide, pharmaceutically acceptable salt, and solvate of a particular parent compound (e.g. a compound of formula (I)), and all such possible compounds are encompassed within the definition of “compound of the invention”. Hence, a compound of the invention (to the extent chemically possible in view of formula (I)) expressly includes any one of the following: (1) a compound of formula (I) (which may also be referred to herein as a “free base form” of the compound); (2) a tautomer of formula (I); (3) an N-oxide of formula (I); (4) a pharmaceutically acceptable salt of formula (I); (5) a solvate of formula (I); (6) an N-oxide of a tautomer of formula (I); (7) a pharmaceutically acceptable salt of a tautomer of formula (I); (8) a solvate of a tautomer of formula (I); (9) a pharmaceutically acceptable salt of an N-oxide of a tautomer of formula (I); (10) a solvate of an N-oxide of a tautomer of formula (I); (11) a solvate of a pharmaceutically acceptable salt of a tautomer of formula (I); (12) a solvate of a pharmaceutically acceptable salt of an N-oxide of a tautomer of formula (I); (13) a pharmaceutically acceptable salt of an N-oxide of formula (I); (14) a solvate of an N-oxide of formula (I); (15) a solvate of a pharmaceutically acceptable salt of an N-oxide of a tautomer of formula (I); and (16) a solvate of a pharmaceutically acceptable salt of formula (I). Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% compound ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds are also part of the present invention. "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain a N-halo, S(O)2H, or S(O)H. Purely for the avoidance of doubt, it should be noted that wherever a compound is disclosed as being either a particular structure (e.g. a particular general chemical formula, such as of formula (I)) or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, then, unless expressly indicated to the contrary, any disclosed further embodiment of that compound (e.g. “A compound … according to …”), and describing additional limitations to the recited structure, continues to embrace any such tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof. As used herein, "treating and / or preventing" or "treatment and / or prevention" of a disease-state in a mammal, particularly a human, include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., slowing or arresting its development; and / or (c) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms. “Therapeutically effective amount" is intended to include an amount of a compound that is effective to achieve a desirable effect in treating and / or preventing a disease-state. A desirable effect is typically clinically significant and / or measurable, for instance in the context of (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., slowing or arresting its development; and / or (c) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms. The therapeutically effective amount may be one that is sufficient to achieve the desirable effect either when the compound is administered alone, or alternatively when it is administered in combination with one or more further APIs, which either are further compounds of the invention or are different from the compounds of the invention. Furthermore, a therapeutically effective amount is typically an amount that is sufficient to inhibit PERK, again when administered either alone or in combination with one or more further APIs (which may also target PERK, or alternatively may exert their pharmacological effects by a different mechanism). Thus, “therapeutically effective amount” is intended to include an amount of a combination of compounds that each are compounds of the invention that is effective to inhibit PERK. For avoidance of doubt, a “therapeutically effective amount” as recited herein can be achieved by any suitable dosage regimen, including but not limited to exemplary dosage regimens described elsewhere herein. Hence, for example, references herein to administering a therapeutically effective amount of a compound by a particular administration route including achieving the therapeutically effective amount via a single dose or by plural doses administered by the specified administration route. For instance, orally administering a therapeutically effective amount includes both orally administering a single dose and orally administering any plural number of doses, provided that a therapeutically effective amount is thereby achieved by oral administration. In all instances herein of references to a method of treating and / or preventing a condition, unless expressly indicated otherwise, a therapeutically effective amount of compound is typically administered. The present invention further includes compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi- solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th ed., 1985, which is incorporated herein by reference in its entirety. Detailed description of the invention The following aspects provide, in conjunction with the disclosure elsewhere herein, non-limiting exemplary embodiments of the present invention. For the avoidance of doubt, the present invention encompasses the subject-matter defined in any one of these aspects, any combination thereof such as those recited by dependency, and any combination thereof with features of the invention that are disclosed elsewhere herein.

[0002] Aspects 1. A compound that (a) is of formula (I): or (b) is a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, wherein: - X is selected from C(R4E) and N; - R1is selected from hydrogen, methyl, NH2and NHCH3; - R2 is selected from: (a) C1-C6 alkyl, (b) hydrogen, (c) -(CH2)n-N(RN)2 in which n is an integer selected from 0 to 6 and each RN is independently selected from hydrogen and C1-C6alkyl, (d) -(CH2)m-(C3-C6cycloalkyl) in which m is an integer selected from 0 to 6, and (e) -(CH2)p-(4- to 7-membered heterocyclyl) in which p is an integer selected from 0 to 6; in which groups (a) and (c) are optionally substituted with at least one R2aand in which groups (d) and (e) are optionally substituted with at least one R2b; - each instance of R2a is independently selected from F, OH and methoxy, provided that any single carbon atom is substituted with no more than one group selected from OH and methoxy; - each instance of R2b is independently selected from F, OH, methoxy, methyl and =O, provided that any single carbon atom is substituted with no more than one group selected from OH and methoxy; - R3A, R3B, R3C and R3D are independently selected from hydrogen, F, Cl, and methyl; and - R4A, R4B, R4C, R4D and R4E are independently selected from hydrogen, F, Cl, Br, CN, C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy, hydroxy-C1-C3 alkyl, and O- cyclopropyl, wherein the C1-C3alkyl, cyclopropyl, C1-C3alkoxy, hydroxy-C1-C3alkyl and O-cyclopropyl are optionally substituted with at least one F. 2. The compound according to aspect 1, wherein X is C(R4E). 3. The compound according to aspect 2, wherein X is N. 4. The compound according to any one of the preceding aspects, wherein R1is hydrogen or methyl. 5. The compound according to aspect 4, wherein R1is hydrogen. 6. The compound according to aspect 4, wherein R1is methyl. 7. The compound according to any one of aspects 1 to 3, wherein R1is NH2. 8. The compound according to any one of aspects 1 to 3, wherein R1is NHCH3. 9. The compound according to any one of the preceding aspects, wherein R2is selected from: (a) C1-C3 alkyl, (b) hydrogen, (c) -(CH2)n-N(RN)2 in which n is an integer selected from 0 to 3 and each RNis independently selected from hydrogen and C1-C3alkyl, (d) -(CH2)m-(C3-C6cycloalkyl) in which m is an integer selected from 0 to 3, and (e) - (CH2)p-(4- to 7-membered heterocyclyl) in which p is an integer selected from 0 to 3; in which groups (a), (c), (d) and (e) are optionally substituted with an OH group. 10. The compound according to any one of the preceding aspects, wherein R2is methyl. 11. The compound according to any one of aspect 1 to 9, wherein R2is hydrogen. 12. The compound according to any one of the preceding aspects, which (a) is of formula (Ia): or (b) is a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof. 13. The compound according to any one of the preceding aspects, wherein R3Ais selected from F, Cl, and methyl. 14. The compound according to aspect 13, wherein R3Ais F. 15. The compound according to aspect 13, wherein R3A is Cl. 16. The compound according to aspect 13, wherein R3Ais methyl. 17. The compound according to any one of aspects 1 to 12, wherein R3A is hydrogen. 18. The compound according to any one of the preceding aspects, wherein R3B is selected from F, Cl, and methyl. 19. The compound according to aspect 18, wherein R3B is F. 20. The compound according to aspect 18, wherein R3B is Cl. 21. The compound according to aspect 18, wherein R3Bis methyl. 22. The compound according to any one of aspects 1 to 17, wherein R3B is hydrogen. 23. The compound according to any one of the preceding aspects, wherein R3Cis selected from F, Cl, and methyl. 24. The compound according to aspect 23, wherein R3Cis F. 25. The compound according to aspect 23, wherein R3C is Cl. 26. The compound according to aspect 23, wherein R3Cis methyl. 27. The compound according to any one of aspects 1 to 22, wherein R3C is hydrogen. 28. The compound according to any one of the preceding aspects, wherein R3D is hydrogen. 29. The compound according to any one of aspects 1 to 27, wherein R3Dis selected from F, Cl, and methyl. 30. The compound according to any one of the preceding aspects, wherein at least two of R3A, R3B, R3C and R3D are hydrogen. 31. The compound according to aspect 30, wherein two of R3A, R3B, R3Cand R3Dare hydrogen, and the remaining two of R3A, R3B, R3Cand R3Dare not hydrogen. 32. The compound according to aspect 30, wherein three of R3A, R3B, R3Cand R3Dare hydrogen, and the remaining one of R3A, R3B, R3Cand R3Dis not hydrogen. 33. The compound according to any one of aspects 1 to 12, wherein: - R3Ais selected from F, Cl, and methyl; - one of R3B and R3C is hydrogen, and the other of R3B and R3C is selected from hydrogen, F, Cl, and methyl; and - R3Dis hydrogen. 34. The compound according to aspect 33, wherein one of R3B and R3C is hydrogen, and the other of R3B and R3C is selected from hydrogen and F. 35. The compound according to any one of the preceding aspects, wherein R4B, R4C, R4D and R4E are independently selected from hydrogen, F, Cl, CN, C1-C3 alkyl, C1-C3 alkoxy and hydroxy-C1-C3alkyl, wherein the C1-C3alkyl, C1-C3alkoxy and hydroxy-C1- C3alkyl are optionally substituted with at least one F. 36. The compound according to aspect 35, wherein R4B, R4C, R4Dand R4Eare independently selected from hydrogen, F, Cl, CF3, CHF2, OCF3and OCHF2. 37. The compound according to aspect 36, wherein R4B, R4C, R4D and R4E are independently selected from hydrogen and F. 38. The compound according to any one of the preceding aspects, wherein at most two of R4B, R4C, R4Dand R4Eare a group other than hydrogen. 39. The compound according to aspect 38, wherein at most one of R4B, R4C, R4D and R4Eis a group other than hydrogen. 40. The compound according to any one of the preceding aspects, wherein R4B is hydrogen. 41. The compound according to any one of the preceding aspects, wherein R4Dis hydrogen. 42. The compound according to any one of the preceding aspects, wherein R4Eis hydrogen. 43. The compound according to any one of the preceding aspects, wherein R4Ais selected from F, Cl, C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy and O-cyclopropyl, wherein the C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy and O-cyclopropyl are optionally substituted with at least one F. 44. The compound according to aspect 43, wherein R4A is selected from F, Cl, methyl, cyclopropyl and methoxy, wherein the methyl, cyclopropyl and methoxy are optionally substituted with at least one F. 45. The compound according to aspect 43, wherein R4A is selected from F, Cl, CF3, CHF2, OCF3and OCHF2. 46. The compound according to aspect 43, wherein R4A is selected from F, Cl, CF3 and OCF3. 47. The compound according to any one of aspects 1 to 34, wherein: - R4A is selected from F, Cl, methyl, cyclopropyl and methoxy, wherein the methyl, cyclopropyl and methoxy are optionally substituted with at least one F; - X is C(R4E); and - either (a) all of R4B, R4C, R4D and R4E are hydrogen, or (b) three of R4B, R4C, R4D and R4Eare hydrogen and the remaining one of R4B, R4C, R4Dand R4Eis selected from F, Cl, CN, C1-C3alkyl, C1-C3alkoxy and hydroxy-C1-C3alkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy and hydroxy-C1-C3 alkyl are optionally substituted with at least one F. 48. The compound according to aspect 47, wherein: - R4A is selected from F, Cl, CF3, CHF2, OCF3 and OCHF2; - R4B, R4Dand R4Eare hydrogen; and - R4Cis selected from hydrogen, F, Cl, CF3, CHF2, OCF3and OCHF2. 49. The compound according to aspect 48, wherein: - R4Ais selected from F, Cl, CF3and OCF3; and - R4C is selected from hydrogen and F. 50. The compound according to aspect 1, wherein the formula (I) is selected from: N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-fluoro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-phenylacetamide;; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro- 4-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(m-tolyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro- 5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,4- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-(3-fluorophenyl)-2- hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-(3-chlorophenyl)-2- hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(4-chloro- 3-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro- 4-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(6-methylpyridin-2-yl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(2,3- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-fluoro- 5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro- 5-(trifluoromethoxy)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro- 5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(2,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-fluoro- 5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-chloro- 5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- cyclopropylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(2,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-fluoro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-chloro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(2,3- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-methyl-5-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- (difluoromethoxy)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- fluoro-5-(trifluoromethoxy)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chloro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- fluoro-5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chloro-5-methylphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(m-tolyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-methoxy-5-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-methoxyphenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-cyanophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-cyano- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-cyano- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-chlorophenyl)-2- hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-(2-hydroxyethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(2-hydroxyethyl)-5-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chlorophenyl)-2- hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5-difluorophenyl)- 2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chlorophenyl)-2- hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3-chloro-5- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro-5- fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(5,7-diamino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-5-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide N-(4-(7-amino-3-(piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide N-(4-(7-amino-3-(1-methylpiperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide N-(4-(7-amino-3-cyclopropyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; and N-(4-(7-amino-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide. 51. The compound according to aspect 1, wherein the formula (I) is selected from: N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluoro-phenyl]-2-(3,5- difluorophenyl)-2-hydroxy-acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methyl-phenyl]-2-(3,5- difluorophenyl)-2-hydroxy-acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-fluoro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; and N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide. 52. The compound according to aspect 1, wherein the formula (I) is selected from: N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluoro-phenyl]-2-(3,5- difluorophenyl)-2-hydroxy-acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methyl-phenyl]-2-(3,5- difluorophenyl)-2-hydroxy-acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; and N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethyl)phenyl)acetamide. 53. The compound according to aspect 12, wherein the formula (Ia) is selected from: (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-(3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-phenylacetamide;; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluoro-4-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(m-tolyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluoro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,4- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(4- chloro-3-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluoro-4-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(6-methylpyridin-2-yl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(2,3- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- fluoro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- fluoro-5-(trifluoromethoxy)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chloro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(2,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluoro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- dichlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chloro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- cyclopropylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(2,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chloro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chloro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(2,3- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- (difluoromethoxy)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-fluoro-5-(trifluoromethoxy)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-chloro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-fluoro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-chloro-5-methylphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3,5-dichlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(m-tolyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-methoxy-5-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-methyl-5-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-methoxyphenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- (3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-(3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-(3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- (3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(6-(trifluoromethyl)pyridin-2-yl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- (3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-cyanophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- (3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- cyano-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- cyano-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-(2-hydroxyethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(2-hydroxyethyl)-5-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy-2-(3- (trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)- 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy-2-(3- (trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)- 2-(3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)- 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)- 2-(3-chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-hydroxy-2- (3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)- 2-(3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)- 2-hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro-5- fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(5,7-diamino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-5-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (2R)-N-(4-(7-amino-3-(piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (2R)-N-(4-(7-amino-3-(1-methylpiperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (2R)-N-(4-(7-amino-3-cyclopropyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; and (2R)-N-(4-(7-amino-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide. 54. The compound according to aspect 12, wherein the formula (Ia) is selected from: (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluoro-phenyl]-2- (3,5-difluorophenyl)-2-hydroxy-acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methyl-phenyl]-2- (3,5-difluorophenyl)-2-hydroxy-acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; and (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-(3-chlorophenyl)-2-hydroxyacetamide. 55. The compound according to aspect 12, wherein the formula (Ia) is selected from: (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluoro-phenyl]-2- (3,5-difluorophenyl)-2-hydroxy-acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methyl-phenyl]-2- (3,5-difluorophenyl)-2-hydroxy-acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; and (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide. 56. A compound according to any one of the preceding aspects, wherein all of the atoms of the compound are in their natural isotopic form. 57. A compound according to any one of the preceding aspects, which is a tautomer of formula (I). 58. A compound according to any one of the preceding aspects, which is an N-oxide of: (a) formula (I); or (b) the tautomer according to aspect 57. 59. A compound according to any one of the preceding aspects, which is a pharmaceutically acceptable salt of: (a) formula (I); (b) the tautomer according to aspect 57; or (c) the N-oxide according to aspect 58. 60. A compound according to any one of the preceding aspects, which is a solvate of (a) formula (I); (b) the tautomer according to aspect 57; (c) the N-oxide according to aspect 58; or (d) the pharmaceutically acceptable salt according to aspect 59. 61. A compound according to any one of aspects 1 to 56, which is a compound of formula (I). 62. A pharmaceutical composition comprising a compound according to any one of the preceding aspects in association with one or more pharmaceutically acceptable carriers. 63. A compound according to any one of aspects 1 to 61, or a pharmaceutical composition according to aspect 62, for use as a medicament. 64. The use of a compound according to any one of aspects 1 to 61, or a pharmaceutical composition according to aspect 62, for the manufacture of a medicament. 65. A method of treatment for a patient in need thereof, the method comprising administering a compound according to any one of aspects 1 to 61, or a pharmaceutical composition according to aspect 62, to the patient. 66. A compound according to any one of aspects 1 to 61, or a pharmaceutical composition according to aspect 62, for use in a method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity. 67. The use of a compound according to any one of aspects 1 to 61, or a pharmaceutical composition according to aspect 62, for the manufacture of a medicament for use in a method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity. 68. A method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity in a patient, the method comprising administering a compound according to any one of aspects 1 to 61, or a pharmaceutical composition according to aspect 62, to the patient. 69. The compound or pharmaceutical composition for use according to aspect 66, use according to aspect 67, or method according to aspect 68, wherein the disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity is selected from cancers, cellular proliferative disorders, viral infections, autoimmune and neurodegenerative disorders, pre-cancerous syndromes, ocular diseases, Type 1 diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, obesity, and inflammatory diseases. 70. The compound or pharmaceutical composition for use, use, or method according to aspect 69, wherein the disease is cancer. 71. The compound or pharmaceutical composition for use, use, or method according to aspect 69 or 70, wherein the cancer is selected from: brain glioma, glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, non-melanoma skin, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, metastatic melanoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. 72. The compound or pharmaceutical composition for use, use, or method according to aspect 69, wherein the cellular proliferative disorders are selected from benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. 73. The compound or pharmaceutical composition for use, use, or method according to aspect 69, wherein the viral infections comprise the prevention of AIDS development in an HIV-infected patient. 74. The compound or pharmaceutical composition for use, use, or method according to aspect 69, wherein the autoimmune and neurodegenerative diseases are selected from the group consisting of transplant rejection, skin disorders including psoriasis, allergies, asthma, rheumatoid arthritis (RA), multiple sclerosis, systemic lupus erythematosus (SLE), Crohn’s disease, prion-related diseases, Alzheimer’s disease, degenerative nerve diseases, encephalitis, stroke, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Pick’s disease. 75. The compound or pharmaceutical composition for use, use, or method according to aspect 69, wherein the pre-cancerous syndromes are selected from cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis. 76. The compound or pharmaceutical composition for use, use, or method according to aspect 69, wherein the ocular diseases are selected from: rubeosis irides; neovascular glaucoma; pterygium; vascularized glaucoma filtering blebs; conjunctival papilloma; choroidal neovascularization associated with age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema; retinal neovascularization due to diabetes; age-related macular degeneration (AMD); macular degeneration; ocular ischemic syndrome from carotid artery disease; ophthalmic or retinal artery occlusion; sickle cell retinopathy; retinopathy of prematurity; Eale’s Disease; and VonHippel-Lindau syndrome 77. The compound or pharmaceutical composition for use, use, or method according to any one of aspects 63 to 76, wherein the patient is a human. Compounds of the invention The compounds of the invention are as defined in the detailed aspects (i.e. aspects 1 to 61) above. Further preferred sub-aspects of the compounds of the present invention are provided below. Additionally, it is emphasized that all novel intermediates produced the synthesis of compounds of the present invention are also part of the invention, including but not limited to all of the compounds disclosed in the present Examples section. Thus, a compound of the invention is either (a) of formula (I) or (b) is a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof. X is preferably C(R4E). In an alternative aspect, however, X is N. R1is preferably hydrogen or methyl. More preferably R1is hydrogen. However, in an alternative, but still preferred, aspect, R1is methyl. In a further alternative aspect, R1is NH2. In a still further alternative aspect, R1is NHCH3. Preferably R2is selected from: (a) C1-C3alkyl, (b) hydrogen, (c) -(CH2)n-N(RN)2in which n is an integer selected from 0 to 3 and each RNis independently selected from hydrogen and C1-C3 alkyl, (d) -(CH2)m-(C3-C6 cycloalkyl) in which m is an integer selected from 0 to 3, and (e) -(CH2)p-(4- to 7-membered heterocyclyl) in which p is an integer selected from 0 to 3; in which groups (a), (c), (d) and (e) are optionally substituted with an OH group. More preferably R2is methyl or hydrogen. Particularly preferably R2is methyl. Preferably the formula (I) is the formula (Ia). Preferably R3Ais selected from F, Cl, and methyl. One preferred example is wherein R3A is F. Another preferred example thereof is wherein R3A is Cl. A further preferred example thereof is wherein R3Ais methyl. In an alternative aspect, however, R3Ais hydrogen. In one aspect, R3B is selected from F, Cl, and methyl (e.g., R3B is F, or R3B is Cl, or R3B is methyl). In another aspect, R3B is hydrogen. In one aspect, R3Cis selected from F, Cl, and methyl (e.g., R3Cis F, or R3Cis Cl, or R3C is methyl). In another aspect, R3C is hydrogen. Preferably R3D is hydrogen. In an alternative aspect, however, R3D is selected from F, Cl, and methyl. Preferably at least two of R3A, R3B, R3Cand R3Dare hydrogen (although in such aspects, it is preferable that R3A is not hydrogen). For instance, in one such aspect two of R3A, R3B, R3Cand R3Dare hydrogen, and the remaining two of R3A, R3B, R3Cand R3Dare not hydrogen (and in such aspects, it is preferable that R3Ais not hydrogen). In another such aspect, three of R3A, R3B, R3C and R3D are hydrogen, and the remaining one of R3A, R3B, R3C and R3D is not hydrogen (and in such aspects, it is preferable that R3A is not hydrogen). Preferably with respect to R3A, R3B, R3Cand R3D: R3Ais selected from F, Cl, and methyl; one of R3B and R3C is hydrogen, and the other of R3B and R3C is selected from hydrogen, F, Cl, and methyl; and R3Dis hydrogen. Particularly preferable in such aspects is that one of R3Band R3Cis hydrogen, and the other of R3Band R3Cis selected from hydrogen and F. Preferably R4B, R4C, R4D and R4E are independently selected from hydrogen, F, Cl, CN, C1-C3alkyl, C1-C3alkoxy and hydroxy-C1-C3alkyl, wherein the C1-C3alkyl, C1-C3alkoxy and hydroxy-C1-C3 alkyl are optionally substituted with at least one F. More preferably R4B, R4C, R4D and R4E are independently selected from hydrogen, F, Cl, CF3, CHF2, OCF3and OCHF2. More preferably still R4B, R4C, R4Dand R4Eare independently selected from hydrogen and F. Preferably at most two of R4B, R4C, R4D and R4E are a group other than hydrogen. More preferably at most one of R4B, R4C, R4D and R4E is a group other than hydrogen. Preferably R4Bis hydrogen. Preferably R4D is hydrogen. Preferably R4E is hydrogen. Preferably R4Ais selected from F, Cl, C1-C3alkyl, cyclopropyl, C1-C3alkoxy and O-cyclopropyl, wherein the C1-C3alkyl, cyclopropyl, C1-C3alkoxy and O-cyclopropyl are optionally substituted with at least one F. More preferably R4A is selected from F, Cl, methyl, cyclopropyl and methoxy, wherein the methyl, cyclopropyl and methoxy are optionally substituted with at least one F. More preferably still R4Ais selected from F, Cl, CF3, CHF2, OCF3 and OCHF2. Yet more preferably R4A is selected from F, Cl, CF3 and OCF3. With respect to R4A, R4B, R4C, R4Dand R4E, preferably: R4Ais selected from F, Cl, methyl, cyclopropyl and methoxy, wherein the methyl, cyclopropyl and methoxy are optionally substituted with at least one F; X is C(R4E); and either (a) all of R4B, R4C, R4D and R4Eare hydrogen, or (b) three of R4B, R4C, R4Dand R4Eare hydrogen and the remaining one of R4B, R4C, R4Dand R4Eis selected from F, Cl, CN, C1-C3alkyl, C1-C3alkoxy and hydroxy-C1-C3 alkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy and hydroxy-C1- C3alkyl are optionally substituted with at least one F. More preferably in such aspects: R4Ais selected from F, Cl, CF3, CHF2, OCF3and OCHF2; R4B, R4Dand R4Eare hydrogen; and R4C is selected from hydrogen, F, Cl, CF3, CHF2, OCF3 and OCHF2. More preferably still in such aspects: R4A is selected from F, Cl, CF3 and OCF3; and R4C is selected from hydrogen and F. Non-limiting examples of specific, representative compounds of the invention are set out in the above aspects and in the Examples section. PERK inhibition The compounds of the invention are typically capable of inhibiting PERK following administration to a subject. Such a compound is also referred to herein as a “PERK inhibitor”. In one preferred aspect, a compound is a PERK inhibitor when the compound has an IC50of 200 nM or less (preferably 100 nM or less, further preferably 75 nM or less, yet further preferably 50 nM or less, more preferably 25 nM or less, most preferably 10 nM or less) when measured in accordance with the method defined in in the Examples section (specifically under the heading “Biochemical determination of IC50 at PERK enzyme using LanthaScreen Technology” in Example 197). In preferred aspects the compounds of the invention may also exhibit favourable pharmacokinetic properties, including but not limited to the properties discussed in present Example 198. In a preferred aspect, the compounds of the invention have beneficial selectivity for PERK over other physiologically relevant enzymes. For instance, the compounds may have high selectivity for PERK over other kinases (i.e., the compounds may have a favourable kinome selectivity). The compounds may exhibit low or no inhibition of CYP450 enzymes (it being known in the art that inhibition of CYP450 enzymes is associated with higher risks of clinical drug-drug interactions). Examples of CYP450 enzymes include CYP3A4-M, CYP1A2, CYP2C9 and CYP2D6. Still further, the compounds may exhibit low or no inhibition of the hERG channel (it being known that inhibition of the hERG channel is associated with increased cardiovascular risk). Non- limiting examples of suitable protocols for interrogating activity against any of these enzymes are provided in present Example 199. Dosage and formulation The compounds of the invention, when used in a method of treatment, can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Thus, preferably, the compounds of the present invention can be included in a pharmaceutical composition as defined in aspect 62. Preferably the pharmaceutical composition is suitable for oral administration. One exemplary such pharmaceutical composition is a solid dosage form suitable for oral administration (e.g., a tablet, capsule (each of which includes a sustained release or timed release formulation), pill, powder, or granule). Another exemplary such pharmaceutical composition is a liquid dosage form suitable for oral administration (e.g., an elixir, tincture, suspension, syrup, solution or emulsion). Preferably, the compounds or pharmaceutical composition of the invention are for use in a method of treatment comprising administering a therapeutically effective amount of the compound or pharmaceutical composition, and particularly preferably a method of treatment comprising orally administering a therapeutically effective amount of the compound or pharmaceutical composition. Thus, the compounds of the invention are preferably administered in solid dosage forms for oral administration (such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, or granules) or as liquid dosage forms for oral administration (such as, elixirs, tinctures, suspensions, syrups, solutions and emulsions). However, the compounds of the invention may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. The dosage regimen for the compounds of the invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder. By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg / kg of body weight, preferably between about 0.01 to 100 mg / kg of body weight per day, and most preferably between about 1.0 to 20 mg / kg / day. Intravenously, the most preferred doses will range from about 1 to about 10 mg / kg / minute during a constant rate infusion. Compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Compounds of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The compounds are typically administered alongside suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylacetic acid, polyglycolic acid, copolymers of polylacetic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. Compound / composition for use as medicament In an embodiment, the compound or pharmaceutical composition of the present invention is for use as a medicament, as defined in aspect 63. Compound / composition for use in a method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity In another embodiment, the compound or pharmaceutical composition is for use in a method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity, as defined in aspects 66 and 69 to 77. Diseases to be treated The disease to be treated and / or prevented in the present invention is typically a disease or condition where inhibition of PERK is known, or can be shown, to produce a beneficial effect (also described herein as a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity). Non-limiting examples of diseases associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity, that may be susceptible to treatment according to the present invention, include cancers, cellular proliferative disorders, viral infections, autoimmune and neurodegenerative disorders, pre-cancerous syndromes, ocular diseases, Type 1 diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, obesity, and inflammatory diseases. In one preferred aspect, the disease is cancer. Non-limiting examples thereof include brain glioma, glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan- Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, non-melanoma skin, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, metastatic melanoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. One preferred such cancer is pancreatic cancer. Another preferred such cancer is renal cancer. Another preferred such cancer is gastric cancer. Non-limiting examples of cellular proliferative disorders include benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. A non-limiting example of a viral infection is HIV, particularly wherein treatment with the compounds described herein are directed to the prevention of AIDS development in an HIV-infected patient. Non-limiting examples of autoimmune and neurodegenerative diseases include transplant rejection, skin disorders including psoriasis, allergies, asthma, rheumatoid arthritis (RA), multiple sclerosis, systemic lupus erythematosus (SLE), Crohn’s disease, prion-related diseases, Alzheimer’s disease, degenerative nerve diseases, encephalitis, stroke, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Pick’s disease. Non-limiting examples of pre-cancerous syndromes include cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis. Non-limiting examples of ocular diseases include: rubeosis irides; neovascular glaucoma; pterygium; vascularized glaucoma filtering blebs; conjunctival papilloma; choroidal neovascularization associated with age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema; retinal neovascularization due to diabetes; age-related macular degeneration (AMD); macular degeneration; ocular ischemic syndrome from carotid artery disease; ophthalmic or retinal artery occlusion; sickle cell retinopathy; retinopathy of prematurity; Eale’s Disease; and VonHippel-Lindau syndrome. Use for manufacture of a medicament The present invention provides the use of a compound or pharmaceutical composition according to the invention for the manufacture of a medicament, preferably for use in a method for treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity, as defined in aspects 64, 67 and 69 to 77. It will be understood that all preferred disclosure provided above in connection with the compound or pharmaceutical composition according to the invention for use according to the invention is equally contemplated as preferred in the context of the use of a compound or pharmaceutical composition according to the invention, for the manufacture of a medicament according to the present invention. Method of treatment The present invention provides a method of treatment, preferably a method for treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity, the method comprising administering a compound according to the invention, as defined in aspects 65 and 68 to 77. It will be understood that all preferred disclosure provided above in connection with the compound or pharmaceutical composition according to the invention for use according to the invention is equally contemplated as preferred in the context of the method of treatment according to the present invention. Synthesis of the compounds The compounds of the present invention can be prepared by any suitable technique known in the art. Particular methods for forming compounds of formula (I) defined herein are shown below and in the accompanying examples. In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised. It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For Examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. The methodology employed to synthesise a compound of formula (I) will vary depending on the nature of R1, R2, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R4E, R5, R6, R7and X or any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples. The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art. According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I) as hereinbefore described which comprises any one of (a), (b), (c) and (d): (a) preparing a compound of formula (I) wherein R1 and R2 are independently Me or H, in compounds of formula (II), (IV), (V) and (VII) R5 is NH2 or N-PG, and in compounds of formula (VI) R6is a boronic acid or ester (Scheme 1). Compounds of formula (I) may be prepared by reacting a compound of formula (VII) in a Pd coupling reaction (i) with a compound of formula (VI) to generate a compound of formula (V) which undergoes a deprotection step (ii) to generate a compound of formula (IV) followed by a coupling step (iii) with a compound of formula (III) to afford a compound of formula (II) followed by a suitable deprotection step (iv), if required, to generate a compound of formula (I) which can be further purified, if desired, to isolate the individual enantiomers of compound of formula (I):

[0003] Scheme 1 (b) preparing a compound of formula (I) wherein R1 and R2 are independently Me or H, in compounds of formula (IV), (VII) and (VI) R5is NH2or N-PG, and in compounds of formula (IX) R7is a halogen (Scheme 2). Compounds of formula (I) may be prepared by reacting compound of formula (VII) with and Aryl Halide (IX) in an SnAr reaction (i) to generate a compound of formula (VIII), followed by a reduction step (ii) to generate a compound of formula (IV) followed by a coupling step (iii) with a compound of formula (III) to afford a compound of formula (II) followed by a suitable deprotection step (iv), if required, to generate a compound of formula (I) which can be further purified, if desired, to isolate the individual enantiomers of compound of formula (I):

[0004] Scheme 2 (c) preparing a compound of formula (I) wherein R1 is Me or H, and R2 is C1-C6 alkyl, -N(RN)2, -(CH2)m-(C3-C6cycloalkyl) or -(CH2)p-(4- to 7-membered heterocyclyl), R5is NH2or N-PG, and in compounds of formula (VI) R6is a boronic acid or ester (Scheme 3). Compounds of formula (I) may be prepared by reacting a compound of formula (XIV) in bromination reaction (i) to generate a compound of formula (XIII) which undergoes a Pd coupling reaction (ii) with a compound of formula (VI) to generate a compound of formula (XII) which undergoes a deprotection step (iii) to generate a compound of formula (XI) followed by a coupling step (iv) with a compound of formula (III) to afford a compound of formula (X) which undergoes a Pd coupling reaction with a primary or secondary amine, or a boronic acid or ester (v) followed by a suitable deprotection step (iv) then a reduction step, where required (vii) to generate a compound of formula (I) which can be further purified, if desired, to isolate the individual enantiomers of compound of formula (I):

[0005] Scheme 3 Compounds of formula (I) wherein R2is -(CH2)n-N(RN)2in which n is non-zero can be obtained by routine modifications to the methods in Scheme 3 or by other routine synthetic strategies. (d) preparing a compound of formula (I) wherein R1is NH2, N-PG, NHMe, NMe-PG and R2is H or Me, R5is NH2or N-PG, and in compounds of formula (VI) R6is a boronic acid or ester (Scheme 4). Compounds of formula (I) may be prepared by reacting a compound of formula (XX) in a cyclisation reaction (i) and optionally a protection step (ii) to generate a compound of formula (XIX) which undergoes a Pd coupling reaction (iii) with a compound of formula (VI) and optionally a protection step (iv) to generate a compound of formula (XVIII) which undergoes a activation step (v) to generate a compound of formula (XVII) which then undergoes a displacement reaction (vi) followed optionally by a protection step (vii) followed by a deprotection step (viii) to generate a compound of formula (XVI) followed by a coupling step (ix) with a compound of formula (III) to afford a compound of formula (XV) followed by suitable deprotection steps (x) and optionally (xi) to generate a compound of formula (I) which can be further purified, if desired, to isolate the individual enantiomers of compound of formula (I): Scheme 4 In an exemplary specific aspect of process (a) above: Step (i) comprises formation of a hetero aryl bond using copper catalyzed coupling reaction conditions in a polar protic solvent, with a base present. Preferred conditions comprise DMAP and Cu(OAc)2 in MeOH at 0 °C to RT then Step (ii) comprises deprotection. Preferred conditions comprise TFA in DCM at RT. Step (iii) comprises formation of aryl amide in the presence of T3P and DIPEA at 0 °C to RT. Step (iv) comprises deprotection. Preferred conditions comprise 7M NH3 in MeOH or ZnCl2in EtOH at RT to afford compound (I) which can be further purified by SFC or Chiral-HPLC to isolate individual enantiomers of compound of formula (I). In an exemplary specific aspect of process (b) above: Step (i) comprises formation of a hetero aryl bond using SnAr conditions in a polar protic solvent, with a base present. Preferred conditions comprise Cu(OAc)2, Cs2CO3 in DMF at 60 °C then Step (ii) comprises reduction of an aryl nitro group. Preferred conditions comprise Zinc dust and NH4Cl in MeOH at 0 °C to RT. Step (iii) comprises formation of aryl amide in the presence of T3P and DIPEA at 0 °C to RT. Step (iv) comprises deprotection. Preferred conditions comprise 7M NH3 in MeOH or ZnCl2in EtOH at RT to afford compound (I) which can be further purified by SFC or Chiral-HPLC to isolate individual enantiomers of compound of formula (I). In an exemplary specific aspect of process (c) above: Step (i) comprises insertion of a bromine group to a heterocycle. Preferred conditions NBS in DMF at RT then step (ii) formation of a hetero aryl bond using a cross coupling reaction. Preferred conditions comprise Cu(OAc)2, Cs2CO3 in DMF at 60 °C then Step (iii) comprises deprotection. Preferred conditions comprise TFA in DCM at RT. Step (iv) comprises formation of aryl amide in the presence of T3P and DIPEA at 0 °C to RT. Step (v) comprises formation of a C-C bond using Pd catalyzed coupling reaction conditions in a polar protic solvent, with a base present. Preferred conditions comprise Cs2CO3and PdCl2(dppf) in Dioxane / H2O at 80 °C. Step (vi) comprises deprotection. Preferred conditions comprise 7M NH3 in MeOH or ZnCl2in EtOH at RT and optionally step (vi) comprises reduction of a double bond. Preferred conditions Pd / C under an atmosphere of Hydrogen to afford compound (I) which can be further purified by SFC or Chiral-HPLC to isolate individual enantiomers of compound of formula (I). In an exemplary specific aspect of process (d) above: Step (i) comprises cyclisation to a heterocycle. Preferred conditions Trichloroacetyl isocyanate and NH3 in MeOH at RT then step (ii) an optional protection step. Preferred conditions comprising DMF-DMA at 70 °C. Step (iii) comprises formation of a hetero aryl bond using a cross coupling reaction. Preferred conditions comprise Cu(OAc)2, DMAP in MeOH at 60 °C then Step (iv) comprises an optional protection step. Preferred conditions comprising DMF-DMA at 70 °C. Step (v) comprises an activation step. Preferred conditions comprise triflic anhydride and DIPEA in DCM at 0 °C to RT. Step (vi) comprised a displacement reaction. Preferred conditions comprise a protected amine, base at 120°C in the MW then Step (vii) comprises an optional protection step. Preferred conditions comprising DMF-DMA at 70 °C. Step (viii) comprises a deprotection step. Preferred conditions comprise HCl in Dioxane at RT or TFA in DCM at RT. Step (ix) comprises formation of aryl amide in the presence of T3P and DIPEA at 0 °C to RT. Step (x) comprises deprotection. Preferred conditions comprise 7M NH3in MeOH or ZnCl2 in EtOH at RT and optionally step (xi) comprises an additional deprotection step. Preferred conditions TFA in DCM at RT to afford compound (I) which can be further purified by SFC or Chiral-HPLC to isolate individual enantiomers of compound of formula (I). Compounds of formula (III), (VI), (VII), and (IX) are either commercially available, prepared according to the methods described herein, or prepared according to the literature. Examples The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named using conventional IUPAC nomenclature, or as named by the chemical supplier. The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesized according to the step in the description given. Analytical methods: All LCMS spectra were obtained by using one of the below methods. Abbreviation Method Description AM1 LCMS (Method 1) Column: X-Bridge C 18 (50 x 4.6 mm,3.5µ), Mobile phase A: 5mM Ammonium Acetate in Water, Mobile phase B: Acetonitrile+5mM Ammonium Acetate in Water (90:10), Flow rate:1.2ml / min, Column Temperature:45°C, Gradient (Time / %B):0.0 / 10,0.75 / 10,1.25 / 20,2.50 / 60,3.75 / 98,4.25 / 98,4.5 0 / 10, 5.10 / 10 AM2 LCMS (Method 2) Column: Acquity UPLC BEH C 18 (50 x 2.1 mm,1.7µ), Mobile phase A: 0.05% FA in Water Mobile phase B: Acetonitrile+0.05% FA in water in Water (90:10), Flow rate:0.6ml / min Column Temperature:45 °C, Gradient (Time / %B): 0.0 / 05,0.75 / 05,1.50 / 25,2.50 / 60,3.0 / 95,4.0 / 95,4.50 / 05,5.1 0 / 05 All HPLC spectra were obtained by using one of the below methods. Abbreviation Method Description AM3 HPLC (Method 1) Column Name: YMC-Triart C18 (100*4.6 mm), 3um. Mobile phase A: 10 mM Ammonium Bicarbonate in Water, Mobile phase B: Acetonitrile Flow: 1.0 ml / min. AM4 HPLC (Method 2) Column Name: XSelect CSH C18 (100*4.6 mm),3.5um Mobile phase A: 0.05% Formic Acid in Water, Mobile phase B: Acetonitrile, Flow: 1.0 ml / min. AM5 HPLC (Method 3) Column Name: X BRIDGE C18 (50*4.6 mm),3.5um. Mobile phase A: 10 mM Ammonium Bicarbonate in Water, Mobile phase B: Acetonitrile Flow: 1.0 ml / min. AM6 HPLC (Method 4) Column Name: X BRIDGE C18 (50*4.6 mm),3.5um. Mobile phase A: 10 mM Ammonium Bicarbonate in Water, Mobile phase B: Acetonitrile Flow: 1.0 ml / min. AM7 HPLC (Method 5) Column Name: Phenomenex Luna C18 (150*4.6 mm),3um. Mobile phase A: 10 mM Ammonium Bicarbonate In Water. Mobile phase B: Acetonitrile. Flow: 1.0 ml / min. AM8 PREP-HPLC Column:(R, R) Whelk-O1 (21.1 mm x 250mm), 5µ, (Method 1) Flow: 20ml / min, Mobile Phase A: 20mM Ammonium Bicarbonate in Water, Mobile Phase B: Acetonitrile, Method: 60% A and 40%B isocratic, DILUENT: MeOH AM9 PREP-HPLC Column Name: (R, R) Whelk-O1 (250*4.6 mm),5um., (Method 2) Mobile phase A: 10 mM Ammonium Bicarbonate in Water, Mobile phase B: Acetonitrile, Flow: 1.0 ml / min., Gradient (T / %B): 50% B All Chiral HPLC / SFC analytical spectra were obtained by using one of the below methods. Abbreviation Method Description AM10 SFC (Method 1) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 75% CO2 + 25% of (Methanol), ABPR: 100 bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM11 SFC (Method 2) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 70% CO2 + 30% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM12 SFC (Method 3) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 65% CO2 + 35% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM13 SFC (Method 4) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 85% CO2 + 15% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM14 SFC (Method 5) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 70% CO2 + 30% of [HEX: IPA (60:40)], ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM15 SFC (Method 6) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 70 ml / min, Mobile Phase: 60% CO2 + 40% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM16 SFC (Method 7) Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 70 ml / min, Mobile Phase: 70% CO2 + 30% of (0.1%IPAmine in Methanol), ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF AM17 Reverse-Phase- Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Chiral (Method 1) Flow: 14 ml / min, Mobile Phase A: 20mM Ammonium Bicarbonate in Water, Mobile Phase B: Acetonitrile, Method: 55% A and 45%B isocratic, DILUENT: MeOH AM18 Reverse-Phase- Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Chiral (Method 2) Flow: 20 ml / min, Mobile Phase A: 20mM Ammonium Bicarbonate in Water, Mobile Phase B: Acetonitrile, Method: 50% A and 50%B isocratic, DILUENT: (ACN: Water 1:1) AM19 Reverse-Phase- Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Chiral (Method 3) Flow: 20 ml / min, Mobile Phase A: 20mM Ammonium Bicarbonate in Water, Mobile Phase B: Acetonitrile, Method: 55% A and 45%B isocratic, DILUENT: (ACN: Water 1:1)1H NMR spectra were acquired on a Bruker Avance Ⅲ spectrometer at 400 MHz using residual undeuterated solvent as reference. The spectra were processed using interpretation software Mestrelab processor or equivalent software. Purification Methods (PM): Chromatography Purification Column Eluent Eluent Gradient (%) method (flash) PM1 SiO2 Ethyl acetate:Hexane 5:95 PM1a SiO2Ethyl acetate:Hexane 2:98 to 3:97 PM1b SiO2 Ethyl acetate:Hexane 3:97 to 5:95 PM2 SiO2Ethyl acetate:Hexane 6:94 PM2a SiO2 Ethyl acetate:Hexane 40:60 PM2b SiO2Ethyl acetate:Hexane 30:60 to 35:65 PM2c SiO2 Ethyl acetate:Hexane 10:90 to 20:80 PM3 SiO2MeOH:DCM 0:100 to 3:97 PM4 SiO2 MeOH:DCM 0:100 to 4:96 PM5 SiO2MeOH:DCM 2:98 PM5b SiO2 MeOH:DCM 2:98 to 3:97 PM6 SiO2MeOH:DCM 2:98 to 5:95 PM7 SiO2 MeOH:DCM 3:97 PM8 SiO2MeOH:DCM 3:97 to 4:96 PM8a SiO2 MeOH:DCM 4:96 to 5:95 PM9 SiO2 MeOH:DCM 3:97 to 5:95 PM10 SiO2MeOH:DCM 5:95 PM10b SiO2 MeOH:DCM 5:95 to 10:90 PM11 SiO2MeOH:DCM 10:90 Reverse-phase HPLC conditions Purification Column Mobile phase (A:B) Gradient: (Time Method (mins) / %B) (PM) PM12 X Select C18, (100 x A: 0.05% FA in Water 0.01 / 10,01 / 10,07 / 95, 4.6 mm), 5 um B: ACN 11 / 95,11.20 / 10,15 / 10 PM13 Chiral (R, R) Whelk- A: water (20mM A:55% / B:45%, isocratic, O1 (21.1mm x NH4HCO3) Diluent: ACN:water (1:1) 250mm), 5um., Flow: B: ACN 20 ml / min PM14 Chiral (R, R) Whelk- A: water (20mM A:55% / B:45%, isocratic, O1 (21.1mm x NH4HCO3) Diluent: MeOH 250mm), 5um., Flow: B: ACN 14 ml / min PM15 Chiral (R, R) Whelk- A: water (20mM A:60% / B:40%, isocratic, O1 (21.1mm x NH4HCO3) Diluent: MeOH 250mm), 5um., Flow: B: ACN 20 ml / min PM16 Chiral (R, R) Whelk- A: water (20mM A:50% / B:50%, isocratic, O1 (21.1mm x NH4HCO3) Diluent: ACN:water (1:1) 250mm), 5um., Flow: B: ACN 14 ml / min PM17 Chiral (R,R) Whelk- A: water (20mM A:50% / B:50%, isocratic, O1 (21.1mm x 250 NH4HCO3) Diluent: ACN:water (1:1) mm), 5um, Flow: 20 B: ACN mL / min PM18 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 35,15.0 / C18 (250 x 20 mm), NH4HCO3) 55,20.0 / 65,20.5 / 100,22.0 / 5um B: ACN 100,22.5 / 10,25.0 / 10 PM19 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,15.0 / 50,20.0 C18 (250 x 20 mm), NH4HCO3) / 75,21.5 / 95,23.0 / 95,23.1 / 2 5um B: ACN 0,25.0 / 20 PM20 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,5.0 / 25,16.0 / C18 (250 x 20 mm), NH4HCO3) 55,16.5 / 95,19.5 / 95,20.0 / 2 5um B: ACN 0,23.0 / 20, PM21 Chromcore Polar-C-18 A: water (20mM 0.0 / 15,3.0 / 15,8.0 / 35,18.0 / (250 x 19 mm), 5um NH4HCO3) 45,18.5 / 95,21.5 / 95,22.0 / 1 B: ACN 5,25.0 / 15 PM22 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 25,15.0 / C18 (250 x 20 mm), NH4HCO3) 40,16.5 / 100,18.0 / 100,19.0 5um B: ACN / 10,22.0 / 10 PM23 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,23.0 / 69,23.1 C18 (250 x 20 mm), NH4HCO3) 0 / 98,26.0 / 98,26.1 / 10,30 / 1 5um B: ACN 0 PM24 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 30,15.0 / C18 (250 x 20 mm), NH4HCO3) 45,16.5 / 95,18.5 / 95,19.0 / 1 5um B: ACN 0,25.0 / 10 PM25 Chromcore Polar-C-18 A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 25,15.0 / (250 x 19 mm), 5um NH4HCO3) 40,16.5 / 100,18.0 / 100,19.0 B: ACN / 10,22.0 / 10 PM26 Waters X-Select CSH A: water (20mM 0.0 / 20,3.0 / 20,15.0 / 35,20.0 C18 (250 x 19 mm), NH4HCO3) / 55,21.5 / 95,23.0 / 95,23.1 / 2 5um B: ACN 0,25.0 / 20 PM27 Chromcore Polar-C-18 A: water (20mM 0.0 / 30,3.0 / 30,7.0 / 35,8.0 / 5 (250 x 19 mm), 5um NH4HCO3) 0,15.0 / 80,15.5 / 100,17.5 / 1 B: ACN 00,18.0 / 30,21.0 / 30 PM28 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,7.0 / 40,18.0 / C18 (250 x 20 mm), NH4HCO3) 70,18.5 / 95,21.5 / 95,22.0 / 1 5um B: ACN 0,25.0 / 10 PM29 Chromcore Polar-C-18 A: water (20mM 0.0 / 15,3.0 / 15,10.0 / 30,20.0 (250 x 19 mm), 5um NH4HCO3) / 35,20.5 / 95,22.5 / 95,23.0 / 1 B: MeCN:MeOH 0,27.0 / 10 (70:30) PM30 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,20.0 / 75,21.0 C18 (250 x 20 mm), NH4HCO3) / 95,24.0 / 95,24.5 / 20,28.0 / 2 5um B: ACN 0 PM31 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 25,18.0 / C18 (250 x 20 mm), NH4HCO3) 40,18.5 / 95,21.5 / 95,22.0 / 1 5um B: ACN 0,25.0 / 10 PM32 Waters X-Select CSH A: water (20mM 0.0 / 20,2.0 / 20,18.0 / 60,18.5 C18 (250 x 19 mm), NH4HCO3) / 95,21.5 / 95,22.0 / 20,25.0 / 2 5um B: ACN 0 PM33 Chiral: (R,R) Whelk- A: water (10mM A:50% / B:50%, isocratic, O1 (21.1mm x 250 NH4HCO3) mm), 5um, Flow: 20 B: ACN mL / min PM34 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 35,15.0 / C18 (250 x 20 mm), NH4HCO3) 65,16.5 / 95,18.5 / 95,19.0 / 1 5um B: ACN 0,23.0 / 10 PM35 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 10,3.0 / 10,5.0 / 30,18.0 / C18 (250 x 19 mm), B: ACN 45,18.5 / 95,21.5 / 95,22.0 / 1 5um 0,25.0 / 10 PM36 Poroshell HPH C18 A: water (20mM 0.0 / 10,3.0 / 10,8.0 / 25,15.0 / (150 x 21.1 mm), 4um NH4HCO3) 40,20 / 50,21.5 / 95,23.0 / 95, B: ACN 23.5 / 10,26 / 1 PM37 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,5.0 / 25,15.0 / C18 (250 x 20 mm), NH4HCO3) 50,16.0 / 95,19.0 / 95,20.0 / 2 5um B: ACN 0,23.0 / 20 PM38 YMC Actus-Triart A: water (20mM 60% A and 40%B C18 (250 x 20 mm), NH4HCO3) isocratic 5um B: ACN PM39 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 25,15.0 / C18 (250 x 20 mm), NH4HCO3) 50,16.5 / 95,18.5 / 95,19.0 / 1 5um B: ACN 0,23.0 / 10 PM40 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,22.0 / 69,22.1 C18 (250 x 20 mm), NH4HCO3) 0 / 95,26.0 / 95,26.1 / 20,30 / 2 5um B: ACN 0 PM41 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 10,3.0 / 10,20.0 / 55,21.0 C18 (250 x 19 mm), B: ACN / 95,24.0 / 95,24.1 / 10,28.0 / 1 5um 0 PM42 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,7.0 / 25,15.0 / C18 (250 x 20 mm), NH4HCO3) 45,16.0 / 95,19.0 / 95,20.0 / 1 5um B: ACN 0,23.0 / 10 PM43 Poroshell HPH C18 A: water (20mM Gradient: Isocratic (150 x 21.1 mm), 4um NH4HCO3) 0.01 / 10,01 / 10,07 / 95,11 / 95 B: ACN ,11.20 / 10,15 / 10 PM44 Poroshell C18 A: 0.05% FA in Water Gradient: Isocratic (150*4.6 mm), 4um B: ACN 0.01 / 10,01 / 10,07 / 95,11 / 95 ,11.20 / 10,15 / 10. PM45 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,5.0 / 35,16.0 / C18 (250 x 20 mm), NH4HCO3) 53,16.5 / 95,19.5 / 95,20.0 / 1 5um B: ACN 0,23.0 / 10 PM46 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,5.0 / 25,16.0 / C18 (250 x 20 mm), NH4HCO3) 60,16.5 / 95,19.5 / 95,20.0 / 1 5um B: ACN 0,23.0 / 10 PM47 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,5.0 / 45,16.0 / C18 (250 x 20 mm), NH4HCO3) 65.2,16.1 / 100,20.0 / 100,21 5um B: ACN .0 / 20,24.0 / 20 PM48 Hydrosphere C18 A: 0.05% FA in Water 0.01 / 80, 03 / 10, 08 / 25, (250*4.6 mm), 5um B: ACN 20 / 45, 20 / 95, 26 / 95, 26 / 10, 30 / 10 PM49 X select CSH C18 A: 0.05% FA in Water 0.01 / 80, 03 / 10, 08 / 25, (100*4.6 mm), 3.5um B: ACN 20 / 45, 20 / 95, 26 / 95, 26 / 10, 30 / 10 PM50 Chromcore Polar (250 A: 0.05% FA in Water 0.0 / 15,3.0 / 15,8.0 / 35,18.0 / x 19 mm), 5um B: ACN 45,18.5 / 95,21 / 10 PM51 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,5.0 / 20,16.0 / C18 (250 x 20 mm), NH4HCO3) 65,16.5 / 95,19.5 / 95,20.0 / 1 5um B: ACN 0,23.0 / 10 PM52 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 10,3.0 / 10,5.0 / 30,18.0 / C18 (250 x 19 mm), B: ACN 50,18.5 / 95,21.5 / 95,22.0 / 1 5um 0,25.0 / 10 PM53 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 20,3.0 / 20,5.0 / 40,10.0 / C18 (250 x 19 mm), B: ACN 80,15.0 / 90,18.0 / 90,19.0 / 2 5um 0,23.0 / 20 PM54 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,5.0 / 25,15.0 / C18 (250 x 20 mm), NH4HCO3) 50,16.0 / 95,19.0 / 95,20.0 / 1 5um B: ACN 0,23.0 / 10 PM55 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,7.0 / 25,15.0 / C18 (250 x 20 mm), NH4HCO3) 40,16.5 / 100,18.0 / 100,19.0 5um B: ACN / 10,22.0 / 10 PM56 Chromcore Polar (250 A: 0.05% FA in Water 0.0 / 20,3.0 / 20,5.0 / 40,10.0 / x 21.2 mm), 5um B: ACN 80,15.0 / 90,18.0 / 90,19.0 / 2 0,23.0 / 20 PM57 Poroshell C18 A: water (20mM 0.0 / 10,2.0 / 10,5.0 / 50,10.0 / (150*4.6 mm), 4um NH4HCO3) 80,15.0 / 90,18.0 / 95,21.0 / 9 B: ACN 5,21.5 / 10,25.0 / 10 PM58 YMC Actus-Triart A: water (20mM 0.0 / 05,3.0 / 05,8.0 / 25,16.0 / C18 (250 x 20 mm), NH4HCO3) 45,16.5 / 95,19.5 / 95,20.0 / 0 5um B: ACN 5,23.0 / 05 PM59 YMC Actus-Triart A: water (20mM 0 / 10,3.0 / 10,5.0 / 35,16.0 / 68 C18 (100 x.6 mm), NH4HCO3) ,16.0 / 100,18.0 / 100,28 / 10, 5um, B: ACN 21.0 / 10 PM60 YMC Actus-Triart A: water (20mM 0.01 / 10,3.0 / 10,5.0 / 35,19.0 C18 (100 x.6 mm), NH4HCO3) / 63,20.0 / 100,23.0 / 100,23 / 5um, B: ACN 10,26.0 / 10 PM61 POROSHELL HPH, A: water (20mM 0.0 / 10,2.0 / 10,15.0 / 50,20.0 C-18 (150 x 21.2 mm), NH4HCO3) / 90,21.0 / 95,23.0 / 95,23.5 / 1 4um B: ACN 0,26.0 / 10 PM62 YMC Actus-Triart A: water (20mM 0.0 / 10,3.0 / 10,6 / 35,23 / 85,3 C18 (250 x 20 mm), NH4HCO3) 0 / 95 5um B: ACN PM63 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 10,3.0 / 10,5.0 / 35,16.0 / C18 (250 x 19 mm), B: ACN 55,16.5 / 95,19.5 / 95,20.0 / 1 5um 0,23.0 / 10 PM64 Chromcore Polar (250 A: 0.1% FA in Water 0.0 / 10,3.0 / 10,20.0 / 65,20.2 x 19 mm), 5um B: ACN / 95,24.0 / 95,24.2 / 10,28.0 / 1 0 PM65 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,22.0 / 65,23 / 9 C18 (250 x 20 mm), NH4HCO3) 5,26.0 / 95,26.1 / 20,30.0 / 20 5um B: ACN PM66 YMC Actus-Triart A: water (20mM 0.0 / 20,3.0 / 20,5.0 / 40,23.0 / C18 (250 x 20 mm), NH4HCO3) 85,24 / 95,26.0 / 95,26.1 / 20, 5um B: ACN 30.0 / 20 PM67 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 10,3.0 / 10,5.0 / 45,16.0 / C18 (250 x 19 mm), B: ACN 60,16.5 / 95,19.5 / 95,20.0 / 1 5um 0,23.0 / 10 PM68 Chromcore Polar (250 A: 0.1% FA in Water 0.0 / 10,3.0 / 10,20.0 / 65,21.5 x 21.2 mm), 5um B: ACN / 95,23.5 / 95,24.0 / 20,28.0 / 2 0 PM69 YMC Actus-Triart A: water (10mM 0.0 / 20,3.0 / 20,20.0 / 80,21.5 C18 (250*20 mm), NH4HCO3) / 95,23.0 / 95,23.1 / 20,25.0 / 2 5um B: ACN 0 PM70 POROSHELL HPH, A: water (10mM 0.0 / 10,3.0 / 10,20.0 / 50,25.0 C-18 (150 x 21.2 mm), NH4HCO3) / 90,26.0 / 95,28.0 / 95,28.5 / 1 4um B: ACN 0,30.0 / 10 PM71 Poroshell C18 (250 x A: water (20mM 0.0 / 10,3.0 / 10,20 / 47,20.10 / 20 mm), 5um NH4HCO3) 10,25 / 10 B: ACN PM72 YMC Actus-Triart A: water (20mM 0.0 / 30,3.0 / 30,15.0 / 70,20.0 C18 (250 x 20 mm), NH4HCO3) / 85,21.5 / 95,23.0 / 95,23.1 / 3 5um B: ACN 0,25.0 / 30 PM73 Waters X-Select CSH A: 0.1% FA in Water 0.0 / 10,3.0 / 10,8.0 / 35,20.0 / C18 (250 x 19 mm), B: ACN 40,21.0 / 95,23.0 / 95,23.5 / 1 5um 0,27.0 / 10 SFC conditions Purification Method Description Method (PM) PM74 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µm, Flow: 70 ml / min Mobile Phase: 70% CO2 + 30% of (0.1%IPA in MeOH), ABPR: 100bar, Temp: 35 ºC, UV: 220 nm, DILUENT: MeOH + DCM PM75 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250 mm), 5µ, Flow: 60 ml / min, Mobile Phase: 65% CO2 + 35% of (0.05%IPA in Methanol), ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + DCM PM76 SFC purification Column:(R, R) Whelk-O1 (21.1 mm x 250mm), 5µ, Flow: 60ml / min, Mobile Phase A :85% CO2, Mobile Phase B: 15% of Methanol, ABPR : 100bar, Temp : 350C, UV: 220nm, DILUENT: MeOH + THF PM77 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250 mm), 5µ, Flow: 60 ml / min, Mobile Phase: 70% CO2+ 30% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, diluent: MeOH + DCM PM78 SFC purification Column:(R, R) Whelk-O1 (21.1 mm x 250mm), 5µ, Flow: 70ml / min, Mobile Phase A :60% CO2, Mobile Phase B: 40% of Methanol, ABPR: 100bar, Temp: 350C, UV: 220nm, DILUENT: MeOH + DCM PM79 SFC purification Column:(R, R) Whelk-O1 (21.1mm x 250mm),5µ; Flow: 60 ml / min; Mobile Phase:70% CO2+ 30% of [HEX:IPA(60:40)]; ABPR :100bar; Temp:35ºC; UV: 220 nm; DILUENT: MeOH + THF PM80 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 70% CO2 + 30% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH +THF PM81 SFC purification Column: (R,R) Whelk-O1 (21.1 mm x 250 mm ), 5µm, Flow: 60 mL / min, Mobile Phase: 75% CO2 + 25% of Methanol, ABPR: 100 bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF PM82 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ, Flow: 60 ml / min, Mobile Phase: 70% CO2 + 30% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH PM83 SFC purification Column: (R, R) Whelk-O1 (20mm x 250mm), 5µ., Flow: 60 ml / min, Mobile Phase: 75% CO2 + 25% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH PM84 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 70 ml / min, Mobile Phase: 60% CO2 + 40% of Methanol, ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF PM85 SFC purification Column: (R, R) Whelk-O1 (21.1mm x 250mm), 5µ., Flow: 70 ml / min, Mobile Phase: 70% CO2 + 30% of (0.1%IPAmine in Methanol), ABPR: 100bar, Temp: 35ºC, UV: 220 nm, DILUENT: MeOH + THF Abbreviations: Wherein the following abbreviations have been used, the following meanings apply: ACN is acetonitrile, AcCl is acetyl chloride, AM is analytical method, aq. is aqueous, atm. is atmosphere, Boc2O is di-tert-butyl dicarbonate, Celite®is diatomaceous earth, CHCl3-d is deuterated chloroform, conc. is concentrated, Cs2CO3 is cesium carbonate, Cu(OAc)2 is copper(II) acetate, DCM is dichloromethane, DHP is 3,4-dihydropyran, DIPEA is N,N-diisopropylethylamine, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, DMSO-d6 is deuterated dimethyl sulfoxide, DMAP is 4-dimethylaminopyridine, DMF-DMA is N,N-dimethylformamide dimethyl acetal, EA is ethyl acetate, EtOH is ethanol, FA is formic acid, h is hours, H2 is hydrogen gas, HNO3 is nitric acid, H2SO4is sulfuric acid, NMR is nuclear magnetic resonance, HCl is hydrochloric acid, H2O is water, HCOOH is formic acid, HPLC is high performance liquid chromatography, K2CO3 is potassium carbonate, KOAc is potassium acetate, LCMS is liquid chromatography mass spectrometry, MeOH is methanol, MeOH-d4is deuterated methanol, min is minutes, MTBE is 2-methoxy-2-methylpropane, MW is microwave, N2is nitrogen gas, NaHCO3 is sodium bicarbonate, NaOH is sodium hydroxide, Na2SO4is anhydrous sodium sulphate, NBS is N-Bromosuccinimide, NH3 is ammonia, NH4HCO3is ammonium bicarbonate, NH4Cl is ammonium chloride, NH4OH is ammonium hydroxide, O2 is oxygen gas, Pd / C is palladium on carbon, PdCl2(dppf) is [1,1'‑Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, PdCl2(dtbpf) is [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), Pd(OAc)2is palladium(II) acetate Pd(PPh3)4is Tetrakis(triphenylphosphine)palladium(0), PE is petroleum ether, PM is purification method, PMB is p-methoxybenzyl, POCl3 is phosphoryl trichloride, PTSA is para-toluenesulfonic acid, RT is room temperature, rt is retention time, brine is saturated NaCl (aq), SFC is supercritical fluid chromatography, SiO2is silica, Soln is solution, SOR is specific optical rotation, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin layer chromatography, TMSCN is trimethylsilyl cyanide, T3P is propylphosphonic anhydride, Xantphos is 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, ZnCl2 is zinc chloride and ZnI2is zinc iodide. Preparation of intermediates The following preparations describe the methods used for common intermediates required for synthesis of the Examples. Synthesis of intermediate 1.003 rac-2-acetoxy-2-(3-(trifluoromethoxy)phenyl)acetic acid (1.003) To rac-2-Hydroxy-3-(trifluoromethoxy)benzeneacetic acid (CAS: 1214378-55-8, 4.00 g, 16.94 mmol) at 0 °C was added a solution of AcCl (20 mL) over 30 min, then stirred at RT for 16 h. The reaction mixture was reduced in vacuo to yield a residue which was suspended in water (100 mL) and extracted (EA, 30 mL x 3). The combined EA layer was washed (water, 50 mL and brine 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.003 (3.5 g, 12.58 mmol, 74% yield) as a brown gum. LCMS (AM1): rt = 1.94 min, No ionization, 81.35% purity.1H NMR (400 MHz, DMSO-d6): δ 13.41 (brs, 1H), 7.59-7.51 (m, 2H), 7.46 (s, 1H), 7.43 (d, J= 8.0 Hz, 1H), 5.12 (s, 1H), 2.15 (s, 3H) ppm. Synthesis of intermediate 1.006 rac-2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (1.006) To rac-2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (CAS: 349-10-0, 4.00 g, 18.18 mmol) at 0 °C was added a solution of AcCl (20 mL) over 30 min. The reaction mixture was stirred at RT for 16 h then reduced in vacuo to yield a residue which was suspended in water (100 mL) and extracted (EA, 30 mL x 3). The combined organic layer was washed (water 50 mL and brine 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.006 (3.5 g, 13.35 mmol, 73% yield) as a brown gum. LCMS (AM1): rt = 1.94 min, (260.97 [M-H]), 85.15% purity.1H NMR (400 MHz, DMSO-d6): δ 13.48 (brs, 1H), 7.82-7.76 (m, 3H), 7.67 (t, J= 7.6 Hz, 15.2 Hz, 1H), 5.97 (s, 1H), 2.14 (s, 3H) ppm. The mandelic acid intermediates of formula (III) in Table 1 were made following the method of Scheme 5, using the stated acid of formula (IIIA) and the protocols outlined above for intermediates 1.003 and 1.006. Scheme 5 Table 1 Mandelic acid of Mandelic Acid of Analytical data formula (III) IUPAC formula (IIIA) (CAS) Name / No. LCMS (AM1): rt = 1.90 min, (ES- 203.0 [M-Ac]), 88.94 % purity. 1H NMR (400 MHz, DMSO-d6): δ 13.55 (brs, 1H), 7.54 -7.49 (m, 1H), 7.42 - 7.41 rac-2-(3-chloro-5- (m, 1H), 7.34 - 7.31 (m, 1H), 5.92 (s, 1H), rac-2-acetoxy-2-(3- fluorophenyl)-2- 2.15 (s, 3H) ppm. chloro-5- hydroxyacetic acid (CAS fluorophenyl)acetic 1214333-72-8) acid 1.135 (A3) LCMS (AM1): rt = 1.94 min, (ES- 236.0 [M-Ac]), 98.71% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.61 (brs, 1H), 7.76 -7.74 (m, 1H), 7.70 - 7.66 (m, 2H), 6.06 (s, 1H), 2.16 (s, 3H) ppm. rac-2-acetoxy-2-(3- fluoro-5- rac-2-[3-fluoro-5- (trifluoromethyl)phenyl (trifluoromethyl)phenyl]- )acetic acid 1.157 (A4) 2-hydroxyacetic acid (CAS 1214341-24-8) LCMS (AM1): rt = 1.76 min, (ES- 181.0 [M-Ac]), 75.13% purity. rac-2-acetoxy-2-(3- rac-2-(3-fluoro-4- fluoro-4- methylphenyl)-2- methylphenyl)acetic hydroxyacetic acid (CAS acid 1.221 (A9) 1214328-14-9) LCMS (AM1): rt = 1.90 min, (ES- 201.0 [M-Ac]), 88.94 % purity. rac-2-(4-Chloro-3- rac-2-acetoxy-2-(4- fluorophenyl)-2- chloro-3- hydroxyacetic acid fluorophenyl)acetic (CAS 1214376-99-4) acid 1.203 (A13) LCMS (AM2): rt = 1.98 min, (ES- 234.8 [M-H]-), 97.168% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.62 (brs, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 11.6 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), rac-2-(3-fluoro-4- rac-2-acetoxy-2-(3- 6.02 (s, 1H), 2.16 (s, 3H) ppm. (trifluoromethyl)phenyl)- fluoro-4- 2-hydroxyacetic acid (trifluoromethyl)phenyl (CAS 1214343-86-8) )acetic acid 1.222 (A14) LCMS (AM1): rt = 1.67 min, No ionization, 98.64% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (bs, 1H), 7.55 - 7.48 (m, 1H), 7.34 - 7.25 2-(2,3-difluorophenyl)-2- (m, 2H), 6.14 (s, 1H), 2.13 (s, 3H) ppm. rac-2-acetoxy-2-(2,3- hydroxyacetic acid (CAS difluorophenyl)acetic 207974-19-4) acid 1.098 (A15) LCMS (AM1): rt = 1.75 min, No ionization, 61.22% purity. 1H NMR (400 MHz, DMSO-d6): δ 7.67 (t, J = 1.8 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.49 2-(3-bromophenyl)-2- – 7.47 (m, 1H), 7.38 (t, J = 7.8 Hz, 1H), 2-acetoxy-2-(3- hydroxyacetic acid (CAS 5.85 (s, 1H), 2.13 (s, 3H) ppm bromophenyl)acetic 49839-81-8) acid 1.206 (A16) LCMS (AM1): rt = 2.46 min, No ionization, 93.57% purity. 1H NMR (400 MHz, DMSO-d6): δ = 13.62 (bs, 1H), 7.48 – 7.45 (m, 1H), 7.42 – 7.40 (m, 1H), 7.35 (bs, 1H), 5.99 (s, 1H), 2.15 2-(3-fluoro-5- rac-2-acetoxy-2-(3- (s, 3H). (trifluoromethoxy)phenyl) fluoro-5- -2-hydroxyacetic acid (trifluoromethoxy)phen (CAS 1806382-54-6) yl)acetic acid 1.154 (A17) LCMS (AM1): rt = 1.80 min, (ES- 196.9 [M-Ac]-), 92.14 % purity. 1H NMR (400 MHz, CDCl3): δ 7.27 (s, 1H), 7.18 (s, 1H),7.16 (s, 1H), 5.85 (s, 2-(3-chloro-5- 1H), 2.34 (s, 3H), 2.19 (s, 3H) ppm. rac-2-acetoxy-2-(3- methylphenyl)-2- chloro-5- hydroxyacetic acid (CAS methylphenyl)acetic 1261673-64-6) acid 1.141 (A18) LCMS (AM2): rt = 2.03 min, (260.90 [M– H]–), 92.35 % purity. 1H NMR (400 MHz, DMSO-d6): δ 13.56 (S, 1H), 7.69 (t, J = 1.9 Hz ,1H), 7.53 (d, J 2-(3,5-dichlorophenyl)-2- = 1.9 Hz, 2H), 5.93 (s, 1H), 2.15 (s, 3H) rac-2-acetoxy-2-(3,5- hydroxyacetic acid (CAS ppm. dichlorophenyl)acetic 35599-94-1) acid 1.115 (A19) LCMS (AM1): rt = 1.83min, ES- 249.0 [M-Ac], 96.82% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (brs, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.29 (s, 1H), 5.95 (s, 1H), 3.86 (s, 3H), 2.16 (s, 2-hydroxy-2-(3-methoxy- rac-2-acetoxy-2-(3- 3H) ppm. 5- methoxy-5- (trifluoromethyl)phenyl)ac (trifluoromethyl)phenyl etic acid (CAS 1214372- )acetic acid 1.160 94-7) (A20) LCMS (AM1): rt = 1.86 min, (ES- 230.9 [M-Ac]), 100% purity. 1H NMR (400 MHz, DMSO-d6): δ 12.27 (bs, 1H), 7.60 (m, 3H), 5.93 (s, 1H), 2.42 2-hydroxy-2-(3-methyl-5- (s, 3H), 2.15 (s, 3H) ppm. rac-2-acetoxy-2-(3- (trifluoromethyl)phenyl)ac methyl-5- etic acid (CAS 1214334- (trifluoromethyl)phenyl 58-3) )acetic acid 1.162 (A21) LCMS (AM1): rt = 1.76 min, ES- 216.0 [M-Ac], 90.90 % purity. 1H NMR (400 MHz, DMSO-d6): δ 13.38 (brs, 1H), 7.08-7.07 (m, 2H), 7.01-7.00 (m, 2-(3-chloro-5- 1H), 5.81 (s, 1H), 3.78 (s, 3H), 2.13 (s, rac-2-acetoxy-2-(3- methoxyphenyl)-2- 3H) ppm. chloro-5- hydroxyacetic acid (CAS methoxyphenyl)acetic 1261851-12-0) acid 1.138 (A22) 1H NMR (400 MHz, DMSO) δ 13.52 (bs, 1H), 7.80-7.79 (t, J = 2 Hz, 1H), 7.66 -7.65 (t, J = 1.32 Hz, 1H), 7.56 - 7.55 (t, J = 1.44 Hz, 1H), 5.92 (s, 1H), 2.16 (s, 3H) 2: 2-(acetyloxy)-2-(3- 2-(3-bromo-5- bromo-5-chlorophenyl) chlorophenyl)-2- acetic acid 1.130 (A23) hydroxyacetic acid (CAS 1261670-04-5) LCMS (AM1): rt = 2.48, (ES- 294.9 [M- Ac]–), 72.43% purity. 1H NMR (400 MHz, DMSO-d6): = 13.62 (bs, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 6.06 (s, 1H), 2.16 (s, 3H) 2-acetoxy-2-[3-bromo- 2-[3-bromo-5- 5- (trifluoromethyl)phenyl]- (trifluoromethyl)phenyl 2-hydroxy-acetic acid ]acetic acid 1.144 (CAS 1214339-37-3) (A24) LCMS (AM1): rt = 1.77 min, (ES- 244.9 [M-Ac]), 65.08% purity. 2-acetoxy-2-(3-bromo- 2-(3-bromo-5- 5-fluorophenyl)acetic fluorophenyl)-2- acid 1.149 (A25) hydroxyacetic acid (CAS 1214350-06-7)1H NMR (400 MHz, DMSO): δ 13.35 (bs, 1H), 7.41 (d, 2H), 7.34 (s,1H), 5.82 (s, 1H), 4.32 (t, 2H), 2.91 (t, 2H), 2.14 (s, 3H), 1.97 (s, 3H) ppm 2-acetoxy-2-(3-(2- rac-2-acetoxy-2-(3- acetoxyethyl)-5- chloro-5-(2- chlorophenyl)acetic acid hydroxyethyl)phenyl)a 1.122 cetic acid 1.123 (A26) LCMS (Method 2): rt= 2.92 min, 349.2 [M+H]+1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H), 7.34 (s, 1H), 4.41 (t, J = 9 Hz, 2H), 3.08 (t, J = 2-hydroxy-2-[3-(2- 7Hz, 2H), 2.51 (s, 3H), 1.97 (s, 3H) rac-2-acetoxy-2-(3-(2- hydroxyethyl)-5- hydroxyethyl)-5- (trifluoromethyl)phenyl]ac (trifluoromethyl)phenyl etic acid 1.108 )acetic acid 1.109 (A27) LCMS (AM1): rt = 1.89 min, (ES- 253.0 [M-Ac]), 93.96% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.63 (brs, 1H), 7.95 (s, 1H), 7.87 (s, 1H),7.81 (s, 1H), 6.07 (s, 1H), 2.16 (s, 3H) ppm. 2-(3-chloro-5- rac-2-acetoxy-2-(3- (trifluoromethyl) phenyl)- chloro-5- 2-hydroxyacetic acid (trifluoromethyl)phenyl (CAS 1214340-32-5) )acetic acid 1.127 (A28) LCMS (AM1): rt = 1.62 min, No ionization, 99.17% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.58 (bs, 1H), 7.37 - 7.32 (m, 3H), 6.09 (s, 1H), 2.13 (s, 3H) ppm. rac-2-acetoxy-2-(2,5- 2-(2,5-difluorophenyl)-2- difluorophenyl)acetic hydroxyacetic acid (CAS acid 1.101 (A29) 207853-61-0) LCMS (AM2): rt = 1.81min, (259.1 [M– H]–), 82.57% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.30 (brs, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.26 (t, J = 2-(3-(difluoro methoxy) rac-2-acetoxy-2-(3- 74.5 Hz, 1H), 7.22 (d, J = 8.0, 2.2 Hz, 1H), phenyl)-2-hydroxyacetic (difluoromethoxy)phen 5.86 (s, 1H), 2.13 (s, 3H) ppm. acid (CAS 1214331-46-0) yl)acetic acid 1.112 (A30) LCMS (AM1): rt = 1.67 min, (264.1 [M+H]+), 72.53% purity. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (s, 1H), 8.20 (t, J = 8.0 Hz, 1H), 7.96 (d, J = 12.32 Hz, 1H), 7.91 (d, J = 7.88 Hz, 2-hydroxy-2-(6- 2-acetoxy-2-(6- 1H), 6.06 (s, 1H), 2.14 (s, 3H) ppm. (trifluoromethyl)pyridin-2- (trifluoromethyl)pyridi yl)acetate (CAS 1346542- n-2-yl)acetic acid 1.219 65-1) Synthesis of intermediate (R)-1.009 (R)-2-(3,5-difluorophenyl)-2-hydroxyacetic acid ((R)-1.008) To a suspension of Amino Lipase PS (Immobilized on diatomite (Celite®) ratio of Celite:Enzyme: 1:1 w / w) (8 g) in MTBE (80 mL) was added to rac- 2-(3,5- difluorophenyl)-2-hydroxyacetic acid (CAS: 132741-31-2, 4.00 g, 21.27 mmol) and vinyl acetate (97.95 mL, 1063.82 mmol), the resultant reaction mixture was stirred at 45°C for 24 h. The insoluble residue was then filtered and washed with MTBE (150 mL). The filtrate was reduced in vacuo to yield a residue which was stirred in DCM (20 mL) for 10 min, the solid obtained was filtered, washed (DCM, 8 mL) and dried under vacuum to yield compound (R)-1.008 (1.4 g, 100% ee), (35% yield) as a white solid. LCMS (AM2): rt = 1.69 min, (187.1 [M-H]-), 100% purity.1H NMR (400 MHz, DMSO-d6): δ 12.89 (brs, 1H), 7.18 – 7.10 (m, 3H), 6.09 (brs, 1H), 5.09 (s, 1H) ppm. SOR = -110.99°(C = 0.33 in MeOH). (R)-2-(3,5-difluorophenyl)-2-hydroxyacetic acid ((R)-1.009) To compound (R)-1.008 (1.40 g, 21.27 mmol) at 0 °C, was added a solution of AcCl (8 mL) over 30 min. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was then reduced in vacuo to yield a residue, which was suspended in water (100 mL) and extracted (EA, 30 mL x 3). The combined organic layer was washed (water 50 mL and brine 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford compound (R)-1.009 (1.5 g, 6.52 mmol, 87.57% yield, 100% ee) as off white solid. LCMS (AM2): rt = 2.62 min, (229.05 [M–H]–), 100% purity. HPLC (AM3): rt = 4.47 min, 99.85% purity. SFC (Method 7): rt = 3.05 min, ee = 100%. SOR value = -85.57° (C = 0.33 in MeOH)1H NMR (400 MHz, DMSO-d6): δ 13.53 (brs, 1H), 7.34 – 7.28 (m, 1H), 7.23 – 7.18 (m, 2H), 5.91 (s, 1H), 2.13 (s, 3H) ppm. The compounds of the present invention may be prepared enantioselectivity using chiral intermediates such as compound (R)-1.009 following the methods outlined below. Synthesis of intermediate 1.019 (E)-N,N-dimethyl-N'-(3-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)formimidamide (1.019) To a solution of 3-Methyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (CAS: 7057-22-9, 5 g, 33.521 mmol) in 1,4-dioxane (50 mL) was added DMF-DMA (6.68 mL, 50.282 mmol) and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to RT and was reduced in vacuo to obtain a solid which was triturated (DE, 30 mL) to afford compound 1.019 (5 g, 33.52 mmol, 75% yield) as yellow solid. LCMS (AM2): rt = 0.34 min, (205.09 [M+H]+), 95.34% purity.1H NMR (400 MHz, DMSO-d6): δ 13.16 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 3.22 (s, 3H), 3.18 (s, 3H), 2.45 (s, 3H) ppm. Synthesis of intermediate 1.025 tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-2,3-difluorophenyl)carbamate (1.024) To a solution of DMAP (0.957 g, 7.83 mmol) and Cu(OAc)2 (0.178 g, 0.979 mmol) in MeOH (10 mL) was added compound 1.019 (0.4 g, 1.958 mmol) , then (4-((tert- butoxycarbonyl)amino)-2,3-difluorophenyl)boronic acid (CAS:2377608-58-5, 1.069 g, 3.917 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h, then diluted with DCM (100 mL), the organic layer washed (aq. NH4Cl (50 mL x 2)), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM8) to afford compound 1.024 (0.41 g, 0.950 mmol, 47% yield) as a light-yellow solid. LCMS (AM1): rt= 2.41 min, (432.3 [M+H]+), 96.29% purity.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 3.13 (s, 3H), 2.67 (s, 3H), 2.53 (s, 3H), 1.49 (s, 9H) ppm. (E)-N'-(1-(4-amino-2,3-difluorophenyl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)- N,N-dimethylformimidamide (1.025) To a solution of compound 1.024 (0.41 g, 0.95 mmol) in DCM (10 mL) was added TFA (0.542 g, 4.75 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was reduced in vacuo to yield a residue, which was dissolved in DCM (50 mL), the organic layer washed (aq.10% NaHCO3, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue, which was purified (PM7) to afford compound 1.025 (0.3 g, 0.905 mmol, 95% yield) as off white solid. LCMS (AM1): rt= 1.98 min, (332.20 [M+H]+), 94.23% purity.1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.46 (s, 1H), 7.02 (td, J = 8.3, 2.0 Hz, 1H), 6.61 (td, J = 8.8, 1.9 Hz, 1H), 5.75 – 5.73 (m, 2H), 3.13 (s, 3H), 2.71 (s, 3H), 2.50 (m, 3H) ppm. Synthesis of intermediate 1.026 rac-[(4-{7-[(E)-[(dimethylamino)methylidene]amino]-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl}-2,3-difluorophenyl)carbamoyl][3-(trifluoromethoxy)phenyl]ethyl acetate (1.026) To a solution of compound 1.025 (58.6 mg, 0.211 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (136.0 mg, 1.06 mmol), compound 1.003 (70 mg, 0.211 mmol) and T3P (50% w / w soln in EA, 201 mg, 634 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with water (30 mL), extracted (DCM, 20 mL X 2). The combined organic layer was washed (aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM7) to afford compound 1.026 (100 mg, 0.169 mmol, 85% yield) as a yellow solid. LCMS (AM1): rt= 2.44 min, (592.3 [M+H]+), 85.84% purity.1H NMR (400 MHz, DMSO-d6): δ 10.64 (brs, 1H), 8.81 (s, 1H), 8.53 (s, 1H), 7.64-7.55 (m, 4H), 7.52 – 7.48 (m, 2H), 6.24 (s, 1H), 3.11 (s, 3H), 2.62 (s, 3H), 2.47 (s, 3H), 2.19 (s, 3H). Synthesis of intermediate 1.027 rac-(E)-2-((4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-2,3-difluorophenyl)amino)-2-oxo-1-(3- (trifluoromethyl)phenyl)ethyl acetate (1.027) To a solution of compound 1.025 (150 mg, 0.453 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (292.9 mg, 2.26 mmol), compound 1.006 (118.2 mg, 0.453 mmol) and T3P (50% w / w soln in EA, 432.14 mg, 1.35 mmol). The reaction mixture was stirred at RT for 2 h then diluted with water (30 mL) and extracted (EA, 20 mL x 2). The combined organic layer was washed (aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to yield a residue, which was purified (PM5) to afford compound 1.027 (200 mg, 0.169 mmol, 76%) as a yellow solid. LCMS (AM1): rt = 2.42 min, (576.3 [M+H]+): 93.85% purity.1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.82 (s, 1H), 8.51 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 7.76 Hz, 1H),7.82 (d, J= 7.84 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.61 (m, 1H), 7.40 (m, 1H), 6.29 (s, 1H), 3.12 (s, 3H), 2.63 (s, 3H), 2.53 (s, 3H), 2.20 (s, 3H) ppm. Synthesis of intermediate 1.028 rac-(3,5-difluorophenyl)[(4-{7-[(E)-[(dimethylamino)methylidene]amino]-3-methyl- 1H-pyrazolo[4,3-d]pyrimidin-1-yl}-2,3-difluorophenyl)carbamoyl]ethyl acetate (1.028) To a solution of compound 1.025 (200.0 mg, 0.604 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (389 mg, 3.018 mmol), rac-2-acetoxy-2-(3,5-difluorophenyl) acetic acid (CAS: 1253521-12-8, 208 mg 0.905 mmol) and T3P (50% w / w soln in EA, 959 mg, 3.018 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with water (30 mL) and extracted (EA, 20 mL x 2). The combined organic layer was washed (aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM7) to afford compound 1.028 (250 mg, 0.462 mmol, 76%) as a yellow solid. LCMS (AM1): rt = 2.35 min, (544 [M+H]+), 97% purity.1H NMR (400 MHz, DMSO-d6) δ 10.64(s, 1H), 8.82 (s, 1H), 8.50 (s, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.41-7.30 (m, J = 7.7 Hz, 4H), 6.21 (d, 1H), 3.12 (s, 3H),2.64 (s, 3H), 2.52(s, 3H),2.20 (s, 3H). Synthesis of intermediate 1.034 tert-butyl N-[4-[7-[(E)-dimethylaminomethyleneamino]-3-methyl-pyrazolo[4,3- d]pyrimidin-1-yl]-3-fluoro-phenyl]carbamate (1.033) To a solution of DMAP (1.2 g, 9.79 mmol) and Cu(OAc)2(0.443 g, 2.45 mmol) in MeOH (20 mL) was added compound 1.019 (1.0 g, 4.89 mmol) then 4-[(tert- butoxycarbonyl)amino]-2-fluorophenylboronic acid (CAS:1415960-56-3,1.87 g, 7.34 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM (100 mL), washed (aq. NH4Cl, 50 mL X 2), dried (Na2SO4), filtered and reduced in vacuo to yield a residue which was purified (PM8) to afford Compound 1.033 (1.37 g, 3.31 mmol, 68% yield) as white solid. LCMS (AM2): rt = 2.03 min, (414.23 [M+H]+), 100% purity.1H NMR (400 MHz, CDCl3): δ 9.07 (brs, 1H), 8.53 (s, 1H), 7.58 – 7.49 (m, 1H), 7.40 (t, J = 8.3 Hz, 1H), 7.03-7.00 (m, 1H), 6.64 (s, 1H), 3.21 (s, 3H), 2.78 (s, 3H), 2.67 (s, 3H), 1.53 (s, 9H) ppm. N'-[1-(4-amino-2-fluoro-phenyl)-3-methyl-pyrazolo[4,3-d]pyrimidin-7-yl]-N,N- dimethyl-formamidine (1.034) To a solution of compound 1.033 (1 g, 3.378 mmol) in DCM (20 mL) was added TFA (5 mL) and the mixture was stirred at RT for 3 h. The reaction mixture was reduced in vacuo to yield a residue, which was diluted in EA (50 mL) and washed (aq.10% NaHCO3, 50 mL X 2). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM4) to afford compound 1.034 (1 g, 3.194 mmol, 94 % yield) as a light yellow solid. LCMS (AM1): rt = 1.90 min, (314.3 [M+H]+), 96.38% purity.1H NMR:(400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.43 (s, 1H), 7.10 (t, J = 8.5 Hz, 1H), 6.46 – 6.38 (m, 2H), 5.62-5.60 (m, 2H), 3.31 (s, 3H), 3.11 (s, 3H), 2.71 (s, 3H) ppm. Synthesis of intermediate 1.035 rac-[(4-{7-[(E)-[(dimethylamino)methylidene]amino]-3-methyl-1H-pyrazolo [4,3- d]pyrimidin-1-yl}-3-fluorophenyl)carbamoyl][3-(trifluoromethoxy) phenyl] ethyl acetate (1.035) To a solution of compound 1.034 (280 mg, 0.894 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (0.778 mL, 4.468 mmol), compound 1.003 (248.58 mg, 0.894 mmol) and T3P (50% w / w soln in EA, 1.06 mL, 4.468 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with water (20 mL) and extracted (DCM, 20 mL X 2). The combined organic layer was washed (aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM7) to afford compound 1.035 (300 mg, 0.522 mmol, 59% yield) as a white solid. LCMS (AM1): rt = 2.30 min, (574.2 [M+H]+), 90.29% purity.1H NMR (400 MHz, DMSO-d6): δ 10.79 (s, 1H), 8.78 (s, 1H), 8.47 (s, 1H), 7.69 (dd, J = 12.2, 2.2 Hz, 1H), 7.65 – 7.47 (m, 5H), 7.47 – 7.31 (m, 1H), 6.07 (s, 1H), 3.09 (s, 3H), 3.2 (s, 3H), 2.50 (s, 3H), 2.2 (s, 3H) ppm. Synthesis of intermediate 1.036 rac-(E)-2-((4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-fluorophenyl)amino)-2-oxo-1-(3-(trifluoromethyl)phenyl)ethyl acetate (1.036) To a solution of compound 1.034 (200 mg, 0.638 mmol) in DCM (3 mL) at RT was added DIPEA (0.55 mL, 3.191 mmol), compound 1.006 (167 mg, 0.638 mmol) and T3P (50% w / w soln in EA, 1.10 mL, 3.191 mmol). The reaction mixture was stirred for 2 h then diluted with water (30 mL) and extracted (DCM, 20 mL X 2). The combined organic layer was washed (aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM9) to afford compound 1.036 (260 mg, 0.466 mmol, 73% yield) as a white solid. LCMS (AM2): rt = 2.06 min, (558.24 [M+H]+), 99.46% purity.1H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.73 – 7.67 (m, 2H), 7.51 (t, J = 8.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 3.09 (s, 3H), 2.55 (s, 3H), 2.49 (s, 3H), 2.20 (s, 3H) ppm. Synthesis of intermediate 1.037 rac- (E)-1-(3,5-difluorophenyl)-2-((4-(7(((dimethylamino)methylene)amino)-3-methyl- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)amino)-2-oxoethyl acetate (1.037) To a solution of compound 1.034 (200 mg, 0.638 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.55 mL, 3.191 mmol), rac-2-acetoxy-2-(3,5-difluorophenyl) acetic acid (CAS:1253521-12-8, 220 mg, 0.957 mmol) and T3P (50% w / w soln in EA, 1.95 mL, 6.383 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with water (30 mL) and extracted (DCM, 20 mL X 2). The combined organic layer was washed with aq. NH4Cl (50 mL), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM9) to afford compound 1.037 (250 mg, 0.466 mmol, 74% yield) as off white solid. LCMS (AM2): rt = 2.07 min, (526.4 [M+H]+), 97.24% purity.1H NMR (400 MHz, DMSO-d6): δ 10.66 (s, 1H), 8.24 (s, 1H), 7.64 – 7.54 (m, 4H), 7.43 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.07 (s, 1H), 2.46 (s, 3H), 2.19 (s, 3H), 1.97 (s, 3H), 1.90 (s, 3H) ppm. Synthesis of intermediate 1.038 rac-(3-chlorophenyl)[(4-{7-[(E)-[(dimethylamino)methylidene]amino]-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl}-3-fluorophenyl)carbamoyl]ethyl acetate (1.038) To a solution of compound 1.034 (200.0 mg, 0.638 mmol,) in DCM (5 mL), was added DIPEA (0.55 mL, 3.191 mmol), 2-(acetyloxy)-2-(3-chlorophenyl)acetic acid (CAS: 947156-24-3, 145.93 mg, 0.638 mmol) and T3P (50% w / w soln in EA, 0.757 mL, 3.191 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with water (30 mL) and extracted (DCM, 20 mL X 2). The combined organic layer was washed (aq. NH4Cl, 50 mL), dried (Na2SO4), and reduced in vacuo to obtain a residue that was purified (PM9) to afford compound 1.038 (270 mg, 0.516 mmol, 81% yield) as a white solid. LCMS (AM1): rt = 2.24 min, (524.2 [M+H]+), 97.58% purity.1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.78 (s, 1H), 8.47 (s, 1H), 7.70 (dd, J = 12.2, 2.3 Hz, 1H), 7.61 (s, 1H), 7.53 – 7.49 (m, 4H), 7.39 (d, J = 8.9 Hz, 1H), 6.01 (s, 1H), 3.2 (s, 3H), 3.10 (s, 3H), 2.57 (s, 3H), 2.19 (s, 3H) ppm. Synthesis of intermediate 1.044 tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.043) To a solution of DMAP (1.2 g, 9.793 mmol) and Cu(OAc)2(0.45 g, 2.448 mmol) in MeOH (10 mL) at RT under O2atm. was added compound 1.019 (1 g, 4.896 mmol) and (4-((tert- butoxycarbonyl)amino)-2-methylphenyl)boronic acid (CAS:2246582-46-5, 1.2 g, 4.896 mmol). The reaction mixture was stirred at RT for 16 h, then filtered through Celite®, diluted with aq. NH4Cl (50 mL) and extracted (EA, 50 mL X 3). The combined organic layer was washed (brine, 50 mL), dried (Na2SO4), and reduced in vacuo to yield a residue, which was purified (PM11) to afford compound 1.043 (0.75 g, 1.833 mmol, 37.41% yield) as yellow solid. LCMS (AM1): rt = 2.21 min, (410.3 [M+H]+), 93.94% purity.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.5, 2.2 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 3.32 (s, 3H), 3.07 (s, 3H), 2.57 (s, 3H), 1.89 (s, 3H), 1.49 (s, 9H) ppm. (E)-N'-(1-(4-amino-2-methylphenyl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)- N,N-dimethylformimidamide (1.044) To a solution of compound 1.043 (0.75 g, 1.832 mmol) in DCM (10 mL) was added TFA (2.1 mL, 27.50 mmol) at RT and stirred for 16 h. The reaction mixture was reduced in vacuo to yield a residue, which was diluted with DCM (60 mL). The organic layer was washed (aq. NaHCO3, 30 mL), dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.044 (0.450 g, 1.454 mmol, 79.42% yield) as brown solid. The compound was used in the next step without further purification. LCMS (AM1): rt = 1.82 min, (310.2 [M+H]+), 91.74% purity.1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.41 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.46 – 6.40 (m, 2H), 5.19 (s, 2H), 3.08 (s, 3H), 2.64 (s, 3H), 2.49 (s, 3H), 1.76 (s, 3H) ppm. Synthesis of intermediate 1.045 rac-(E)-2-((4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)amino)-2-oxo-1-(3-(trifluoromethoxy)phenyl)ethyl acetate (1.045) To a solution of compound 1.044 (0.3 g, 0.97 mmol) in DCM (10 mL) at 0 °C in the round bottom flask, DIPEA (0.8 mL, 4.85 mmol), T3P (50% w / w soln in EA, 3.1 mL, 4.85 mmol) and compound 1.003 (0.323 g, 1.164 mmol) were added. The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield a residue, which was purified (PM9) to afford compound 1.045 (0.2 g, 0.351 mmol, 36% yield) as off white solid. LCMS (AM2): rt = 2.05 min, (570.23 [M+H]+), 99.29% purity.1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 7.61 (d, J = 5.0 Hz, 2H), 7.55 – 7.53 (m, 2H), 7.48 – 7.43 (m, 2H), 7.22 (d, J = 8.5 Hz, 1H), 6.07 (s, 1H), 3.06 (s, 3H), 2.51 (s, 3H), 2.48 (s, 3H), 2.20 (s, 3H), 1.92 (s, 3H) ppm. Synthesis of intermediate 1.048 3-methyl-1-(2-methyl-4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (1.047) To a solution of 3-Methyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (CAS: 7057-22-9, 0.8 g, 5.369 mmol) in DMF (8 mL), was added 2-Fluoro-5-nitrotoluene (CAS: 455-88-9; 0.83 g, 5.369 mmol) and Cs2CO3(1.749 g, 5.369 mmol). The reaction mixture was stirred at 60 °C for 3 h, then diluted with water (30 mL) and extracted (EA, 50 mL X 3). The combined organic layer was washed (brine, 30 mL), dried (Na2SO4), filtered and reduced in vacuo to yield a crude mixture which was purified (PM10) to yield compound 1.047 (0.4 g, 1.41 mmol, 26.21% yield) as yellow solid. LCMS (AM2): rt = 1.74 min, (285.37 [M+H]+), 100% purity.1H NMR (400 MHz, DMSO-d6): δ 8.38 – 8.28 (m, 2H), 8.20 (dd, J = 8.6, 2.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.65 (br, 2H), 2.48 (s, 3H), 2.29 (s, 3H) ppm. 1-(4-amino-2-methylphenyl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (1.048) To a solution of compound 1.047 (1.1 g, 3.869 mmol) in MeOH (10 mL) at 0°C was added zinc dust (1.265 g, 19.347 mmol), then 2M NH4Cl (aq.) solution (2.128 g, 38.694 mmol). The reaction mixture was stirred for 2 h at RT, diluted with DCM (25 mL) and filtered through a pad of Celite®. The filtrate was reduced in vacuo to afford a residue which was purified (PM10) to afford compound 1.048 (0.8 g, 3.15 mmol, 81.3% yield). LCMS (AM2): rt = 0.53 min, (255.36 [M+H]+), 99% purity. Synthesis of intermediate 1.049 rac-2-((4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)amino)-1-(3,5-difluorophenyl)-2-oxoethyl acetate (1.049) To a solution of compound 1.048 (0.2 g, 0.787 mmol) and rac-2-acetoxy-2-(3,5- difluorophenyl) acetic acid (CAS:1253521-12-8, 0.36 g, 1.575 mmol) in DCM (5 mL), was added DIPEA (0.66 mL, 3.935 mmol) and T3P (50% w / w soln in EA, 2.0 mL, 3.15 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (25 mL) and extracted (DCM, 25 mL X 3). The combined organic layer was washed (brine, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford a residue, which was purified (PM10) to afford compound 1.049 (0.18 g, 0.385 mmol, 49.07% yield) as yellow solid. LCMS (AM1): rt = 2.21 min, (467.3 [M+H]+), 96.7% purity.1H NMR (400 MHz, DMSO-d6): δ 10.66 (s, 1H), 8.24 (s, 1H), 7.35 – 7.25 (m, 4H), 7.20 – 7.17 (m, 2H), 6.24 (brs, 2H), 6.05 (s, 1H), 2.47 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H) ppm. Synthesis of intermediate 1.050 rac-[1-(3-chlorophenyl)-2-[4-[7-[(E)-dimethylaminomethyleneamino]-3-methyl- pyrazolo[4,3-d]pyrimidin-1-yl]-3-methyl-anilino]-2-oxo-ethyl] acetate (1.050) To a solution of compound 1.044 (0.25 g, 0.808 mmol) in DCM (5 mL) was added DIPEA (0.7 mL, 4.04 mmol), 2-(acetyloxy)-2-(3-chlorophenyl)acetic acid (CAS: 947156-24-3, 0.222 g, 0.970 mmol) and T3P (50% w / w soln in EA, 2.57 mL, 4.04 mmol). The reaction mixture was stirred at RT for 2 h then diluted with water (30 mL) and extracted (DCM, 20 mL X 3). The combined organic layer was washed (sat. aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to yield a residue. The residue was purified (PM6) to afford compound 1.050 (0.3 g, 0.645 mmol, 71% yield) as white solid. LCMS (AM1): rt = 2.22 min, (520.3 [M+H]+), 93.29% purity.1H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1H), 8.71 (s, 1H), 8.44 (s, 1H), 7.62 (s, 1H), 7.54 – 7.52 (m, 2H), 7.49 – 7.47 (m, 3H), 7.21 (d, J = 8.5 Hz, 1H), 6.02 (s, 1H), 3.05 (s, 3H), 2.50 (s, 3H), 2.49 (s, 3H), 2.19 (s, 3H), 1.91 (s, 3H) ppm. Synthesis of intermediate 1.056 tert-butyl N-(3-chloro-4-{7-[(E)-[(dimethylamino)methylidene]amino]-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl}phenyl)carbamate (1.055) To a solution of DMAP (1.807 g, 14.368 mmol) and Cu(OAc)2 (0.666 g, 3.692 mmol) in ACN (40 mL) was added compound 1.019 (1.5 g, 7.345 mmol), then (4-((tert- butoxycarbonyl)amino)-2-chlorophenyl)boronic acid (CAS:1421754-24-6, 2.592 g, 9.548 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h under O2 atmosphere, then diluted with DCM (100 mL) and washed (sat. aq. NH4Cl, 50mL X 2). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield a residue which was purified (PM8) to afford compound 1.055 (1.32 g, 38% yield) as light-yellow solid. LCMS (AM2): rt = 2.00 min, (430.22 [M+H]+), 94.52% purity.1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.76 (s, 1H), 8.46 (s, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.47 – 7.41 (m, 2H), 3.09 (s, 3H), 2.57 (s, 3H), 2.51 (s, 3H), 1.50 (s, 9H) ppm. N'-[1-(4-amino-2-chlorophenyl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-N,N- dimethylmethanimidamide (1.056) To a solution of compound 1.055 (2.5 g, 5.827 mmol) in DCM (10 mL) was added TFA (1.32 g, 11.654 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was reduced in vacuo to yield a residue which was dissolved in DCM (200 mL) and washed (10% aq. NaHCO3solution, 100 mL x 2). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.056 (1.8 g, 5.471 mmol, 93%) as off white solid. LCMS (AM1): rt = 1.87 min, (330.2 [M+H]+), 86.42% purity.1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.42 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.5, 2.4 Hz, 1H), 5.62 – 5.60 (m, 2H), 3.09 (s, 3H), 2.65 (s, 3H), 2.48 (s, 3H) ppm. Synthesis of intermediate 1.057 rac-[2-[3-chloro-4-[3-methyl-7-[(E)-methylaminomethyleneamino] pyrazolo[4,3- d]pyrimidin-1-yl]anilino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl] acetate (1.057) To a stirred solution of compound 1.056 (150 mg, 0.455 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (294 mg, 2.796 mmol), compound 1.006 (178 mg, 0.682 mmol) and T3P (50% w / w soln in EA, 1.778 g, 2.796 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with water (30 mL) and extracted (DCM, 20 mL x 2). The combined organic layer was washed (sat. aq. NH4Cl, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue, which was purified (PM7) to afford compound 1.057 (170 mg, 0.29 mmol, 65% yield) as yellow solid. LCMS (AM1): rt = 2.42 min, (574.3 [M+H]+), 88.32% purity.1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.59 – 7.47 (m, 2H), 6.11 (s, 1H), 3.06 (s, 3H), 2.45 (s, 3H), 2.21 (s, 3H) ppm. Synthesis of intermediate 1.058 rac-[(3-chloro-4-{7-[(E)-[(dimethylamino)methylidene]amino]-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl}phenyl)carbamoyl](3-chlorophenyl)ethylacetate (1.058). To a solution of compound 1.019 (600 mg, 1.82 mmol) in DCM (20 mL) at 0 °C, was added DIPEA (1.58 mL, 9.09 mmol), 2-(acetyloxy)-2-(3-chlorophenyl)acetic acid (CAS 947156-24-3, 621 mg, 2.72 mmol) and T3P (50% w / w soln in EA, 2.8 g, 9.09 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with DCM (100 mL), washed (sat. aq. NH4Cl solution, 50 mL x 3), dried (Na2SO4), and reduced in vacuo to obtain crude compound 1.058 (300 mg, 0.697 mmol, 37.31% yield) as yellow solid. The crude was used in the next step without purification. LCMS (AM1): rt = 2.26 min, (540.2 [M+H]+), 73.58% purity. Synthesis of intermediate 1.072 (E)-N,N-dimethyl-N'-(1H-pyrazolo[4,3-d]pyrimidin-7-yl)formimidamide (1.066) To a solution of 1H-pyrazolo[4,3-d]pyrimidin-7-amine (CAS 13877-56-0, 7.0 g, 48.82 mmol) in 1,4-dioxane (50 mL) was added DMF-DMA (18.15 g, 166.51 mmol) and the reaction mixture heated to 100 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain a solid which was triturated with DE (50 mL) to afford compound 1.066 (7.5 g, 39.17 mmol, 80.23 % yield) as off white solid. LCMS (AM1): rt = 1.60 min, (191.1 [M+H]+), 99.34% purity.1H NMR (400 MHz, DMSO-d6): δ 13.61 (brs, 1H), 8.93 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 3.23 (s, 3H), 3.20 (s, 3H) ppm. (E)-N'-(3-bromo-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N,N-dimethylformimidamide (1.067) To a solution of compound 1.066 (7.5 g, 39.17 mmol) in DMF (50 mL) was added NBS (8.37 g, 47.31 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was reduced in vacuo to obtain a solid which was triturated with DE (30 mL) to afford compound 1.067 (7.5 g, 26.52 mmol, 67.72% yield) as yellow solid. LCMS (AM1): rt = 1.89 min, (271.1 [M+H]+), 95.17 % purity.1H NMR (400 MHz, DMSO-d6): δ 13.99 (s, 1H), 8.95 (s, 1H), 8.45 (s, 1H), 3.25 (s, 3H), 3.21 (s, 3H) ppm. tert-butyl (E)-(4-(3-bromo-7-(((dimethylamino)methylene)amino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.068) To a solution of DMAP (5.448 g, 44.593 mmol) and Cu(OAc)2(3.632 g, 11.148 mmol) in MeOH (20 mL) was added compound 1.067 (6 g, 22.296 mmol) followed by (4-((tert- butoxycarbonyl)amino)-2-methylphenyl)boronic acid (CAS 2246582-46-5, 5.598 g, 22.296 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h, then diluted with DCM (100 mL). The organic layer was washed (sat. aq. NH4Cl, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM8) to afford compound 1.068 (6 g, 12.43 mmol, 56 % yield) as a light-yellow solid. LCMS (AM1): rt = 2.52 min, (474.1 [M+H]+), 98.30% purity.1H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.78 (s, 1H), 8.49 (s, 1H), 7.47 (s, 1H), 7.34 (dd, J = 2.04, 6.56 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 5.75 (s, 1H), 3.10 (s, 3H), 2.57 (s, 3H), 1.90 (s, 3H), 1.49 (s, 9H) ppm. (E)-N'-(1-(4-amino-2-methylphenyl)-3-bromo-1H-pyrazolo[4,3-d]pyrimidin-7-yl)- N,N-dimethylformimidamide (1.069) To a solution of compound 1.068 (6 g, 12.43 mmol) in DCM (50 mL) was added TFA (15 mL) and the mixture was stirred at RT for 3 h. The reaction mixture was reduced in vacuo to yield a residue, which was dissolved in DCM (300 mL). The organic layer was washed (10% aq. NaHCO3, 200 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM7) to afford compound 1.069 (4.3 g, 11.06 mmol, 89% yield) as brown solid. LCMS (AM1): rt = 2.14 min, (374.1 [M+H]+), 96.24% purity.1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.47 (s, 1H), 6.93 (d, J = 8.32 Hz, 1H), 6.47 (d, J = 2.12 Hz, 1H), 6.45 – 6.43 (m, 1H), 5.29 (s, 2H), 3.11 (s, 3H), 2.65 (s, 3H), 1.78 (s, 3H) ppm. (E)-2-((4-(3-bromo-7-(((dimethylamino)methylene)amino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)amino)-1-(3,5-difluorophenyl)-2-oxoethyl acetate (1.070) To a solution of compound 1.069 (4.3 g, 11.06 mmol) in DCM (40 mL) at 0 °C, was added DIPEA (10.007 mL, 57.45 mmol), compound 1.003 (2.645 g, 11.49 mmol) and T3P (50% w / w soln in EA, 13.641 mL, 57.45 mmol). The reaction mixture was stirred for 2 h, then diluted with water (100 mL) and extracted (DCM, 100 mL x 2). The combined organic layer was washed (sat. NH4Cl (aq.), 50 mL), dried (Na2SO4), filtered and reduced in vacuo to yield a residue which was purified (PM7) to afford compound 1.070 (3.6 g, 5.77 mmol, 52.13% yield) as a yellow solid. LCMS (AM1): rt= 2.48 min, (586.1 [M+H]+), 94.00% purity.1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.77 (s, 1H), 8.50 (s, 1H), 7.55 (d, J = 7.56 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.35 - 7.27 (m, 5H), 6.05 (s, 1H), 3.08 (s, 3H), 2.49 (s, 3H), 2.21 (s, 3H), 1.93 (s, 3H) ppm. (E)-2-(3,5-difluorophenyl)-N-(4-(7-(((dimethylamino)methylene)amino)-3-vinyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxyacetamide (1.071) To a solution of compound 1.070 (200 mg, 0.341mmol) and 2-ethenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolan (315.18 g, 2.046 mmol) in 1,4-dioxane (4.0 mL) and H2O (1 mL) was added Cs2CO3(333.38mg, 1.023 mmol) in the sealed tube. The reaction mixture was degassed with N2and PdCl2(dppf) (24.93 mg, 0.034 mmol), added and the reaction mixture stirred at 90 °C for 16 h. The reaction mixture was cooled to RT and diluted with DCM (50 mL). The combined organic layer was washed (H2O, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM10) to afford compound 1.071 (0.150 g, 0.238 mmol, 76% yield) as yellow solid. LCMS (AM1): rt = 2.40 min, (492.2 [M+H]+), 84.91% purity.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 7.67 (s, 1H), 7.62 - 7.55 (m, 1H), 7.54 - 7.50 (m, 1H), 7.26 - 7.17 (m, 4H), 7.02 - 6.91 (m, 1H), 6.78 - 6.65 (m, 1H), 5.65 (dd, J = 2.16, 8.96 Hz, 1H), 5.21 (d, J = 5.12 Hz, 1H), 3.07 (s, 3H) ,2.49 (s, 3H), 1.92 (s, 3H) ppm. N-(4-(7-amino-3-vinyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide (1.072) To a solution of compound 1.071 (140 mg, 0.285 mmol) in EtOH (5 mL) was added ZnCl2(388.28 mg, 2.848 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture cooled to RT and reduced in vacuo to yield a residue which was purified (PM5) to afford compound 1.072 (110 mg, 0.244 mmol, 86 % yield) as brown solid. LCMS (AM1): rt = 2.29 min, (437.2 [M+H]+), 97.12% purity.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.31 (s, 1H), 7.83 (d, J = 7.76 Hz, 1H), 7.75 (t, J = 7.48 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.35 (d, J = 8.52 Hz, 1H), 7.25 (d, J = 6.36 Hz, 2H), 7.21 - 7.16 (m, 1H), 6.98 -6.91 (m, 1H), 6.80 (d, J = 4.84 Hz, 1H), 6.68 (dd, J = 2.02, 7.84 Hz, 1H), 6.32 (brs ,1H), 5.64 (dd, J = 2.04, 9.2 Hz, 1H), 5.21 (d, J = 4.88 Hz, 1H), 1.97 (s, 3H) ppm. Synthesis of intermediate 1.082 7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-ol (1.073) To a solution of 4-amino-3-methyl-1H-pyrazole-5-carbonitrile (CAS 28745-14-4, 2.0 g, 16.38 mmol) in THF (30 mL) at 0°C was added dropwise trichloro acetyl isocyanate (4.625 g, 24.56 mmol) and the reaction mixture stirred at RT for 3 h. To the reaction mixture at 0°C was added a MeOH (5mL) then the mixture reduced in vacuo to obtain a residue. To the residue at 0°C was added dropwise 7M ammonia in MeOH (50mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was reduced in vacuo to obtain a residue, which was triturated (DE, 200 mL) to afford compound 1.073 (2 g, 11.44 mmol, 69.86 % yield) as white solid. LCMS (AM1): rt = 0.57 min, (166.1 [M+H]+), 94.47 % purity.1H NMR (400 MHz, DMSO-d6): δ 12.09 (brs, 1H), 7.82 (s, 1H), 5.88 (s, 2H), 2.12 (s, 3H) ppm. (E)-N'-(5-hydroxy-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N,N- dimethylformimidamide (1.074) To a solution of compound 1.073 (2 g, 11.44 mmol) in 1,4-dioxane (10 mL) was added DMF-DMA (6.458 mL, 18.165 mmol) and the reaction mixture heated to 100 °C for 2 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain a solid which was triturated (DE, 30 mL) to afford compound 1.074 (1.1 g, 3.42 mmol, 29.91% yield) as yellow solid. LCMS (AM1): rt = 2.60 min, (221.2 [M+H]+), 68.51% purity.1H NMR (400 MHz, DMSO-d6): δ 13.43 (brs, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 3.09 (s, 3H), 2.98 (s, 3H), 2.12 (s, 3H) ppm. tert-butyl (4-(7-amino-5-hydroxy-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)carbamate (1.075) To a solution of DMAP (0.416 g, 1.29 mmol) and Cu(OAc)2(0.206 g, 1.135 mmol) in MeOH (15 mL) was added compound 1.074 (0.5 g, 2.27 mmol) followed by (4-((tert- butoxycarbonyl)amino)-2-methylphenyl)boronic acid (CAS 2246582-46-5, 0.570 g, 2.27 mmol) at 0 °C and purged with O2. The reaction mixture was allowed to stir at RT for 16 h, then diluted (EA, 100 mL). The organic layer was washed (sat. aq. NH4Cl, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM8) to afford the crude compound 1.075 (0.22 g, 0.187 mmol, 14.53% yield) as a Brown solid. LCMS (AM1): rt= 2.14 min, (371.3 [M+H]+), 31.65 % purity. tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-5-hydroxy-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.076) To a solution of compound 1.075 (0.450 g, 1.215 mmol) in 1,4-dioxane (5.0 mL) was added DMF-DMA (434.296 mg, 3.645 mmol) and the reaction mixture heated at 70 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain a solid which was triturated (DE, 30 mL) to afford compound 1.076 (0.450 g, 0.920 mmol, 75.73% yield) as brown solid. LCMS (AM1): rt = 2.19 min, (426.3 [M+H]+), 86.99 % purity.1H NMR (400 MHz, DMSO-d6): δ 10.98 (brs, 1H), 9.42 (s, 1H), 8.60 (s, 1H), 7.51 (s, 1H), 7.38 - 7.35 (m, 2H), 7.21 (d, J = 4.88 Hz, 1H), 3.07 (s, 3H), 2.31 (s, 3H), 1.85 (s, 3H), 1.49 - 1.45 (s, 12H) ppm. (E)-1-(4-((tert-butoxycarbonyl)amino)-2-methylphenyl)-7- (((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl trifluoromethanesulfonate (1.077) To a solution of compound 1.076 (0.45 g, 0.920 mmol) in DCM (5 mL) at 0°C was added Et3N (0.321 g, 3.173 mmol) and Triflic anhydride (447.595mg, 1.586mmol). The mixture was stirred at RT for 4 h. The reaction mixture was diluted with cold water (20mL) and extracted (DCM, 3 X 50 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2a) to afford compound 1.077 (0.250 g, 0.396 mmol, 43.11% yield) as yellow solid. LCMS (AM1): rt= 2.82 min, (558.2 [M+H]+), 98.87 % purity.1H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 8.66 (s, 1H), 7.46 (d, J = 1.56 Hz, 1H), 7.34 (dd, J = 1.92, 6.48 Hz, 1H), 7.17 (d, J = 8.56 Hz, 1H), 3.15 (s, 3H), 2.62 (s, 3H), 2.48 (s, 3H), 1.91 (s, 3H), 1.49 (s, 9H) ppm. tert-butyl (4-(7-amino-5-((4-methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.078) To a solution of compound 1.077 (0.25 g, 0.396 mmol) in DIPEA (2.5 mL) was added 4- methoxy benzylamine (2.5 mL) and the reaction mixture was heated at 120 °C for 1 h. The reaction mixture was cooled to RT, diluted with cold water (20mL) and extracted (EA, 3 X 30 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2a) to afford compound 1.078 (0.130 g, 0.234 mmol, 59.07 % yield) as brown solid. LCMS (AM1): rt = 2.54 min, (490.3 [M+H]+), 88.23% purity.1H NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.36 Hz, 1H), 7.29 (dd, J = 8.52, 7.16 Hz, 1H), 6.91 - 6.83 (m, 6H), 6.27 (t, J = 5.76 Hz, 1H), 4.22 (s, 2H), 3.70 (s, 3H), 2.32 (s, 3H), 1.95 (s, 3H), 1.49 (s, 9H) ppm. tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-5-((4- methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)carbamate (1.079) To a solution of compound 1.078 (0.130 g, 0.234 mmol) in 1,4-dioxane (3 mL) was added DMF-DMA (0.2 mL, 0.798 mmol) and the reaction mixture heated to 100 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain a solid which was triturated (DE, 20 mL) to afford crude compound 1.079 (140 mg, 0.167 mmol, 71.55% yield) as yellow solid. LCMS (AM1): rt = 2.61 min, (545.4 [M+H]+), 65.21% purity. (E)-N'-(1-(4-amino-2-methylphenyl)-5-((4-methoxybenzyl)amino)-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-7-yl)-N,N-dimethylformimidamide (1.080) To a stirred solution of compound 1.079 (160 mg, 0.192 mmol) at 0°C was added 4M HCl in dioxane (2mL). The mixture was stirred at RT for 16 h, then reduced in vacuo to yield a residue which was triturated (DE, 20 mL) to afford crude compound 1.080 (0.125 g, 0.115mmol, 60.46% yield) as brown gum. LCMS (AM2): rt= 1.93 min, (445.3 [M+H]+), 42.17 % purity. (E)-1-(3,5-difluorophenyl)-2-((4-(7-(((dimethylamino)methylene)amino)-5-((4- methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)amino)-2-oxoethyl acetate (1.081) To a solution of compound 1.080 (100 mg, 0.093 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (0.2 mL, 1.125 mmol), compound 1.009 (51.78 g, 0.255 mmol) and T3P (50% w / w soln in EA, 357.68 mg, 1.125 mmol). The reaction mixture was stirred at RT for 30 min, then diluted with water (20 mL) and extracted (DCM, 2 X 30 mL). The organic layer was washed (sat. aq. NH4Cl, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM7) to afford compound 1.081 (60 mg, 0.041 mmol, 43.65% yield) as a yellow solid. LCMS (AM1): rt= 3.72 min, (657.3 [M+H]+), 72.60% purity. N-(4-(7-amino-5-((4-methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin- 1-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (1.082) To a solution of compound 1.081 (60 mg, 0.091 mmol) in EtOH (2 mL) was added ZnCl2 (124 mg, 0.914 mmol). The reaction mixture was stirred at 90 °C for 16 h, then cooled to RT and reduced in vacuo to yield a residue which was dissolved in water (25 mL) and extracted (EA, 3 X 20 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.082 (50 mg, 0.071 mmol, 77.41%) as brown solid. LCMS (AM1): rt= 2.41 min, (560.2 [M+H]+), 79.15% purity. Synthesis of intermediate 1.087 3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (1.083) To a solution of 4-amino-5-methyl-1H-pyrazole-3-carbonitrile (CAS 28745-14-4, 2.50 g, 20.47 mmol) in IPA (50 mL) was added acetamidine acetate (3.627 g, 30.71 mmol) and the reaction mixture heated at 80 °C for 6 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain a brown residue, which was washed with DE (200 mL) to afford compound 1.083 (1.5 g, 9.22 mmol, 44.91% yield) as yellow solid which was used in next step without further purification. LCMS (AM1): rt = 0.89 min, (164.1 [M+H]+), 97.5% purity.1H NMR (400 MHz, DMSO-d6): δ 12.2 (s, 1H), 7.07 (s, 2H), 2.38 (s, 6H) ppm. (E)-N'-(3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N,N-dimethylformimidamide (1.084) To a solution of compound 1.083 (2.0 g, 12.28 mmol) in 1,4-dioxane (15 mL) was added DMF-DMA (2.9 mL, 24.47mmol) and the reaction mixture heated at 100 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain a solid which was triturated with DE (20 mL) to afford compound 1.084 (1.5 g, 6.87 mmol, 56% yield) as off white solid. LCMS (AM1): rt =1.81 min, (219.2 [M+H]+), 71.81% purity.1H NMR (400 MHz, DMSO-d6): δ 13.01 (s, 1H), 8.82 (s, 1H), 3.21 (s, 3H), 3.17(s, 3H), 2.51 (s, 3H), 2.41 (s, 3H) ppm. tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-3,5-dimethyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.085) To a solution of DMAP (1.847 g, 15.12 mmol) and Cu(OAc)2 (0.458 g, 2.52 mmol) in MeOH (12 mL) was added compound 1.084 (1.1 g, 5.04 mmol) followed by (4-((tert- butoxycarbonyl)amino)-2-methylphenyl)boronic acid (CAS:2246582-46-5, 1.898 g, 7.56 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h, then diluted with DCM (100 mL). The organic layer was washed (sat. aq. NH4Cl, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM3) to afford compound 1.085 (1.35 g, 3.19 mmol, 63% yield) as light-yellow solid. LCMS (AM1): rt = 2.40 min, (424.3 [M+H]+), 98.22% purity.1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.64 (s, 1H), 7.43 (s, 1H), 7.31 (dd, J = 8.48, 2.0 Hz, 1H), 7.11 (d, J = 8.52 Hz, 1H), 3.06 (s, 3H), 2.56 (s, 3H), 2.53 (s, 3H), 2.47 (s, 3H), 1.88 (s, 3H), 1.49 (s, 9H) ppm. (E)-N'-(1-(4-amino-2-methylphenyl)-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)- N,N-dimethylformimidamide (compound 1.086) To a solution of compound 1.085 (1.35 g, 3.188 mmol) in DCM (10 mL), was added TFA (8 mL) dropwise at 0 °C, then the reaction warmed to RT and stirred for 3 h. The reaction mixture was reduced in vacuo to yield a residue, which was dissolved in DCM (150 mL). The organic layer was washed (10% aq. NaHCO3, 50 mL x 3). dried (Na2SO4), filtered and reduced in vacuo to yield compound 1.086 (1.0 g, 3.09 mmol, 97% yield) as off white solid. LCMS (AM1): rt = 2.00 min, (324.2 [M+H]+), 96.42% purity.1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 6.85 (d, J = 8.28 Hz, 1H), 6.45 – 6.39 (m, 2H), 5.17 (s, 2H), 3.07 (s, 3H), 2.63 (s, 3H), 2.51 (s, 3H), 2.45 (s, 3H), 1.76 (s, 3H) ppm. (E)-1-(3,5-difluorophenyl)-2-((4-(7-(((dimethylamino)methylene)amino)-3,5-dimethyl- 1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)amino)-2-oxoethyl acetate (1.087) To a solution of compound 1.086 (0.07 g, 0.216 mmol) and rac-2-acetoxy-2-(3,5- difluorophenyl) acetic acid (CAS 1253521-12-8, 0.074 g, 0.325 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (0.18 mL, 1.082 mmol) and T3P (50% w / w soln in EA, 0.51 mL, 0.866 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed (brine, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford a residue, which was purified (PM10) to afford compound 1.087 (0.06 g, 0.149 mmol, 69.01% yield) as white solid. LCMS (AM2): rt= 1.83 min, (536.4 [M+H]+), 100% purity.1H NMR (400 MHz, DMSO-d6): δ10.50 (s, 1H), 8.63 (s, 1H), 7.51 (d, J = 2.2Hz, 1H), 7.47 – 7.45 (dd, J = 2.32, 6.08 Hz, 1H), 7.35-7.32 (m, 1H),7.31-7.25 (m, 2H), 7.19 (d, J = 8.48 Hz, 1H), 6.04 (s, 1H), 3.04 (s, 3H), 2.53 (s, 3H), 2.49 (s, 3H) 2.47 (s, 3H), 2.20 (s, 3H) 1.91 (s, 3H) ppm. Synthesis of intermediate 1.088 (R,E)-1-(3,5-difluorophenyl)-2-((4-(7-(((dimethylamino)methylene)amino)-3,5- dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)amino)-2-oxoethyl acetate (1.088) To a solution of compound 1.086 (0.14 g, 0.4329 mmol), pyridine (0.1 mL, 1.30 mmol) and compound (R)-1.009 (0.15 g, 0.6493 mmol) in DMF (2 mL) was added T3P (50% w / w soln in EA, 0.65 mL, 2.16 mmol) at -10°C. The reaction mixture was stirred for 2 h, then diluted with water (25 mL) and extracted (EA, 30 mL x 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM9) to afford compound 1.088 (0.16 g, 0.276 mmol, 63.93% yield, 99% ee) as light-yellow solid. LCMS (AM2): rt = 1.94 min, (536.18 [M+H]+), 92.64% purity. SFC (AM10): rt = 2.710 min, ee = 99.72%.1H NMR (400 MHz, DMSO-d6): δ10.51 (s, 1H), 8.63 (s, 1H), 7.51 (d, J = 2.04 Hz, 1H), 7.47 – 7.45 (dd, J = 2.32, 6.08 Hz, 1H), 7.35-7.32 (m, 1H),7.30 - 7.26 (m, 2H), 7.19 (d, J = 8.48 Hz, 1H), 6.04 (s, 1H), 3.04 (s, 3H), 2.53 (s, 3H), 2.48 (s, 3H), 2.47 (s, 3H), 2.20 (s, 3H) 1.91 (s, 3H) ppm. Synthesis of intermediate 1.090 tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.088) To a solution of compound 1.068 (200 mg, 0.422 mmol) in MeOH (4.0 mL) was added Zn (139.53 mg, 2.11 mmol) and aq.NH3 (2.0 mL). The reaction mixture was stirred at 0°C for 15 min. The reaction mixture was reduced in vacuo to yield a residue, water (50 mL) was added to the residue and extracted (EA, 50 mL x 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield crude product compound 1.088 (80 mg, 0.202 mmol, 47.90 %) as a solid. LCMS (AM1): rt = 2.35 min, (396.3 [M+H]+), 79.97% purity.1H NMR: (400 MHz, DMSO) δ 9.46 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.08 (s, 3H), 2.56 (s, 3H), 1.90 (s, 3H), 1.49 (s, 9H). (E)-N'-(1-(4-amino-2-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N,N- dimethylformimidamide (1.089) To a solution of compound 1.088 (80 mg, 0.2020 mmol) in DCM (2.0 mL) at 0°C was added TFA (0.2 mL) and the reaction mixture was stirred at RT for 1h. The reaction mixture was reduced in vacuo to yield a residue.10% aq. NaHCO3 (20 mL) was added to the residue and extracted (EA, 50 mL x 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield crude compound 1.089 (50 mg, 0.1689 mmol, 83.62 %) as a solid. LCMS (AM1): rt = 1.96 min, (296.2 [M+H]+), 91.37% purity.1H NMR: (400 MHz, DMSO) δ 8.72 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.47 - 6.42 (m, 2H), 5.23 (s, 2H), 3.08 (s, 3H), 2.64 (s, 3H),1.74 (s, 3H) ppm. (R,E)-1-(3,5-difluorophenyl)-2-((4-(7-(((dimethylamino)methylene)amino)-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)amino)-2-oxoethyl acetate (1.090) To a solution of compound 1.089 (50 mg, 0.1689 mmol) in DCM (2 mL) and pyridine (40.36 mg, 0.507 mmol) at 0 °C, was added compound (R)-1.009 (77.70 mg, 0.3378 mmol) and T3P (50% w / w soln in EA, 268 mg, 0.8445 mmol). The reaction mixture was stirred at RT for 2 h then diluted with water (50 mL) and extracted (DCM, 50 mL x 2). The combined organic layer was washed (brine, 50mL), dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM7) to afford compound 1.090 (60 mg, 0.1062 mmol, 69.84% yield) as a white solid. LCMS: (AM1): rt= 2.33 min, (508.3 [M+H]+), 86.84% purity.1H NMR: (400 MHz, DMSO) δ 10.59 (s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.55 -7.54 (m, 1H), 7.49 - 7.47 (m, 1H), 7.35 - 7.24 (m, 4H), 6.06 (s, 1H), 3.06 (s, 3H), 2.49 (s, 3H), 2.20 (s, 3H), 1.90 (s, 3H) ppm. Synthesis of intermediate 1.095 tert-butyl (4-(7-amino-5-((4-methoxybenzyl)(methyl)amino)-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)carbamate (1.091) To a solution of compound 1.077 (0.2 g, 0.359 mmol) in DIPEA (2 mL) was added 1-(4- methoxyphenyl)-N-methylmethanamine (2 mL). The reaction mixture was heated at 120 °C for 1 h in the MW, cooled then diluted with cold water (20 mL) and extracted (EA, 3 X 30 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2a) to afford compound 1.091 (0.17 g, 0.338 mmol, 94.10% yield) as brown solid. LCMS (AM1): rt = 2.71 min, (504.3 [M+H]+), 87.78% purity.1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.55 (s, 1H), 7.40 (dd, J = 8.4, 2.1 Hz, 1H), 7.20 (d, J = 8.0 Hz, 3H), 6.86 (d, J = 8.6 Hz, 2H), 5.75 (brs, 1H), 4.78 (d, J = 4.2 Hz, 2H), 3.71 (s, 3H), 3.00 (s, 3H), 2.35 (s, 3H), 1.96 (s, 3H), 1.49 (s, 9H) ppm. tert-butyl (E)-(4-(7-(((dimethylamino)methylene)amino)-5-((4- methoxybenzyl)(methyl)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)carbamate (1.092) To a solution of compound 1.091 (0.16 g, 0.318 mmol) in 1,4-dioxane (3 mL) was added DMF-DMA (0.113 mg, 0.953 mmol) and the reaction mixture heated at 70 °C for 3 h. The reaction mixture was cooled to RT and reduced in vacuo to obtain crude residue which was purified (PM3) to afford compound 1.092 (0.17 g, crude) as brown solid. LCMS (AM1): rt = 2.81 min, (559.4 [M+H]+), 62.48% purity. (E)-N'-(1-(4-amino-2-methylphenyl)-3-methyl-5-(methylamino)-1H-pyrazolo[4,3- d]pyrimidin-7-yl)-N,N-dimethylformimidamide (1.093) To a solution of compound 1.092 (0.17 g, 0.304 mmol) in DCM (3 mL) at 0 °C was added TFA (0.5 mL) and the reaction mixture stirred at RT for 48h. The reaction mixture was reduced in vacuo to yield a residue which was basified with 10% NaHCO3 (aq.) (50 mL) and extracted (EA, 3 X 10 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford mixture of compound 1.093 and compound 1.094 (0.08 g, crude) as brown solid. LCMS (AM1): rt = 2.02 min, (339.2 [M+H]+), 21.81% purity for compound 1.093, and rt = 1.91 min, (284.2 [M+H]+), 55.27% purity for compound 1.094. 1-(4-amino-2-methylphenyl)-N5,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidine-5,7- diamine (1.094) To a crude mixture of compound 1.093 and compound 1.094 (80 mg, 0.236 mmol) in EtOH (3 mL) was added ZnCl2(161 mg, 1.182 mmol). The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture cooled to RT and reduced in vacuo to yield a residue, which was dissolved in water (20 mL) and extracted (EA, 3 X 20 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.094 (66 mg, 0.233 mmol, 98%) as brown solid. LCMS (AM1): rt = 1.91 min, (284.2 [M+H]+), 91.88% purity. 2-((4-(7-amino-3-methyl-5-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)amino)-1-(3,5-difluorophenyl)-2-oxoethyl acetate (1.095) To a solution of compound 1.094 (66 mg, 0.233 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (0.150 mg, 1.165 mmol), compound 1.009 (53.6 mg, 0.233 mmol) and T3P (50% w / w soln in EA, 742 mg, 1.165 mmol). The reaction mixture was stirred at RT for 3 h, then diluted with water (20 mL) and extracted (DCM, 2 X 30 mL). The combined organic layer was washed (sat. aq. NH4Cl, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM3) to afford compound 1.095 (80 mg, 0.161 mmol, 69% yield) as a brown solid. LCMS (AM1): rt = 2.31 min, (496.2 [M+H]+), 92.39% purity.1H NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 7.66 – 7.54 (m, 2H), 7.35 – 7.22 (m, 4H), 6.12 – 6.09 (m, 1H), 6.04 (s, 1H), 5.75 (brs, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 1.98 (s, 3H) ppm. Synthesis of intermediate 1.108 3-(trifluoromethyl)-5-vinylbenzaldehyde (1.103) To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (CAS: 477535-41-4, 6 g, 23.714 mmol) in DMF: H2O (60 :15 mL) was added 2-ethenyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (18.26 g, 118.57 mmol), Pd(OAC)2 (0.53 g, 2.371 mmol), Na2CO3 (5.02 g, 47.42 mmol) and PPh3 (1.24 g , 4.73 mmol). The reaction mixture was heated to 80° C for 16 h, then cooled to RT, before being quenched (water, 300 mL) and extracted with EA (2 x 200 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM1a) to afford compound 1.103 (3.20 g, 16 mmol, 67%) as a colourless liquid. LCMS (AM2): rt = 3.78, No ionization, 98.97% purity. , 7.86 (s, 1H), 6.83 mL) at RT was added PTSA (0.36 g, 2.098 mmol) and ethylene glycol (3.51 g, 62.95 mmol). The reaction mixture was heated to 120° C for 16 h, then cooled to RT, diluted (water, 200 mL) and extracted (EA, 2 x 200 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM1a) to afford compound 1.104 (2.50 g, 10.24 mmol, 48%) as a colourless liquid. LCMS (AM1): rt = 3.88, No ionization, 98.27% purity. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.62 (s, 2H), 6.77 – 6.70 (m, 1H), 5.84 (t, J = 7.4 Hz, 1H), 5.36 (d, J = 10.9 Hz, 1H), 4.14 – 4.09 (m, 2H), 4.07 – 4.03 (m, 2H). 5-methyl-4-nitro-1H-pyrazole-3-carbonitrile. (1.105) To a solution of compound 1.104 (1.0 g, 4.095 mmol) in THF (10 mL) at 0° C was added dropwise 9-BBN (1.99 mL, 8.190 mmol). The reaction mixture was warmed and stirred at RT for 16 hours. Hydrogen peroxide (4 mL), 2M NaOH (2 mL) and MeOH solution (10 mL) were added at 0° C successively, then the reaction mixture was stirred at RT for 4 h. The reaction mixture was quenched (water, 100 mL) and extracted (EA, 2 x 100 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2b) to afford compound 1.105 (0.49 g, 1.87 mmol, 45%) as a colourless liquid. LCMS (AM2): rt = 3.18 min, (263.1 [M+H]+), 70.65% purity.1H NMR (400 MHz, CDCl3): δ 7.61 (brs, 1H), 7.53 (brs, 1H), 7.48 (brs, 1H), 5.81 (s, 1H), 4.15 – 4.11 (m, 2H), 4.09 – 4.03 (m, 2H), 3.89 (t, J = 1.7 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H). (3-(1,3-dioxolan-2-yl)-5-(trifluoromethyl)phenethoxy)(tert-butyl)dimethylsilane (1.106) To a solution of compound 1.105 (0.49 g, 1.87 mmol) in DCM (10 mL) at 0° C was added imidazole (0.36 g, 5.720 mmol) and TBDMS chloride (0.858 g, 5.720 mmol) and the reaction mixture stirred at RT for 4 h. The reaction mixture was quenched (water x 200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM1b) to afford compound 1.106 (0.60 g, 1.59 mmol, 42%) as a colourless liquid. LCMS (AM1): rt = 0.69 min, No ionisation, 93.24% purity. 3-(2-hydroxyethyl)-5-(trifluoromethyl)benzaldehyde (1.107) To a solution of compound 1.106 (0.70 g, 1.859 mmol) in acetone (7 mL) was added PTSA.H2O (0.035 g, 0.186 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched (water, 50 mL) and extracted (DCM, 2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2b) to afford compound 1.107 (0.30 g, 1.37 mmol, 74%) as a colourless liquid. LCMS (AM2): rt = 2.86, No ionization, 98.06% purity.1H NMR (400 MHz, CDCl3): δ 10.05 (s, 1H), 8.00 (brs, 1H), 7.95 (brs, 1H), 7.76 (brs, 1H), 3.95 (t, J = 6.3 Hz, 2H), 3.01 (t, J = 6.3 Hz, 2H). 2-hydroxy-2-[3-(2-hydroxyethyl)-5-(trifluoromethyl)phenyl]acetic acid (compound 1.108) To a solution of compound 1.107 (0.30 g, 1.375 mmol) in TMS Cyanide (0.35 mL, 2.75 mmol) at 0° C was added ZnI2 (0.043 g, 0.137 mmol). The reaction mixture was stirred at 0° C for 2 h, then conc. HCl (1 mL) added and stirred at 80° C for 16 h. The reaction mixture was quenched with aq. Sodium bicarbonate (50 mL) and extracted (EA, 100 mL). The aq. layer was acidified with conc. HCl and then extracted with EA (2 x 100 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo obtain compound 1.108 (0.20 g, 0.75 mmol, crude) as a pale yellow liquid. The product was used crude in the next step. LCMS (AM2): rt = 2.59 min, 262.1 [M-H]-, 30% Purity. Synthesis of intermediate 1.122 2-(3-chloro-5-vinylphenyl)-1,3-dioxolane (1.119) To a solution of 3-Chloro-5-ethenylbenzaldehyde (CAS 1645957-02-3, 3.5 g, 21.0 mmol) in Toluene (40 mL) was added PTSA (0.36 g, 2.101 mmol) and ethylene glycol (2.34 mL, 42.016 mmol) at RT and the reaction mixture heated to 120° C for 16 h. The reaction was cooled to RT, diluted (water, 200 mL) and extracted (ethyl acetate, 2 x 200 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM1a) to afford compound 1.119 (3.0 g, 14.28 mmol, 67%) as a colourless liquid. LCMS (AM1): rt = 2.50 min, 167.1 [M+H]+.100 % purity1H NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 6.78 - 6.71 (m, 1H), 5.97 - 5.93 (d, J = 17.6 Hz, 1H), 5.74 (s, 1H), 5.37 – 5.35 (d, J = 11.0 Hz, 1H), 4.09 – 4.01 (m, 2H), 3.99 - 3.93 (m, 2H). 2-(3-chloro-5-(1,3-dioxolan-2-yl)phenyl)ethan-1-ol (1.120) To a solution of compound 1.119 (1.5 g, 7.121 mmol) in THF (10 mL) at 0° C was added 9-BBN (28.4 mL, 14.24 mmol) dropwise and the reaction mixture stirred at RT for 16 h. hydrogen peroxide (1 mL), 2M NaOH (2 mL) and MeOH solution (10 mL) at 0° C were added successively and the reaction mixture stirred at RT for 4 h. The reaction mixture was quenched (water, 100 mL) and extracted (EA, 2 x 100 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2b) to afford compound 1.120 (0.7 g, 2.6 mmol, 42%) as a colourless liquid. LCMS (AM2): rt = 2.06 min, 229.1 [M+H]+, 46% purity. 3-chloro-5-(2-hydroxyethyl)benzaldehyde (compound 1.121) To a solution of compound 1.120 (700 mg, 3.061 mmol) in acetone (7 mL) was added PTSA.H2O (58 mg, 0.306 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched (water, 50 mL) and extracted (DCM, 2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM2b) to afford compound 1.121 (0.320 g, 1.73 mmol, 56%) as a colourless liquid.1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 7.77 (t, J = 1.72 Hz, 1H), 7.73 (t, J = 1.42 Hz, 1H), 7.66 - 7.65 (m, 1H), 3.66 - 3.63 (m, 2H), 2.82 (t, J = 6.4 Hz, 2H) ppm. 2-(3-chloro-5-(2-hydroxyethyl)phenyl)-2-hydroxyacetic acid (1.122) To a solution of compound 1.121 (300 mg, 1.625 mmol) in TMS Cyanide (321 mg, 3.25 mmol) at 0° C was added ZnI2 (51.86 mg, 0.162 mmol). The reaction mixture was stirred at 0° C for 2 h, then conc. HCl (1 mL) was added and the reaction mixture was stirred at 80° C for 16 h. The reaction mixture was quenched with aq. Sodium bicarbonate (50 mL) and extracted (EA, 100 mL). The aq. layer was acidified with conc. HCl and then extracted with EA (2 x 100 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo obtain a compound 1.122 (0.30 g, 1.30 mmol, crude) as a pale-yellow liquid. The product was used crude in the next step.1H NMR (400 MHz, DMSO-d6): δ 12.73 (brs, 1H), 7.36 - 7.21 (m, 3H), 5.03 (s, 1H), 4.31 (m, 2H), 3.59 (t, 1H), 2.93 (t, 2H) ppm. Synthesis of intermediate 1.132 1-(3-bromo-5-chlorophenyl)-2-((3-chloro-4-(7-(((dimethylamino)methylene)amino)-3- methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl)amino)-2-oxoethyl acetate (1.131) To a solution of compound 1.130 (100 mg, 0.303 mmol) in DCM (5 mL) at 0 °C, was added DIPEA (195 mg,1.6 mmol), compound 1.056 (93 mg 0.303 mmol) and T3P (482 mg, 1.51 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted (water, 30 mL) and extracted (EA, 20 mL x 2). The combined organic layer was washed (aq. NH4Cl solution, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified, (PM7) to afford compound 1.131 (150 mg,0.242 mmol, 79.87 %) as a yellow solid. LCMS (AM1): rt = 2.43 min, (617.9 [M-H]-), 94.32 % purity. 2-((3-chloro-4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)phenyl)amino)-1-(3-chloro-5-cyanophenyl)-2-oxoethyl acetate (1.132) To a solution of compound 1.131 (150 mg, 0.24 mmol) in DMF (5 ml) at 25°C, was added Pd(PPh3)4 (27 mg, 0.024 mmol), and Zn(CN)2 (56 mg,0.48 mmol). The reaction mixture was stirred at 160°C for 4h in MW. The reaction mixture was diluted (water, 10 mL) and extracted (EA, 20 mL x 2). The combined organic layer was washed (sat. NaCl solution, 50 mL), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified, (PM7) to afford the compound 1.132 (80 mg, 0.1415 mmol, 58.41%) as a brown oil. LCMS (AM1): rt = 2.26 min, (565.1 [M+H]+), 33.23 % purity. Synthesis of intermediate 1.146 (E)-1-(3-bromo-5-(trifluoromethyl)phenyl)-2-((3-chloro-4-(7- (((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1- yl)phenyl)amino)-2-oxoethyl acetate (1.145) To a solution of compound 1.144 (0.40 g, 1.213 mmol) in DCM (5 mL) at 0° C was added compound 1.056, 0.60 g, 1.819 mmol) and DIPEA (0.782 mL, 6.065 mmol) dropwise. The reaction mixture was stirred at 0° C for 10 min then T3P (50% w / w soln in EA, 2.31 mL, 7.277 mmol) was added and the reaction mixture was stirred at RT for 2h. The reaction mixture was diluted (water, 100 mL), extracted (DCM, 100 mL x 2). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM8) to afford compound 1.145 (0.70 g, 0.944 mmol, 88%) as a pale yellow solid. LCMS: (AM1): rt = 2.43 min, (654.1 [M+2]+), 69.47% purity. (E)-2-((3-chloro-4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)phenyl)amino)-1-(3-cyano-5-(trifluoromethyl)phenyl)-2-oxoethyl acetate (1.146) To a solution of compound 1.145 (0.55 g, 0.842 mmol) in DMF (6 mL) was added Zn(CN)2 (0.197 g, 1.685 mmol) and Pd(PPh3)4(0.097 g, 0.084 mmol). The reaction mixture was stirred at 150° C in MW for 4h. The reaction mixture was diluted (water, 50 mL) and extracted (EA, 50 mL x 2). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM8a) to afford compound 1.146 (0.40 g, 0.521 mmol, 79%) as a pale yellow solid. LCMS: LCMS (Method: 1): rt = 2.94 min, (557.4 [M-Ac]+), 50% purity. Synthesis of Intermediate 1.151 (E)-1-(3-bromo-5-fluorophenyl)-2-((3-chloro-4-(7- (((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1- yl)phenyl)amino)-2-oxoethyl acetate 1.150 To a solution of compound 1.056 (150 mg, 0.606 mmol) and compound 1.149 (229 mg, 0.788 mmol) in DCM (3 mL) at 0 °C, was added T3P (50% w / w soln in EA, 964 mg, 3.032 mmol) and DIPEA (391 mg, 3.032 mmol). The reaction mixture was stirred at RT for 2h, then diluted (water, 20 mL) and extracted (EA, 2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM5b) to afford compound 1.150 (350 mg, 95.73%) as an off white solid. LCMS (AM1): rt= 2.34 min, (604.1 [M+H]+), 96.49% purity. (E)-2-((3-chloro-4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)phenyl)amino)-1-(3-cyano-5-fluorophenyl)-2-oxoethyl acetate (1.151) To a stirred solution of compound 1.150 (250 mg, 0.415 mmol) in DMF (1 mL), was added Zinc cyanide (97 mg, 0.829 mmol) and reaction mixture was degassed (N2) for 15 min, then added Pd(PPh3)4 (48 mg, 0.041 mmol) was added and the reaction mixture was stirred at 150 °C for 4h in MW. The reaction mixture was diluted (water, 20 mL) and extracted (EA, 50 mL x 2). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified, (PM10b) to afford compound 1.151 (200 mg, 87.85%) as an off white solid. The crude was used without purification. LCMS (AM1): rt = 2.71 min, (452.3 [M-CH-DMA, -Ac]), 23.24% purity. Synthesis of Intermediate 1.174 tert-butyl N-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate. (1.173) To a solution of tert-Butyl (4-bromo-2,5-difluorophenyl)carbamate (CAS 1874418-51-5, 10.00 g, 48.08 mmol) and bis(pinacolato)diboron (14.65g, 57.69mmol) in 1,4-dioxane (200 mL) was added KOAc (14.16 g, 144.2 mmol). The reaction mixture was degassed (N2) and PdCl2(dppf).DCM complex (1.96 g, 0.27 mmol) was added, and the reaction was then stirred at 100 °C for 16 h. The reaction mixture was reduced in vacuo to yield a residue which was dissolved (EA, 2 x 200mL), washed (brine, 100mL), dried (Na2SO4), filtered and reduced in vacuo. The residue was purified (PM1) to afford compound 1.173 (8.0 g, 22.53 mmol, 47% yield) as an off white solid. LCMS (AM1): rt = 2.91 min, (354.1 [M–H]–), 63% purity.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 7.66 – 7.62 (m, 1H), 7.26 (dd, J = 10.68, 5.24 Hz, 1H), 1.48 (s, 9H), 1.28 (s, 12H) ppm. (4-((tert-butoxy carbonyl)amino)-2,5-difluorophenyl)boronic acid. (1.174) To a solution of compound 1.173 (6.50 g, 18.30 mmol) in acetone (70 mL) was added MeB(OH)2 (10.95 g, 183.0 mmol) followed by NaOH (0.73 g, 18.30 mmol) in H2O (70 mL). The reaction mixture was stirred at RT for 12 h. The reaction mixture was reduced in vacuo to half the volume, diluted (aq. NH4Cl, 50 mL) and extracted (EA, (2 × 100 mL)). The combined organic layer was washed (sat. aq. NH4Cl, 50 mL × 3), dried (Na2SO4), filtered and reduced in vacuo. The residue was triturated (hexane) and dried under reduced pressure to afford compound 1.174 (3.5 g, 12.82 mmol, 70% yield) as an off white solid. LCMS (AM1): rt= 2.36 min, (272.0 [M−H]−), 96% purity.1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.10 – 8.09 (m, 2H), 7.53 – 7.47 (m,1H), 7.34 – 7.26 (m, 1H), 1.47 (s, 9H). Synthesis of intermediate 1.189 rac-(E)-2-(3,5-difluorophenyl)-N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)-7- (((dimethylamino)methylene)amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-hydroxyacetamide (1.188).

[0006] To a solution of compound (1.070) (200 mg, 0.341mmol) and 2-(3,6-dihydro-2H-pyran-4- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 287944-16-5, 71.65 mg, 0.341 mmol) in 1,4-dioxane: H2O (4:1, 10 mL) was added Cs2CO3 (333 mg, 1.02 mmol) in a sealed tube. The reaction mixture was degassed (N2) then PdCl2(dppf) (24.9 mg, 0.034 mmol) was added and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted (EA, 50 mL), washed (H2O, 50mL x 2), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM10) to afford compound 1.188 (0.150 g, 0.274 mmol, 80% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 7.66 (d, J = 2.08 Hz, 1H), 7.60 (dd, J = 2.2, 6.28 Hz, 1H), 7.42 (br s, 1H), 7.26 - 7.17 (m, 4H), 6.76 (d, J = 4.96 Hz, 1H), 5.21 (d, J = 5 Hz,1H), 4.33 (d, J = 2.48 Hz, 2H), 3.87 - 3.84 (m, 2H), 3.41 - 3.35 (m, 2H), 3.07 (s, 3H), 2.61 (s, 2H), 1.91 (s, 3H) ppm. rac-N-(4-(7-amino-3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)- 3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (1.189) To a solution of compound 1.188 (150 mg, 0.274 mmol) in EtOH (3 mL) was added ZnCl2 (186 mg, 1.37 mmol). The reaction mixture was stirred at 90 °C for 16 h then reduced in vacuo to yield a residue which was purified (PM5) to afford the compound 1.189 (130 mg, 0.245 mmol, 89.74 % yield) as a brown solid. LCMS (AM1): rt = 2.27 min, (493.2 [M+H]+), 93.13% purity.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 8.12 Hz, 1H), 7.75-7.73 (m, 1H), 7.57-7.47 (m, 2H), 7.42 (s, 1H), 7.34 (d, J = 8.56 Hz, 1H), 7.25 (d, J = 6.44 Hz, 2H), 7.21-7.16 (m, 1H), 6.79 (d, J = 4.92 Hz, 1H), 6.26 (br s, 1H), 5.22 (d, J = 4.92 Hz, 1H), 4.31 (d, J = 2.36 Hz, 2H), 3.84 (t, J = 5.44 Hz, 2H), 2.59 - 2.56 (m, 2H), 1.97 (s, 3H) ppm. Synthesis of intermediate 1.193 rac-Tert-butyl (E)-4-(1-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)-7-(((dimethylamino)methylene)amino)-1H-pyrazolo[4,3-d]pyrimidin- 3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.191). To a stirred solution of Compound 1.070 (200 mg, 0.341mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (CAS 286961-14-6, 105 mg, 0.341 mmol) in 1,4-dioxane:H2O (4:1, 10 mL) was added Cs2CO3(332 mg, 1.02 mmol) in a sealed tube. The reaction mixture was degassed (N2) then PdCl2(dppf) (24.9 mg, 0.034 mmol) was added and the reaction was stirred at 100 °C for 16 h. The reaction mixture was diluted (EA, 50 mL), washed (H2O, 50 mL x 2), dried (Na2SO4), filtered, and reduced in vacuo to yield a residue which was purified (PM10) to afford compound 1.191 (0.150 g, 0.274 mmol, 80% yield) as a white solid. LCMS (AM1): rt = 2.64 min, (647.3 [M+H]+), 76.81% purity. rac-Tert-butyl 4-(7-amino-1-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)- carboxylate (1.192)

[0007] To a solution of compound 1.191 (150 mg, 0.274 mmol) in EtOH (3 mL) was added ZnCl2(186 mg, 1.37 mmol). The reaction mixture was stirred at 90 °C for 16 then reduced in vacuo to yield a residue which was purified (PM5) to afford the compound 1.192 (130 mg, 0.219 mmol, 96% yield) as a white solid. LCMS (AM1): rt = 2.52 min, (592.3 [M+H]+), 93.84% purity.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.30 (s, 1H), 7.82 (d, J = 7.84 Hz, 1H), 7.75 (t, J = 7.92 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.39 (br s, 1H), 7.34 (d, J = 8.56 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.21-7.16 (m, 1H), 6.79 (d, J = 4.88 Hz, 1H), 6.29 (br s, 1H), 5.22 (d, J = 4.92 Hz, 1H), 4.10 (br s, 2H), 3.55 (s, 2H), 2.60 (s, 2H), 1.96 (s, 3H), 1.43 (s, 9H) ppm. rac-Tert-butyl 4-(7-amino-1-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2- methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidine-1-carboxylate (1.193) To a solution of compound 1.192 (0.130 g, 0.264 mmol) in MeOH (5 mL) was added Pd / C (0.20 g). The reaction mixture was stirred in a steel bomb in the presence of H2 gas (70 psi) at RT for 4 h. The reaction mixture was filtered through a pad of Celite™ and reduced in vacuo to yield a residue which was purified (PM5) to afford compound 1.193 (100 mg, 0.168 mmol, 76% yield) as a white solid. LCMS (AM.44 min, (594.2 [M+H]+), 98.93 % purity.1H NMR (400 MHz, DMSO-d6) δ = 10.23 (s, 1H), 8.23 (s, 1H), 7.80 (d, J = 6.84 Hz,1H), 7.73-7.71 (m, 1H), 7.57-7.48 (m, 1H),7.31 (d, J = 8.52 Hz, 1H), 7.26-7.17 (m, 3H), 6.81 (d, J = 4.72 Hz, 1H), 6.28 (br s, 1H), 5.21 (d, J = 4.16 Hz, 1H), 3.99 (d, J = 10.36 Hz, 2H), 3.29-3.22 (m, 2H), 2.93 (br s, 2H), 2.01 – 1.91 (m, 6H), 1.83-1.75 (m, 2H), 1.40 (s, 9H) ppm. Synthesis of intermediate 1.195 rac-(E)-N-(4-(3-cyclopropyl-7-(((dimethylamino)methylene)amino)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (1.195) To a solution of compound 1.070 (150 mg, 0.256 mmol) and cyclopropylboronic acid (CAS: 411235-57-9, 21.97 mg, 0.256 mmol) in 1,4-dioxane: H2O (4:1,10 mL) was added K2CO3(70.6 mg, 0.51 mmol) in a sealed tube. The reaction mixture was degassed (N2,) then PdCl2(dppf) (16.67 mg, 0.026 mmol) was added and stirred at 100 °C for 16 h. The reaction mixture was diluted (EA, 50 mL) and washed (H2O, 50 mL x 2). The organic layer was dried (Na2SO4), filtered, and reduced in vacuo to yield a residue which was purified (PM5b) to afford compound 1.195 (115 mg, Crude) as off white solid. LCMS (AM1): rt= 2.37 min, (506.3 [M+H]+), 66.86% purity. Synthesis of intermediate 1.198 rac-N-(4-(7-amino-3-(1-methylpiperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (1.197)

[0008] To a solution of compound 1.070 (150 mg, 0.256 mmol) and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (CAS 454482-11-2, 114 mg, 0.512 mmol) in 1,4-dioxane:H2O (4:1, 10 mL) was added K2CO3(70.6 mg, 0.512 mmol). The reaction mixture was degassed (N2) then PdCl2(dppf) (18.7 mg, 0.026 mmol) was added and the reaction was stirred at 100 °C for 16 h in a sealed tube. The reaction mixture was diluted (EA, 50 mL) then washed (H2O, 50 mL x 2). The organic layer was dried (Na2SO4), filtered, and reduced in vacuo to obtain a residue which was purified (PM10) to afford compound 1.197 (85 mg, Crude) as a brown solid. LCMS (AM1): rt = 2.15 min, (561.3 [M+H]+), 45.61% purity. rac-N-(4-(7-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3- d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide (1.198) To a solution of compound 1.197 (85 mg, 0.141 mmol) in EtOH (3 mL) was added ZnCl2 (192 mg, 1.41 mmol). The reaction mixture was stirred at 90 °C for 16 h then reduced in vacuo to yield a residue which was dissolved (EA, 50 mL), and washed (H2O, 50 mL x 2), The organic layer was dried (Na2SO4), filtered, and reduced in vacuo to afford compound 1.198 (90 mg, Crude) as a brown solid. LCMS (AM1): rt = 2.06 min, (506.3 [M+H]+), 72.06% purity. Synthesis of intermediate 1.201 rac-2-(3,5-difluorophenyl)-N-(4-{7-[(E)-[(dimethylamino)methylidene]amino]-3- (prop-1-en-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl}-3-methylphenyl)-2- hydroxyacetamide (1.200) To a solution of compound 1.070 (150 mg, 0.256 mmol) and 4,4,5,5-tetramethyl-2-(prop- 1-en-2-yl)-1,3,2-dioxaborolane (CAS-126726-62-3, 129 mg, 0.767 mmol) in 1,4- dioxane:H2O (4:1, 10 mL) was added K2CO3 (167 mg, 0.512 mmol) in a sealed tube. The reaction mixture was degassed (N2), then PdCl2(dppf) (19 mg, 0.026 mmol) was added, and the reaction was stirred at 100 °C for 16 h. The reaction mixture was diluted (EA, 50 mL) and washed (H2O, 50 mL x 2). The organic layer was dried (Na2SO4), filtered, and reduced in vacuo to obtain a residue which was purified (PM10) to afford the compound 1.200 (130 mg, Crude) as an off-white solid. LCMS (AM1): rt = 2.53 min, (506.2 [M+H]+), 75.01% purity. rac-N-{4-[7-amino-3-(prop-1-en-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-3- methylphenyl}-2-(3,5-difluorophenyl)-2-hydroxyacetamide (1.201) To a solution of compound 1.200 (130 mg, 0.257 mmol) in EtOH (10 mL) was added ZnCl2 (350 mg, 2.57 mmol). The reaction mixture was stirred at 90 °C for 16 h then reduced in vacuo. The residue was diluted (DCM, 50 mL) and washed (H2O, 50 mL x 2). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield a residue which was purified (PM10) to afford the compound 1.201 (100 mg, Crude) as an off-white solid. LCMS (AM1): rt = 2.43 min, (451.16 [M+H]+), 88.48% purity.1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.75 (m, 1H), 7.37 (d, J = 5.44 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.20-7.14 (m, 1H), 6.77 (s, 1H), 6.22 (br s, 1H), 5.47 (s, 1H), 5.23 (d, J = 4.92 Hz 1H), 3.44 – 3.36 (m, 1H), 2.49 (s,3H), 1.97 (s, 3H). Synthesis of intermediate 1.207 2-((4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)amino)- 1-(3-bromophenyl)-2-oxoethyl acetate (1.207) To a solution of compound 1.048 (419.173 mg, 1.535 mmol), DIPEA (1.016 ml, 5.906 mmol) and compound 1.206 (300.0 mg, 1.181 mmol) in DMF (5 mL) was added T3P (50% solution in EA, 1877.953 mg, 5.906 mmol) at 0° C and the reaction was stirred at RT for 4 h. The reaction mixture was quenched with ice cooled water (10 mL) and extracted (EA, 20 mL x 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM10) to afford compound 1.207 (150.0 mg, 0.294 mmol, 24.93% yield) as a light-yellow solid. LCMS (AM2): rt = 2.23 min, (509.2 [M+H]+), 90 % purity.1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.63 – 7.55 (m, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.00 (s, 1H), 5.75 (s, 1H), 2.47 (s, 3H), 2.18 (s, 3H), 1.97 (s, 3H) ppm. Synthesis of Intermediate 1.215 methyl 2-(6-methylpyridin-2-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (1.213) A solution of methyl 2-hydroxy-2-(6-methylpyridin-2-yl)acetate (CAS 1669439-28-4, 0.6 g, 3.311 mmol), DHP (1.114 g, 13.246 mmol, 4 eq) and TsOH.H2O (0.063 g, 0.331 mmol, 0.1 eq) in DCM (15 mL) was heated at 70 °C for 4 h. The reaction mixture was cooled to RT, reduced in vacuo, then purified (PM2c) to afford compound 1.213 (0.76 g, 2.49mmol, 87% yield) as a colourless oil. LCMS (AM1): rt = 2.28 min, (266.2 [M+H]+), 96.66% purity. sodium 2-(6-methylpyridin-2-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate. (1.214) To a solution of compound 1.213 (0.55 g, 2.074 mmol) in MeOH (5 mL) was added NaOH (0.083 g, 2.074 mmol, 1 eq) and H2O (0.1 mL) and the reaction mixture stirred at RT for 4 h. The reaction mixture was reduced in vacuo and washed hexane (1 x 100 mL) to afford compound 1.214 (0.56 g, 2.05 mmol, 99% yield) as a white solid. LCMS (AM1): rt = 1.67 min, (252.2 [M+H]+), 97.36% purity.1H NMR (400 MHz, DMSO-d6): δ 7.56 (td, J = 7.7, 2.4 Hz, 1H), 7.17 (t, J = 8.1 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.79 (s, 1H), 3.90 – 3.60 (m, 1H), 3.36 – 3.30 (m, 2H), 2.42 (s, 3H), 1.79 – 1.42 (m, 6H) ppm. N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(6- methylpyridin-2-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetamide.(1.215) To a mixture of compound 1.214 (0.15 g, 0.59 mmol), compound 1.048 (0.242 g, 0.885 mmol) and HATU (0.336 g, 0.885 mmol) in DMF (4 mL) was added DIPEA (0.527 mL, 2.949 mmol) and the reaction mixture stirred for 16 h at RT. The reaction mixture was diluted (water, 20 mL) and extracted (EA, 2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM8a) to afford compound 1.215 (0.07 g, 0.148 mmol, 25% yield) as a light-yellow solid. LCMS (AM1): rt = 2.12 min, (488.3 [M+H]+), 97.63% purity. Synthesis of Intermediate 1.220 (E)-2-((3-chloro-4-(7-(((dimethylamino)methylene)amino)-3-methyl-1H-pyrazolo[4,3- d]pyrimidin-1-yl)phenyl)amino)-2-oxo-1-(6-(trifluoromethyl)pyridin-2-yl)ethyl acetate (1.220). To a mixture of compound 1.056 (0.12 g, 0.364 mmol), compound 1.219 (0.192 g, 0.728 mmol) and HATU (207.54 mg, 0.546 mmol, 1.5 eq) in DMF (3 mL) was added DIPEA (0.325 mL, 1.819 mmol) and the reaction mixture stirred for 16 h at RT. The reaction mixture was diluted (water, 20 mL) and extracted (EA, 2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to afford compound 1.220 (0.19 g, crude). The crude was used in the next step without further purification. LCMS (AM1): rt = 2.21 min, (575.3 [M+H]+), 51.85% purity. Example 1 rac-N-(4-{7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl}-2,3-difluorophenyl)- 2-hydroxy-2-[3-(trifluoromethoxy)phenyl]acetamide To a solution of compound 1.026 (100 mg 0.169 mmol) in EtOH (5 mL) was added ZnCl2(115 mg, 0.845 mmol) and the reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM12) to afford Example 1 (22 mg, 0.044 mmol, 26%) as white solid. LCMS (AM2): rt= 2.95 min, (495.31 [M+H]+), 97.2% purity. HPLC (AM3): rt = 6.26 min, 97.16% purity.1H NMR (400 MHz, DMSO-d6): δ 10.03 (brs, 1H), 8.29 (s, 1H), 7.81 (dd, J = 9.0, 4.9 Hz, 1H), 7.58 – 7.44 (m, 3H), 7.36 – 7.24 (m, 2H), 6.79 (brs, 2H), 5.38 (s, 1H), 2.47 (s, 3H). The enantiomers of Example 1 were separated by SFC-chiral column chromatography (PM81). Example 2 Isomer 1 - 65 mg (0.131 mmol, 32.5% yield) as white solid. LCMS (AM2): rt = 2.90 min, (495.16 [M+H]+), 95.19% purity. HPLC (AM4): rt = 6.33 min, 97.52% purity. SFC (AM10): rt = 3.15 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.04 (brs, 1H), 8.29 (s, 1H), 7.81 (dd, J = 9.0, 4.9 Hz, 1H), 7.58 – 7.44 (m, 3H), 7.33 – 7.26 (m, 2H), 6.79 (brs, 3H), 5.38 (s, 1H), 2.47 (s, 3H) ppm. Example 3 Isomer 2 - 65 mg (0.131 mmol, 32.5% yield) as white solid. LCMS (AM2): rt = 2.90 min, (495.16 [M+H]+), 95.82% purity. HPLC (AM4): rt = 6.32 min, 98.00% purity. SFC (AM10): rt = 4.39 min, ee = 100%1H NMR (400 MHz, DMSO-d6): δ 10.08 (brs, 1H), 8.29 (s, 1H), 7.81 (dd, J = 9.0, 4.9 Hz, 1H), 7.58 – 7.44 (m, 3H), 7.33 – 7.26 (m, 2H), 6.90 (brs, 1H), 6.79 (brs, 2H), 5.38 (s, 1H), 2.47 (s, 3H) ppm. Example 4 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide To a stirred solution of compound 1.027 (200 mg 0.169 mmol) in EtOH (5 mL) was added ZnCl2 (115 mg, 0.845 mmol) and was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to afford a residue, which was purified (PM5) to afford Example 4 (110 mg, 0.210 mmol, 32%) as a white solid. LCMS (AM1): rt = 2.03 min, ESI+(M+H) +: 479.2, 99.67% purity. HPLC (AM5): rt = 5.26 min, 96.0% purity.1H NMR (400 MHz, DMSO-d6) δ: δ 8.29 (s, 1H), 7.91 (s, 1H), 7.86 – 7.97 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.27 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 6.78 (brs, 2H), 5.43 (s, 1H), 2.47 (s, 3H) ppm. The enantiomers of Example 4 were separated by reverse-phase-chiral column chromatography (PM13). Example 5 Isomer 1 – 50 mg (0.104 mmol, 45.45% yield) as white solid. LCMS (AM1): rt = 2.05 min, 479.13 [M+H]+), 98.72% purity. HPLC (AM3): rt = 6.75, 96.6% purity. Reverse-Phase-Chiral HPLC (AM5): rt = 8.714 min, % ee = 100%1H NMR (400 MHz, DMSO-d6) δ: δ10.04 (brs, 1 H) 8.29 (s, 1H), 7.91 (s, 1H), 7.86 – 7.97 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.27 (dd, J = 8.8 Hz, 4.0 Hz,1H), 6.78 (brs, 2H), 5.43 (s, 1H), 2.47 (s, 3H) ppm. Example 6 Isomer 2 - 50 mg (0.104 mmol, 45.26% yield) as white solid. LCMS (AM1): rt = 2.05 min, 479.2 [M+H]+), 99.237% purity. HPLC (AM3): rt = 6.75, 98.2% purity. Reverse-Phase Chiral HPLC (AM19): rt = 10.347 min, % ee = 99%1H NMR (400 MHz, DMSO-d6) δ: δ10.11(brs, 1H) 8.29 (s, 1H), 7.91 (s, 1H), 7.86 – 7.79 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.27 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 6.78 (brs, 2H), 5.43 (s, 1H), 2.47 (s, 3H) ppm. Example 7 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.028 (250 mg 0.460 mmol, 1.0 eq), in EtOH (5 mL) at RT was added ZnCl2 (625.6 mg, 4.603 mmol) and reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was purified (PM10) to afford Example 7 (150 mg, 36% yield) as a white solid. LCMS (AM1): rt = 2.96 min, (447.2 [M+H]+), 99.90% purity. HPLC (AM3): rt = 6.45 min, 98.2% purity,1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.82 – 7.79 (m, 1H), 7.30 – 7.17 (m, 4H), 6.78 (brs, 3H), 5.35 (s,1H), 2.46 (s, 3H) The enantiomers of Example 7 were separated by SFC-chiral column chromatography (PM74). Example 8 Isomer 1 - 28 mg, 0.062 mmol, 16% yield, as white solid. LCMS (AM2): rt = 2.73 min, (447.16 [M+H]+), 99.90% purity. HPLC (AM3): rt = 6.44 min, 100% purity, SFC (AM16): rt = 2.16 min, 97.68%, % ee = 95.37%1H NMR (400 MHz, DMSO-d6) δ 10.07(s, 1H), 8.29 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.30 – 7.17 (m, J = 7.7 Hz, 4H), 6.78 (brs, 3H), 5.36 (s,1H), 2.46 (s, 3H). Example 9 Isomer 2 - 38 mg, 0.085 mmol,16% yield, as white solid. LCMS (AM2): rt = 2.73 min, (447.16 [M+H]+), 98.07% purity. HPLC (AM3): rt = 6.44 min, 97.34% purity. SFC (AM16): rt = 2.73 min, % ee = 97.53%, % ee = 95.07%.1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.29 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.30 – 7.17 (m, J = 7.7 Hz, 4H), 6.78 (brs, 3H), 5.36 (s,1H), 2.46 (s, 3H). Example 9 (isomer 2) can also be synthesised from the chiral intermediate compound (R)- 1.009 using chiral synthetic methods analogous to those described elsewhere herein (e.g., with reference to the synthesis of Examples 38 and 40). Example 9 (isomer 2) is therefore (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide. Example 10 rac-N-[4-(7-amino-3-methyl-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluoro-phenyl]-2- hydroxy-2-[3-(trifluoromethoxy)phenyl]acetamide To a solution of compound 1.035 (300 mg, 0.523 mmol) in EtOH (5 mL) was added ZnCl2 (356.53 mg, 2.616 mmol) at RT and reaction mixture was heated to 90 °C for 16h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM10) to afford Example 10 (300 mg, 60% yield) as a white solid. LCMS (AM1): rt = 3.09 min, (477.2 [M+H]+), 98.35% purity. HPLC (AM3): rt = 6.69 min, 98.72% purity.1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.26 (s, 1H), 7.94 (dd, J = 12.7, 2.2 Hz, 1H), 7.72 (d, J = 9.0, 1.4 Hz, 1H), 7.57 -7.45 (m, 4H), 7.31 (dd, J = 8.0, 2.5 Hz, 1H), 6.88 (s, 1H), 6.55 (s, 2H), 5.26 (s, 1H), 2.46 (s, 3H) ppm. The enantiomers of Example 10 were separated by SFC-chiral column chromatography (PM75). Example 11 Isomer 1 - 72 mg (0.151 mmol, 26% yield), as white solid. LCMS (AM1): rt = 2.94 min, (477.2 [M+H]+), 98.92% purity. HPLC (AM6): rt = 6.48 min, 97.41% purity. SFC (AM10): rt = 3.563 min, ee = 100%1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.27 (s, 1H), 7.95 (d, J = 12.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.58 – 7.45 (m, 4H), 7.32 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 4.7 Hz, 1H), 6.52 - 6.51 (m, 2H), 5.27 – 5.25 (m, 1H), 2.46 (s, 3H) ppm. Example 12 Isomer 2 - 79 mg (0.165 mmol, 26% yield), as white solid. LCMS (AM1): rt = 2.82 min, (477.14 [M+H]+), 99.35% purity. HPLC (AM6): rt = 6.42 min, 98.44% purity. SFC (AM10): rt = 5.578 min, ee = 99.81%.1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.26 (s, 1H), 7.93 (dd, J = 12.7, 2.3 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.58 – 7.45 (m, 4H), 7.32 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 6.54 – 6.52 (m, 2H), 5.25 (m, 1H), 2.46 (s, 3H) ppm. Example 13 rac-N-[4-(7-amino-3-methyl-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluoro-phenyl]-2- hydroxy-2-[3-(trifluoromethyl)phenyl]acetamide To a solution of compound 1.036 (260 mg, 0.466 mmol), in EtOH (5 mL) was added ZnCl2 (317.86 mg, 2.332 mmol) and the reaction mixture was stirred at 90 °C for 16h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM10) to afford Example 13 (160 mg, 0.347 mmol, 74% yield) as a white solid. LCMS (AM2): rt = 2.78 min, (461.40 [M+H]+), 99.52% purity. HPLC (AM3): rt = 6.57 min, 99.50% purity.1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.26 (s, 1H), 7.96 – 7.91 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.65 – 7.61 (m, 1H), 7.47 (t, J = 8.7 Hz, 1H), 6.88 (s, 1H), 6.55 (brs, 2H), 5.32 (s, 1H), 2.46 (s, 3H) ppm. The enantiomers of Example 13 were separated by reverse-phase-chiral HPLC column chromatography (PM14). Example 14 Isomer 1 - 58.24 mg (0.128 mmol, 36.88% yield), as a white solid. LCMS (AM1): rt = 3.05 min, (461.3 [M+H]+), 99.89% purity. HPLC (AM3): rt = 6.58 min, 99.78% purity. Reverse-Phase-Chiral HPLC (AM17): rt = 7.84 min, ee = 98.78%.1H NMR : (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.26 (s, 1H), 7.96 – 7.91 (m, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.65 – 7.61 (m, 1H), 7.47 (t, J = 8.7 Hz, 1H), 6.86 (brs, 1H), 6.55 (brs, 2H), 5.32 (s, 1H), 2.46 (s, 3H) ppm. Example 15 Isomer 2 - 54.33 mg (0.119 mmol, 34.38% yield), as white solid. LCMS (AM1): rt = 3.04 min, (461.2 [M+H]+), 99.86% purity. HPLC (AM3): rt = 6.57 min, 99.84% purity. Reverse-Phase-Chiral HPLC (AM17): rt = 9.55 min, ee = 99.54%.1H NMR : (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 8.26 (s, 1H), 7.96 – 7.91 (m, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.65 – 7.61 (m, 1H), 7.47 (t, J = 8.7 Hz, 1H), 6.86 (d, J = 4.5 Hz, 1H), 6.55 (s, 2H), 5.32 (d, J = 4.1 Hz, 1H), 2.46 (s, 3H) ppm. Example 16 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.037 (250 mg, 0.476 mmol) in EtOH (5 mL) at RT was added ZnCl2 (648.49 mg, 4.758 mmol), and the reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM10) to afford Example 16 (160 mg, 0.373 mmol, 78% yield) as white solid. LCMS (AM2): rt = 2.66 min, (429.39 [M+H]+), 99.10% purity. HPLC (AM3): rt = 6.25 min, 97.41% purity.1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.27 (s, 1H), 7.94 (dd, J = 12.8, 2.3 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 8.7 Hz, 1H), 7.27 – 7.17 (m, 3H), 6.89 (s, 1H), 6.54 (brs, 2H), 5.23 (s, 1H), 2.46 (s, 3H) ppm. The enantiomers of Example 16 were separated by SFC column chromatography (PM76). Example 17 Isomer 1 - 50 mg (0.119 mmol, 32% yield) as white solid. LCMS (AM2): rt = 2.62 min (429.3 [M+H]+:) 96.93% purity. HPLC (AM6): rt = 5.99 min, 95.26% purity. SFC (AM13): rt = 4.05 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.27 (s, 1H), 7.93 (dd, J = 12.7, 2.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.48 (t, J = 8.7 Hz, 1H), 7.28 – 7.16 (m, 3H), 6.88 (d, J = 4.6 Hz, 1H), 6.55 (brs, 2H), 5.24 (d, J = 4.0 Hz, 1H), 2.46 (s, 3H) ppm. Example 18 Isomer 2 - 94 mg (0.219 mmol, 58% yield) as white solid. LCMS (AM2): rt = 2.62 min (429.3 [M+H]+) 95.11% purity. HPLC (AM6): rt = 5.99 min, 99.88% purity. SFC (AM13): rt = 5.86 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.27 (s, 1H), 7.93 (dd, J = 12.7, 2.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 8.8 Hz, 1H), 7.28 – 7.16 (m, 3H), 6.88 (d, J = 4.6 Hz, 1H), 6.55 (brs, 2H), 5.24 (d, J = 4.0 Hz, 1H), 2.46 (s, 3H) ppm. Example 19 rac-N-[4-(7-amino-3-methyl-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluoro-phenyl]-2-(3- chlorophenyl)-2-hydroxy-acetamide To a solution of compound 1.038 (270.0 mg, 0.515 mmol,) in EtOH (5 mL) at RT was added ZnCl2(351.22, 2.577 mmol). The reaction mixture was heated to 90 °C for 16 h then cooled to RT and reduced in vacuo to yield a residue which was dissolved in water (25 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM10) to afford Example 19 (219 mg, 0.514 mmol, 99% yield) as a white solid. LCMS (AM1): rt = 2.91 min, (427.2 [M+H]+), 99.57% purity. HPLC (AM3): rt = 6.32 min, 99.58% purity.1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.26 (s, 1H), 7.95 (dd, J = 12.8 Hz, 2.2 Hz, 1H), 7.72 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.54 (brs, 1H), 7.51 – 7.45 (m, 2H), 7.41 – 7.34 (m, 2H), 6.75 (s, 1H), 6.54 (brs, 2H), 5.20 (s, 1H), 2.46 (s, 3H) ppm. The enantiomers of Example 19 were separated by Chiral SFC column chromatography (PM77). Example 20 Isomer 1 - 75 mg (0.175 mmol, 34% yield), as a white solid. LCMS (AM2): rt = 2.67 min, (427.15 [M+H]+), 98.42% purity. HPLC (AM6): rt = 6.35 min, 98.86% purity. SFC (AM11): rt = 3.58 min, ee = 100%.1H NMR : (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.26 (s, 1H), 7.95 (dd, J = 12.8, 2.2 Hz, 1H), 7.72 (d, J = 8.8, 1H), 7.60 (s, 1H), 7.51 – 7.45 (m, 2H), 7.41 – 7.34 (m, 2H), 6.76 (brs, J = 4.2 Hz, 1H), 6.55 (brs, 2H), 5.20 (d, J = 3.6 Hz, 1H), 2.46 (s, 3H) ppm. Example 21 Isomer 2 - 74 mg (0.173 mmol, 34%), as a white solid LCMS (AM2): rt = 2.67 min, (427.11 [M+H]+), 99.76% purity. HPLC (AM6): rt = 6.36 min, 99.75% purity. SFC (AM11): rt = 6.218 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.26 (s, 1H), 7.95 (dd, J = 12.7, 2.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 1.9 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.41 – 7.34 (m, 2H), 6.76 (brs, 1H), 6.56 (brs, 2H), 5.20 (s, 1H), 2.46 (s, 3H) ppm. Example 22 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide To a stirred solution of compound 1.045 (0.2 g, 0.351 mmol) in EtOH (10 mL) was added ZnCl2 (0.477 g, 3.512 mmol). The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 3 X 20 mL). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM3) to afford Example 22 (0.15 g, 0.317 mmol, 90% yield) as off white solid. LCMS (AM1): rt = 3.08 min, (473.2 [M+H]+), 99.88% purity. HPLC (AM3): rt = 6.64 min, 99.75% purity.1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 6.7 Hz, 1H), 7.74 (t, J = 7.0 Hz, 1H), 7.59 – 7.50 (m, 3H), 7.33 – 7.27 (m, 2H), 6.73 (d, J = 4.8 Hz, 1H), 6.17 (brs, 2H), 5.24 (d, J = 4.8 Hz, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. The enantiomers of Example 22 were separated by SFC column chromatography (PM78). Example 23 Isomer 1 - 51 mg (0.107 mmol, 34.67% yield) as white solid. LCMS (AM2): rt = 2.75 min, (473.4 [M+H]+), 99.74% purity. HPLC (AM3): rt = 6.65 min, 99.84% purity. SFC (AM15): rt = 1.7 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 6.5 Hz, 1H), 7.74 (t, J = 6.5 Hz, 1H), 7.59 – 7.50 (m, 3H), 7.32 – 7.27 (m, 2H), 6.72 (d, J = 4.8 Hz, 1H), 6.17 (brs, 1H), 5.24 (d, J = 4.4 Hz, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. Example 24 Isomer 2 - 54 mg (0.110 mmol, 34.67% yield) as white solid. LCMS (AM2): rt = 2.78 min, (473.17 [M+H]+), 98.10% purity. HPLC (AM3): rt = 6.65 min, 98.03% purity. SFC (AM15): rt = 2.18 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.73 (t, J = 6.8 Hz, 1H), 7.59 – 7.50 (m, 3H), 7.32 – 7.27 (m, 2H), 6.72 (d, J = 4.8 Hz, 1H), 6.14 (brs, 1H), 5.24 (d, J = 4.0 Hz, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. Example 25 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.049 (0.18 g, 0.124 mmol) in MeOH (3 mL), NH3 (7M in MeOH, 3 mL) and stirred at RT for 1 h. The reaction mixture was reduced in vacuo to afford a residue which was diluted with water (50 mL) and extracted (EA, 25 mL X 2). The combined organic layer was washed (brine, 30 mL), dried (Na2SO4), filtered and reduced in vacuo to yield a residue which was purified (PM10) to afford Example 25 (0.15 g, 0.353 mmol, 91%) as off-white solid. LCMS (AM2): rt = 2.58 min, (425.3 [M+H]+), 99.37% purity. HPLC (AM7): rt = 6.69 min, 97.78% purity.1H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.30 – 7.24 (m, 3H), 7.21 – 7.15 (m, 1H), 6.79 (d, J = 4.8 Hz, 1H), 6.17 (brs, 2H), 5.22 (d, J = 4.8 Hz, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. The enantiomers of Example 25 were separated by reverse phase-chiral column chromatography (PM15). Example 26 Isomer 1 - 52 mg (0.122 mmol, 34.67% yield) as white solid. LCMS (AM1): rt = 2.82 min, (425.3 [M+H]+), 100% purity. HPLC (AM3): rt = 6.18 min, 100% purity. Reverse-Phase-Chiral (AM19): rt = 6.48 min, ee = 99.2%.1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.73 (t, J = 6.8 Hz, 1H), 7.30 – 7.22 (m, 3H), 7.21 – 7.15 (m, 1H), 6.81 (brs, 1H), 6.19 (brs, 2H), 5.22 (s, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. Example 27 Isomer 2 - 59 mg (0.138 mmol, 39.15% yield) as white solid. LCMS (AM2): rt = 2.55 min, (425.4 [M+H]+), 99.84% purity. HPLC (AM3): rt = 6.19 min, 99.84% purity. Reverse-Phase-Chiral (AM19): rt = 7.75 min, ee = 99.12%.1H NMR (400 MHz, DMSO-d6): δ10.20 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.27 – 7.23 (m, 2H), 7.21 – 7.15 (m, 1H), 6.80 (s, 1H), 6.19 (brs, 1H), 5.22 (s, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. Example 28 rac-(N-(4-{7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl}-3-methylphenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide To a solution of compound 1.050 (0.3 g, 0.577 mmol) in EtOH (10 mL) was added ZnCl2(0.78 g, 5.769 mmol) and the reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to afford a residue which was purified (PM10) to afford Example 28 (0.3 g, 61% yield) as off white solid. LCMS (AM2): rt = 2.63 min, (423.43 [M+H]+), 99.88% purity.1H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.43 – 7.36 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 6.17 (brs, 1H), 5.18 (s, 1H), 2.49 (s, 3H), 1.96 (s, 3H) ppm. The enantiomers of Example 28 were separated by SFC-chiral column chromatography (PM79). Example 29 Isomer 1 - 56.4 mg (0.1 mmol, 26.73% yield) as white solid. LCMS (AM1): rt = 2.75 min, (423.2 [M+H]+, 99.60% purity. HPLC (AM6): rt = 5.80 min, 98.26% purity. SFC (AM14): rt = 4.14 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.74 (t, J = 6.4 Hz, 1H), 7.61 (s, 1H), 7.51 – 7.49 (m, 1H), 7.43 – 7.36 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 4.8 Hz, 1H), 6.17 (brs, 2H), 5.19 (d, J = 4.8 Hz, 1H), 2.49 (s, 3H), 1.96 (s, 3H) ppm. Example 30 Isomer 2 - 58.6 mg (0.37 mmol, 26.74% yield) as white solid. LCMS (AM1): rt = 2.75 min, (423.2 [M+H]+), 99.90% purity. HPLC (AM6): rt = 5.83 min, 99.57% purity. SFC (AM14): rt = 7.50 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.74 (t, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.43 – 7.36 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 4.8 Hz, 1H), 6.17 (brs, 1H), 5.19 (d, J = 4.4 Hz, 1H), 2.49 (s, 3H), 1.96 (s, 3H) ppm. Example 31 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide To a solution of compound 1.057 (170 mg 0.296 mmol) in EtOH (5 mL) at RT was added ZnCl2(403 mg, 2.963 mmol) and reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (50 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4) and reduced in vacuo to yield the crude compound which was purified (PM7) to afford Example 31 (0.13 g, 0.272 mmol, 92% yield) as off-white solid. LCMS (AM2): rt = 2.78 min, (477.4 [M+H]+), 95.35% purity. HPLC (AM3): rt = 6.70 min, 95.88% purity.1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.25 (s, 1H), 8.17 (dd, J = 18.0, 2.4 Hz, 1H), 7.94 – 7.84 (m, 3H), 7.71 – 7.61 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H), 6.86 (t, J = 5.8 Hz, 1H), 6.41 (brs, 2H), 5.32 (d, J = 4.0 Hz, 1H), 2.46 (s, 3H) ppm. The enantiomers of Example 31 were separated by reverse-phase-chiral column chromatography (PM17). Example 32 Isomer 1 - 68 mg (0.14 mmol, 57% yield) as white solid. LCMS (AM1): rt = 3.09 min, (477.2 [M+H]+), 99.27% purity. HPLC (AM3): rt = 6.70 min, 99.07% purity. Reverse-Phase Chiral HPLC (AM18): rt = 9.13 min, ee = 99.72%.1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 8.25 (s, 1H), 8.17 (dd, J = 18.0, 2.4 Hz, 1H), 7.91 – 7.84 (m, 3H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 6.41 (brs, 2H), 5.32 (s, 1H), 2.46 (s, 3H) ppm. Example 33 Isomer 2 - 65 mg (0.13 mmol, 56% yield) as white solid. LCMS (AM1): rt = 3.09 min, (477.2 [M+H]+), 99.80% purity. HPLC (AM3): rt = 6.70 min, 97.77% purity. Reverse-Phase-Chiral HPLC (AM18): rt = 11.48 min, ee = 99.68%.1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.25 (s, 1H), 8.17 (dd, J = 18.0, 2.4 Hz, 1H), 7.92 – 7.84 (m, 3H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 6.41 (brs, 2H), 5.32 (s, 1H), 2.46 (s, 3H) ppm. Example 34 rac-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chloro phenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide To a solution of compound 1.058 (300 mg, 0.555 mol) in EtOH (15 mL) was added ZnCl2 (756.85 mg, 5.555 mmol) and the resulting reaction mixture heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (50 mL) and extracted (DCM, 150 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product, which was purified (PM7) to afford Example 34 (220 mg, 0.4972 mmol, 89.4% yield) as white solid. LCMS (AM2): rt = 2.76 min, (443.01 [M+H]+), 99.13% purity. HPLC (AM3): rt = 6.48 min, 97.57% purity.1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.26 (s, 1H), 8.17 (dd, J = 16.4, 2.0 Hz, 1H), 7.91 – 7.84 (m, 1H), 7.61 (s, 1H), 7.54 – 7.49 (m, 2H), 7.44 – 7.37 (m, 2H), 6.76 (s, 1H), 6.41 (brs, 1H), 5.20 (s, 1H), 2.46 (s, 3H) ppm. The enantiomers of Example 34 were separated by SFC-chiral column chromatography (PM81). Example 35 Isomer 1 - 59.9 mg (0.135 mmol, 54.4% yield) as white solid. LCMS (AM1): rt = 2.82 min, (443.2 [M+H]+), 100% purity. HPLC (AM3): rt = 6.07 min, 99.68% purity. SFC (AM12): rt = 3.98 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.25 (s, 1H), 8.15 (dd, J = 12.4, 2.4 Hz, 1H), 7.88 – 7.83 (m, 1H), 7.59 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.50 – 7.48 (m, 1H), 7.43 – 7.36 (m, 2H), 6.76 (s, 1H), 6.41 (brs, 2H), 5.20 (s, 1H), 2.46 (s, 3H) ppm. Example 36 Isomer 2 - 68.75 mg (0.155 mmol, 63.63% yield) as white solid. LCMS (AM1): rt = 2.82 min, (443.2 [M+H]+), 99.65% purity. HPLC (AM3): rt = 6.07 min, 99.89% purity. SFC (AM12): rt = 7.26 min, ee = 100%.1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.25 (s, 1H), 8.15 (dd, J = 12.0, 2.0 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.59 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.43 – 7.36 (m, 2H), 6.76 (s, 1H), 6.41 (brs, 2H), 5.20 (s, 1H), 2.46 (s, 3H) ppm. Example 37 rac-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)- 2-(3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.087 (0.08 g 0.149 mmol) in EtOH (5 mL) at RT was added ZnCl2 (0.203 g, 1.49 mmol) and the reaction mixture heated to 90 °C for 16 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 20 mL X 3). The combined organic layer was dried (Na2SO4) and reduced in vacuo to yield the crude product which was purified (PM12) to afford Example 37 (0.05 g, 0.112 mmol, 76.34%) as white solid. LCMS (AM1): rt= 2.92 min, (439.2 [M+H]+), 98.31% purity. HPLC (AM3): rt = 6.30 min, 99.80% purity.1H NMR (400 MHz, DMSO-d6): δ10.17 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.27 – 7.20 (m, 3H), 7.18-7.15 (m, 1H), 6.78 (d, J = 4.8 Hz, 1H), 6.05 (brs, 2H), 5.22 (d, J = 4.8 Hz, 1H), 2.43 (s, 6H), 1.95 (s, 3H) ppm. Example 38 (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.088 (0.15 g, 0.28 mmol) in EtOH (5 mL) at RT was added ZnCl2 (0.19 g, 1.40 mmol). and the reaction mixture heated to 50 °C for 48 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with EA (20 mL). The organic layer was washed (brine, 30 mL x 3), dried (Na2SO4), filtered and reduced in vacuo to yield a residue which was purified (PM10) to afford Example 38 (0.05 g, 0.112 mmol, 40.31% yield, 99% ee) as white solid. LCMS (AM1): rt= 2.91 min, (439.2 [M+H]+), 98.99% purity. HPLC (AM6): rt = 6.29 min, 98.73% purity. SFC (AM15): rt = 3.444 min, ee = 99.08%.1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.27-7.24 (m, 3H), 7.21-7.15 (m, 1H), 6.78 (d, J = 5.2 Hz, 1H), 6.04 (brs, 2H), 5.21 (d, J = 4.8 Hz, 1H), 2.43 (s, 6H), 1.95 (s, 3H). Example 39 rac-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide

[0009] To a solution of compound 1.070 (200 mg, 0.331 mmol) in MeOH (2 mL) and aq. NH3 (2 mL) was added Zn dust (216 mg, 3.309 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was reduced in vacuo to yield a residue which was diluted with water (25 mL) and extracted (EA, 20 mL X 2). The combined organic layer was dried (Na2SO4), filtered and reduced in vacuo to yield the crude product which was purified (PM73) to afford Example 39 (0.012 g, 0.029mmol, 8% yield) as a white solid. LCMS (AM1): rt = 2.86 min, (411.2 [M+H]+), 99.08% purity.1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.28 (d, J = 7.3 Hz, 2H), 7.84 - 7.82 (m, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.18 - 7.13 (m, 1H), 6.81 (d, J = 4.9 Hz, 1H), 6.24 (brs, 2H), 5.23 (d, J = 4.5 Hz, 1H), 1.95 (s, 3H) ppm. Example 40 (2R)-N-(4-(7-amino-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.090 (350 mg, 0.69 mmol) in EtOH (5 mL) was added ZnCl2 (939.88 mg, 6.897 mmol) and the reaction mixture was stirred at 50 °C for 48 h. The reaction mixture was cooled to RT and reduced in vacuo to yield a residue which was diluted with water (30 mL) and extracted (EA, 3 X 50 mL). The combined organic layer was washed (aq. NH4Cl, 3 x 30 mL), dried (Na2SO4), filtered and reduced in vacuo to obtain a residue which was purified (PM15) to afford Example 40 (120 mg, 0.290 mmol, 61.23% yield) as white solid. LCMS (AM1): rt = 2.86 min, (411.2 [M+H]+), 99.50% purity. HPLC (AM3): rt = 6.13 min, 99.58% purity. SFC (AM13): rt = 4.151 min, ee = 98.60%.1H NMR (400 MHz, DMSO-d6): 10.21 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.21 - 7.15 (m, 1H), 6.79 (d, J = 5.2 Hz, 1H), 6.24 (brs, 2H), 5.22 (d, J = 4.8 Hz, 1H), 1.95 (s, 3H) ppm. Example 41 rac-N-(4-(7-amino-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.072 (0.110 g, 0.244 mmol) in MeOH (5 mL) was added 10% Pd / C (0.171 g, 1.26 mmol) at RT, and the reaction mixture hydrogenated in a steel bomb in the presence of H2for 4 h. The reaction mixture was filtered through Celite®and diluted with DCM (100 mL). The combined organic layer was washed (H2O, 50 mL x 2), dried (Na2SO4), filtered and reduced in vacuo to afford a residue which was purified (PM61) to afford Example 41 (35 mg, 0.0798 mmol, 32.61%) as a white solid. LCMS (AM1): rt = 3.02 min, (439.2 [M+H]+), 100% purity. HPLC (AM3): rt = 6.56 min, 99.84 % purity.1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.24(s, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.73 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.28 – 7.24 (m, 2H), 7.21-7.16 (m, 1H), 6.78 (d, J = 4.8 Hz, 1H), 6.18 (brs, 2H), 5.22 (d, J = 4.84 Hz, 1H), 2.92 (m, 2H), 1.96 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H) ppm. Example 42 N-(4-(5,7-diamino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.082 (0.040 g, 0.073 mmol) in DCM (3 mL) was added TFA (2 mL) at 0 °C, the mixture was stirred at RT for 48 h. The reaction mixture was then reduced in vacuo to yield a residue which was purified (PM33) to afford Example 42 (9 mg, 0.0204 mmol, 28.65% yield) as off white solid. LCMS (AM1): rt= 2.79 min, (440.3 [M+H]+), 100% purity. HPLC (AM6): rt = 6.00 min, 98.34% purity.1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.25-7.15 (m, 4H), 6.78 (d, J = 5.2 Hz, 1H), 5.79 (brs, 4H), 5.20 (d, J = 4.8Hz, 1H), 2.32 (s, 3H), 1.97 (s, 3H). Example 43 N-(4-(7-amino-3-methyl-5-(methylamino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3- methylphenyl)-2-(3,5-difluorophenyl)-2-hydroxyacetamide To a solution of compound 1.095 (80 mg, 0.161 mmol) in MeOH (1 mL) was added 7M NH3in MeOH (0.5 mL) at 0°C. The reaction mixture was stirred at RT for 5 min, then reduced in vacuo to yield a residue which was purified (PM3) to afford EXAMPLE 43 (14 mg, 0.030 mmol, 19% yield) as a brown solid. LCMS (AM1): rt = 2.96 min, (454.2 [M+H]+), 97.06% purity. HPLC (AM3): rt = 4.772 min, 95.01% purity.1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.77 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.27 - 7.15 (m, 4H), 6.77 (d, J = 4.8 Hz, 1H), 6.14 (brs, 1H), 5.69 (brs, 2H), 5.21 (d, J = 5.2 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.33 (s, 3H), 1.97 (s, 3H) ppm. The following compounds were made following the method of Scheme 1, using the stated acid, aryl and heterocycle coupling partners and using the protocols outlined above for Examples, 28, 31, 34 and 39-40. The structures of each acid of formula (III), Ar of formula (VI), and Het of formula (VII) are outlined below in Tables 2, 3, and 5. Example Chemical IUPAC Acid of Ar of Het of Analytical name formula formula formula (III) (VI) (VII) A1 AR1 H1 LCMS (AM2): rt = 2.74 min, (445.2 [M+H]+), 99% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 9.93 (brs, 1H), 8.28 (s, 1H-pyrazolo[4,3- 1H), 8.13 – 8.09 (m, 1H), 7.67 – 44 d]pyrimidin-1-yl)- 7.62 (m, 1H), 7.59 (s, 1H), 7.50 2,5- (d, J = 7.4 Hz, 1H), 7.44 – 7.38 difluorophenyl)-2- (m, 2H), 6.86 (brs, 1H), 6.78 (3-chlorophenyl)- (brs, 2H), 5.35 (s, 2H), 2.47 (s, 2- 3H) ppm. hydroxyacetamide Purification Method: PM15 N-(4-(7-amino-3- A1 AR1 H1 LCMS (AM2): rt = 2.80 min, methyl-1H- (445.29 [M+H]+), 98.65% pyrazolo[4,3- purity. 45 d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 2,5- d6): δ 9.93 (s, 1H), 8.28 (s, 1H), difluorophenyl)-2- 8.11 (dd, J = 11.8, 6.9 Hz, 1H), (3-chlorophenyl)- 7.65 (dd, J = 10.8, 6.8 Hz, 1H), 2- 7.59 (s, 1H), 7.51 (d, J = 8.0 Hz, hydroxyacetamide 1H), 7.44 – 7.37 (m, 2H), 6.76 (Isomer 1) (m, 3H), 5.35 (s, 1H), 2.47 (s, 3H) ppm. Purification Method: PM80 A1 AR1 H1 LCMS (AM2): rt = 2.80 min, N-(4-(7-amino-3- (445.12 [M+H]+), 100% purity. methyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 9.93 (s, 1H), 8.28 (s, 1H), d]pyrimidin-1-yl)- 8.11 (dd, J = 11.8, 6.9 Hz, 1H), 2,5- 7.65 (dd, J = 10.8, 6.8 Hz, 1H), difluorophenyl)-2- 7.59 (s, 1H), 7.51 (d, J = 8.0 Hz, (3-chlorophenyl)- 1H), 7.44 – 7.37 (m, 2H), 6.76 2- (brs, 3H), 5.34 (s, 1H), 2.46 (s, hydroxyacetamide 3H) ppm. (Isomer 2) Purification Method: PM78 rac-N-(4-(7- A2 AR1 H1 LCMS (AM1): rt = 3.03 min, amino-3-methyl- (447.2 [M+H]+), 100% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 9.96 (s, 1H), 8.27 (s, 1H), 2,5- 8.11 – 8.06 (m, 1H), 7.67 – 7.63 difluorophenyl)-2- (m, 1H), 7.27 – 7.17 (m, 3H), (3,5- 6.97 (brs, 1H), 6.76 (brs, 2H), difluorophenyl)-2- 5.38 (s, 1H), 2.46 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 N-(4-(7-amino-3- A2 AR1 H1 LCMS (AM2): rt = 2.76 min, methyl-1H- (447.32 [M+ H]+), 95.10% pyrazolo[4,3- purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 2,5- d6): δ 9.97 (s, 1H), 8.28 (s, 1H), difluorophenyl)-2- 8.11 – 8.07 (m, 1H), 7.68 – 7.63 (3,5- (m, 1H), 7.26 – 7.22 (m, 2H), difluorophenyl)-2- 7.20 – 7.17 (m, 1H), 6.98 (s, hydroxyacetamide 1H), 6.75 (s, 2H), 5.39 (s, 1H), (Isomer 1) 2.47 (s, 3H) ppm. Purification Method: PM82 A2 AR1 H1 LCMS (AM2): rt = 2.76 min, N-(4-(7-amino-3- (447.32 [M+H]+), 99.63% methyl-1H- purity. pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 9.97 (s, 1H), 8.28 (s, 1H), 2,5- 8.11 – 8.07 (m, 1H), 7.67 – 7.63 difluorophenyl)-2- (m, 1H), 7.26 – 7.22 (m, 2H), (3,5- 7.20 – 7.17 (m, 1H), 6.98 (s, difluorophenyl)-2- 1H), 6.76 (m, 2H), 5.39 (s, 1H), hydroxyacetamide 2.47 (s, 3H) ppm. (Isomer 2) Purification Method: PM82 A3 AR2 H1 LCMS (AM2): rt = 2.89 min, (461.10 [M+H]+), 99.01% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.44 (s, 1H), 8.25 (s, amino-3-methyl- 1H), 8.16 (dd, J = 17.6, 2.0 Hz, 1H-pyrazolo[4,3- 1H), 7.90 - 7.83 (m, 1H), 7.54 d]pyrimidin-1-yl)- (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 3-chlorophenyl)-2- 7.41.7.35 (m, 2H), 6.90 (s, 1H), (3-chloro-5- 6.41 (brs, 2H), 5.24 (d, J = 3.2 fluorophenyl)-2- Hz, 1H), 2.46 (s, 3H) ppm. hydroxyacetamide Purification Method: PM18 A3 AR2 H1 LCMS (AM1): rt = 3.11 min, (461.1 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- N-(4-(7-amino-3- d6): δ 10.44 (s, 1H), 8.25 (s, methyl-1H- 1H), 8.16 (dd, J = 17.6, 2.4 Hz, pyrazolo[4,3- 1H), 7.90 – 7.83 (m, 1H), 7.54 d]pyrimidin-1-yl)- (d, J = 8.8 Hz,1H), 7.47 (s, 1H), 3-chlorophenyl)-2- 7.42 – 7.35 (m, 2H), 6.92 – 6.88 (3-chloro-5- (m, 1H), 6.42 (brs, 2H), 5.25 (d, fluorophenyl)-2- J = 4.8 Hz, 1H), 2.46 (s, 3H) hydroxyacetamide ppm. (Isomer 1) Purification Method: PM81 A3 AR2 H1 LCMS (AM1): rt = 3.10 min, (461.1 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- N-(4-(7-amino-3- d6): δ 10.44 (s, 1H), 8.25 (s, methyl-1H- 1H), 8.16 (dd, J = 18.0, 2.4 Hz, pyrazolo[4,3- 1H), 7.90 – 7.83 (m, 1H), 7.54 d]pyrimidin-1-yl)- (d, J = 8.8 Hz,1H), 7.47 (s, 1H), 3-chlorophenyl)-2- 7.42 – 7.35 (m, 2H), 6.92 – 6.88 (3-chloro-5- (m, 1H), 6.42 (brs, 2H), 5.25 (d, fluorophenyl)-2- J = 4.8 Hz, 1H), 2.46 (s, 3H) hydroxyacetamide ppm. (Isomer 2) Purification Method: PM81 A3 AR3 H1 LCMS (AM1): rt = 3.05 min, (441.2 [M+H]+), 98.42% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.20 (s, 1H), 8.25 (s, rac-N-(4-(7- 1H), 7.81 (d, J = 5.6 Hz, 1H), amino-3-methyl- 7.73 (m, 1H), 7.47 (s, 1H), 7.38 1H-pyrazolo[4,3- (t, J = 8.8 Hz, 2H), 7.29 (d, J = d]pyrimidin-1-yl)- 8.4 Hz, 1H), 6.80 (d, J = 4.8 Hz, 3-methylphenyl)- 1H), 6.18 (brs, 1H), 5.22 (d, J = 2-(3-chloro-5- 4.8 Hz, 1H), 2.47 (s, 3H), 1.96 fluorophenyl)-2- (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 A3 AR3 H1 LCMS (AM1): rt = 3.03 min, (441.2 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- N-(4-(7-amino-3- d6): δ 10.19 (s, 1H), 8.24 (s, methyl-1H- 1H), 7.80 (d, J = 5.6Hz, 1H), pyrazolo[4,3- 7.73 (t, J = 5.6 Hz, 1H), 7.47 (s, d]pyrimidin-1-yl)- 1H), 7.40 - 7.35 (m, 2H), 7.28 3-methylphenyl)- (d, J = 8.4 Hz, 1H), 6.80 (d, J = 2-(3-chloro-5- 4.8 Hz, 1H), 6.18 (brs, 2H), 5.22 fluorophenyl)-2- (d, J = 4.6 Hz, 1H), 2.47 (s, 3H), hydroxyacetamide 1.96 (s, 3H) ppm (Isomer 1) Purification Method: PM84 A3 AR3 H1 LCMS (AM1): rt = 3.03 min, (441.2 [M+H]+), 100% purity 1H NMR (400 MHz, DMSO- N-(4-(7-amino-3- d6): δ 10.19 (s, 1H), 8.25 (s, methyl-1H- 1H), 7.80 (d, J = 5.6Hz, 1H), pyrazolo[4,3- 7.73 (t, J = 5.6 Hz, 1H), 7.47 (s, d]pyrimidin-1-yl)- 1H), 7.40 - 7.35 (m, 2H), 7.28 3-methylphenyl)- (d, J = 8.4 Hz, 1H), 6.80 (d, J = 2-(3-chloro-5- 4.8 Hz, 1H), 6.17 (brs, 1H), 5.22 fluorophenyl)-2- (d, J = 4.6 Hz, 1H), 2.47 (s, 3H), hydroxyacetamide 1.96 (s, 3H) ppm. (Isomer 2) Purification Method: PM84 A3 AR4 H1 LCMS (AM1): rt = 3.06 min, (445.2 [M+H]+), 99.12% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.45 (s, 1H), 8.27 (s, amino-3-methyl- 1H), 7.94 (dd, J = 12.7, 2.2 Hz, 1H-pyrazolo[4,3- 1H), 7.71 (d, J = 9.0 Hz, 1H), d]pyrimidin-1-yl)- 7.50 – 7.45 (m, 2H), 7.41 – 7.35 3-fluorophenyl)-2- (m, 2H), 6.90 (s, 1H), 6.56 (brs, (3-chloro-5- 2H), 5.24 (s, 1H), 2.46 (s, 3H) fluorophenyl)-2- ppm. hydroxyacetamide Purification Method: PM19 A3 AR4 H1 LCMS (AM1): rt = 3.05 min, N-(4-(7-amino-3- (445.1 [M+H]+), 99.13% purity. methyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 10.45 (s, 1H), 8.26 (s, d]pyrimidin-1-yl)- 1H), 7.94 (dd, J = 12.7, 2.2 Hz, 3-fluorophenyl)-2- 1H), 7.72 - 7.70 (m, 1H), 7.47 (t, (3-chloro-5- J = 8.4 Hz, 2H), 7.41 - 7.35 (m, fluorophenyl)-2- 2H), 6.90 (s, 1H), 6.55 (brs, 2H), hydroxyacetamide 5.24 (s, 1H), 2.46 (s, 3H) ppm. (Isomer 1) Purification Method: PM85 N-(4-(7-amino-3- A3 AR4 H1 LCMS (AM2): rt = 2.76 min, methyl-1H- (445.12 [M+H]+), 96.74% pyrazolo[4,3- purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO-d6 3-fluorophenyl)-2- δ 10.45 (s, 1H), 8.26 (s, 1H), (3-chloro-5- 7.94 (dd, J = 12.7, 2.2 Hz, 1H), fluorophenyl)-2- 7.72-7.70 (m, 1H), 7.47 (t, J=8.4 hydroxyacetamide Hz, 2H), 7.41 – 7.35 (m, 2H), (Isomer 2) 6.91 (s, 1H), 6.55 (brs, 2H), 5.24 (s, 1H), 2.46 (s, 3H) ppm. Purification Method: PM85 A2 AR2 H1 LCMS (AM1): rt = 2.98 min, (445.2 [M+H]+), 98.17% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.44 (s, 1H), 8.26 (s, rac-N-(4-(7- 1H), 8.16 (dd, J = 17.2, 2.3 Hz, amino-3-methyl- 1H), 7.87 (ddd, J = 15.9, 8.7, 2.3 1H-pyrazolo[4,3- Hz, 1H), 7.55 (d, J = 8.7 Hz, d]pyrimidin-1-yl)- 1H), 7.28 – 7.17 (m, 3H), 6.89 3-chlorophenyl)-2- (dd, J = 7.4, 4.8 Hz, 1H), 6.42 (3,5- (brs, 2H), 5.25 (d, J = 4.7 Hz, difluorophenyl)-2- 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM5 A2 AR2 H1 LCMS (AM1): rt = 2.97 min, (445.2 [M+H]+), 99.86% purity. N-(4-(7-amino-3-1H NMR (400 MHz, DMSO- methyl-1H- d6): δ 10.44 (brs, 1H), 8.25 (s, pyrazolo[4,3- 1H), 8.16 (dd, J = 17.2, 2.4 Hz, d]pyrimidin-1-yl)- 1H), 7.90 – 7.83 (m, 1H), 7.54 3-chlorophenyl)-2- (d, J = 8.4 Hz, 1H), 7.28 – 7.17 (3,5- (m, 3H), 6.90 (brs, 1H), 6.41 difluorophenyl)-2- (brs, 2H), 5.24 (s, 1H), 2.46 (s, hydroxyacetamide 3H) ppm. (Isomer 1) Purification Method: P68 N-(4-(7-amino-3- A2 AR2 H1 LCMS (AM1): rt = 2.97 min, methyl-1H- (445.2 [M+H]+), 99.89% purity. pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.43 (s, 1H), 8.25 (s, 3-chlorophenyl)-2- 1H), 8.16 (dd, J = 17.2, 2.4 Hz, (3,5- 1H), 7.90 – 7.83 (m, 1H), 7.54 difluorophenyl)-2- (d, J = 8.4 Hz, 1H), 7.28 – 7.17 hydroxyacetamide (m, 3H), 6.90 – 6.87 (m, 1H), (Isomer 2) 6.41 (brs, 2H), 5.24 (d, J = 4.8 Hz, 1H), 2.46 (s, 3H) ppm. Purification Method: PM82 A1 AR5 H1 LCMS (AM2): rt= 2.77 min, rac-N-(4-(7- (445.08 [M+H]+), 98.9% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): 10.04 (s, 1H), 8.29 (s, 1H), d]pyrimidin-1-yl)- 7.84 - 7.82 (m, 1H), 7.59 (s, 2,3- 1H), 7.51 - 7.49 (m, 1H), 7.44 - difluorophenyl)-2- 7.37 (m, 2H), 7.30 - 7.26 (m, (3-chlorophenyl)- 1H), 6.81 (brs, 2H), 5.33 (d, J = 2- 3.6 Hz, 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM20 N-(4-(7-amino-3- A1 AR5 H1 LCMS (AM1): rt = 3.03 min, methyl-1H- (445.1 [M+H]+), 99.01% purity. pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.04 (brs, 1H), 8.29 (s, 2,3- 1H), 7.85 – 7.81 (m, 1H), 7.60 difluorophenyl)-2- (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), (3-chlorophenyl)- 7.44 – 7.37 (m, 2H), 7.30 – 7.26 2- (m, 1H), 6.78 (brs, 3H), 5.32 (s, hydroxyacetamide 1H), 2.47 (s, 3H) ppm. (Isomer 1) Purification Method: PM81 N-(4-(7-amino-3- A1 AR5 H1 methyl-1H- LCMS (AM2): rt = 2.76 min, pyrazolo[4,3- (445.12 [M+H]+), 98.03% d]pyrimidin-1-yl)- purity. 2,3-1H NMR (400 MHz, DMSO- difluorophenyl)-2- d6): δ 10.02 (brs, 1H), 8.29 (s, (3-chlorophenyl)- 1H), 7.85 – 7.81 (m, 1H), 7.60 2- (s, 1H), 7.50 (dd, J = 7.2, 1.6 hydroxyacetamide Hz, 1H), 7.44 – 7.37 (m, 2H), (Isomer 2) 7.30 – 7.26 (m, 1H), 6.78 (brs, 3H), 5.32 (s, 1H), 2.47 (s, 3H) ppm. Purification Method: PM81 A5 AR1 H1 LCMS (AM1): rt = 2.10 min, rac-N-(4-(7- (477.0 [M-H]-), 99.32% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.06 (brs, 1H), 8.28 (s, d]pyrimidin-1-yl)- 1H), 8.12 – 8.07 (m, 1H), 7.90 2,5- (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), difluorophenyl)-2- 7.71 – 7.62 (m, 3H), 6.76 (brs, hydroxy-2-(3- 2H), 5.46 (d, J = 4.0 Hz, 1H), (trifluoromethyl)p 2.47 (s, 3H) ppm. henyl)acetamide Purification Method: PM21 N-(4-(7-amino-3- A5 AR1 H1 LCMS (AM1): rt = 3.18 min, methyl-1H- (479.2 [M+H]+), 97.26%. pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.00 (s, 1H), 8.28 (s, 2,5- 1H), 8.12 – 8.07 (m, 1H), 7.90 difluorophenyl)-2- (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), hydroxy-2-(3- 7.71 – 7.62 (m, 3H), 6.93 (brs, (trifluoromethyl)p 1H), 6.76 (brs, 2H), 5.47 (s, 1H), henyl)acetamide 2.46 (s, 3H) ppm. (Isomer 1) Purification Method: PM82 A5 AR1 H1 LCMS (AM2): rt = 2.89 min, N-(4-(7-amino-3- (479.13 [M+H]+), 98.99% methyl-1H- purity. pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.00 (brs, 1H), 8.28 (s, 2,5- 1H), 8.12 – 8.07 (m, 1H), 7.90 difluorophenyl)-2- (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), hydroxy-2-(3- 7.71 - 7.62 (m, 3H), 6.93 (brs, (trifluoromethyl)p 1H), 6.76 (brs, 2H), 5.47 (s, 1H), henyl)acetamide 2.46 (s, 3H) ppm. (Isomer 2) Purification Method: PM82 rac-N-(4-(7- A6 AR4 H2 LCMS (AM1): rt = 2.28 min, amino-3,5- (491.2 [M+H]+), 100% purity. dimethyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 10.45 (s, 1H), 7.93 (dd, J d]pyrimidin-1-yl)- = 12.8, 2.0 Hz, 1H), 7.70 (dd, J 3-fluorophenyl)-2- = 8.6, 1.4 Hz, 1H), 7.58 – 7.50 hydroxy-2-(3- (m, 3H), 7.44 (t, J = 8.8 Hz, (trifluoromethoxy) 1H), 7.31 (d, J = 7.9 Hz, 1H), phenyl)acetamide 6.82 (d, J = 4.7 Hz, 1H), 6.45 (brs, 2H), 5.26 (d, J = 4.7 Hz, 1H), 2.44 (s, 3H), 2.42 (s, 3H) ppm. Purification Method: PM22 A6 AR4 H2 LCMS (AM1): rt = 3.15 min, (491.2 [M+H]+), 98.77% purity 1H NMR (400 MHz, DMSO- N-(4-(7-amino- d6): δ 10.45 (brs, 1H), 7.93 (dd, 3,5-dimethyl-1H- J = 2.3, 12.8 Hz, 1H), 7.70 (dd, J pyrazolo[4,3- = 1.6, 8.8 Hz, 1H), 7.58 - 7.49 d]pyrimidin-1-yl)- (m, 3H), 7.44 (t, J = 8.7 Hz, 3-fluorophenyl)-2- 1H), 7.33 - 7.31 (m, 1H), 6.82 hydroxy-2-(3- (brs, 1H), 6.45 (brs, 2H), 5.26 (s, (trifluoromethoxy) 1H), 2.44 (s, 3H), 2.43 (s, 3H) phenyl)acetamide ppm. (Isomer 1) Purification Method: PM81 A6 AR4 H2 LCMS (AM2): rt = 2.82 min, (491.2 [M+H]+), 99.37% purity. 1H NMR (400 MHz, DMSO- N-(4-(7-amino- d6): δ 10.45 (s, 1H), 7.93 (dd, J 3,5-dimethyl-1H- = 12.8, 2.3 Hz, 1H), 7.70 (dd, J pyrazolo[4,3- = 8.4, 1.6 Hz, 1H), 7.58 – 7.49 d]pyrimidin-1-yl)- (m, 3H), 7.44 (t, J = 8.7 Hz, 3-fluorophenyl)-2- 1H), 7.31 (d, J = 8.0 Hz, 1H), hydroxy-2-(3- 6.82 (s, 1H), 6.45 (brs, 2H), 5.26 (trifluoromethoxy) (s, 1H), 2.44 (s, 3H), 2.43 (s, phenyl)acetamide 3H) ppm. (Isomer 2) Purification Method: PM81 A6 AR1 H1 LCMS (AM2): rt = 2.93 min, (495.18 [M+H]+), 98.37% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 9.97 (s, 1H), 8.28 (s, 1H), 1H-pyrazolo[4,3- 8.12 – 8.06 (m, 1H), 7.67 – 7.62 d]pyrimidin-1-yl)- (m, 1H), 7.58 – 7.56 (m, 1H), 2,5- 7.54-7.50 (m, 2H), 7.32 (d, J = difluorophenyl)-2- 8.0 Hz,1H), 6.91 (brs, 1H), 6.76 hydroxy-2-(3- (brs, 1H), 5.41 (s, 1H), 2.46 (s, (trifluoromethoxy) 3H) ppm. phenyl)acetamide Purification Method: PM15 A6 AR1 H1 LCMS (AM1): rt = 2.11 min, N-(4-(7-amino-3- (495.2 [M+H]+), 98.54% purity. methyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 9.94 (brs, 1H), 8.27 (s, d]pyrimidin-1-yl)- 1H), 8.09 (dd, J = 6.8, 11.7 Hz, 2,5- 1H), 7.65 (dd, J = 6.9, 10.7 Hz, difluorophenyl)-2- 1H), 7.58 – 7.50 (m, 3H), 7.32 hydroxy-2-(3- (d, J = 8.0 Hz, 1H), 6.88 (brs, (trifluoromethoxy) 1H), 6.75 (brs, 2H), 5.40 (s, 1H), phenyl)acetamide 2.46 (s, 3H) ppm. (Isomer 1) Purification Method: PM81 A6 AR1 H1 LCMS (AM1): rt = 2.11 min, N-(4-(7-amino-3- (495.2 [M+H]+), 99.04% purity. methyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 9.94 (brs, 1H), 8.27 (s, d]pyrimidin-1-yl)- 1H), 8.09 (dd, J = 11.7, 6.8 Hz, 2,5- 1H), 7.65 (dd, J = 6.9, 10.7 Hz, difluorophenyl)-2- 1H), 7.58 – 7.50 (m, 3H), 7.32 hydroxy-2-(3- (d, J = 8.0 Hz, 1H), 6.93 (brs, (trifluoromethoxy) 1H), 6.75 (s, 2H), 5.41 (s, 1H), phenyl)acetamide 2.46 (s, 3H) ppm (Isomer 2) Purification Method: PM81 rac-N-(4-(7- A1 AR5 H2 LCMS (AM2): rt= 2.66 min, amino-3,5- (459.3 [M+H]+), 97.68% purity. dimethyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 10.02 (brs, 1H), 7.84 - d]pyrimidin-1-yl)- 7.79 (m, 1H), 7.59 (s, 1H), 7.51 2,3- - 7.48 (m, 1H), 7.44 - 7.37 (m, difluorophenyl)-2- 2H), 7.26 - 7.23 (m, 1H), 6.80 (3-chlorophenyl)- (brs, 1H), 6.69 (brs, 2H), 5.31 (s, 2- 1H), 2.45 (s, 3H), 2.43 (s, 3H) hydroxyacetamide ppm. Purification Method: PM23 A1 AR5 H2 LCMS (AM1): rt = 3.06 min, N-(4-(7-amino- (459.1 [M+H]+), 99.81% purity 3,5-dimethyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 10.02 (brs, 1H), 7.82 – d]pyrimidin-1-yl)- 7.79 (m, 1H), 7.59 (t, J = 1.9 2,3- Hz, 1H), 7.51 - 7.49 (m, 1H), difluorophenyl)-2- 7.44 - 7.37 (m, 2H), 7.26 – 7.23 (3-chlorophenyl)- (m, 1H), 6.80 (brs, 1H), 6.69 2- (brs, 2H), 5.32 (s, 1H), 2.45 (s, hydroxyacetamide 3H), 2.43 (s, 3H) ppm. (Isomer 1) Purification Method: PM81 A1 AR5 H2 LCMS (AM1): rt = 3.06 min, N-(4-(7-amino- (459.1 [M+H]+), 99.82% purity 3,5-dimethyl-1H-1H NMR (400 MHz, DMSO- pyrazolo[4,3- d6): δ 10.02 (s, 1H), 7.82 - 7.79 d]pyrimidin-1-yl)- (m, 1H), 7.59 (s, 1H), 7.50 - 2,3- 7.49 (m, 1H), 7.46 – 7.35 (m, difluorophenyl)-2- 2H), 7.26 – 7.23 (m, 1H), 6.81 (3-chlorophenyl)- (brs, 1H), 6.69 (brs, 2H), 5.31 (s, 2- 1H), 2.45 (s, 3H), 2.43 (s, 3H) hydroxyacetamide ppm. (Isomer 2) Purification Method: PM81 rac-N-(4-(7- A7 AR2 H1 LCMS (AM2): rt = 2.60 min, amino-3-methyl- (427.36 [M+H]+), 99.64% 1H-pyrazolo[4,3- purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 3-chlorophenyl)-2- d6): δ 10.43 (s, 1H), 8.24 (s, (3-fluorophenyl)- 1H), 8.15 (dd, J = 12.9, 2.3 Hz, 2- 1H), 7.91 – 7.81 (m, 1H), 7.53 hydroxyacetamide (d, J = 8.7 Hz, 1H), 7.43 – 7.33 (m, 3H), 7.18 – 7.10 (m, 1H), 6.77 (s, 1H), 6.39 (s, 2H), 5.20 (s, 1H), 2.46 (s, 3H) ppm. Purification Method: PM7 A2 AR6 H1 LCMS (AM1): rt = 2.81 min, (411.3 [M+H]+), 99.73% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.26 (s, 1H), 8.27 (s, amino-3-methyl- 1H), 7.90 (d, J = 9.2 Hz, 2H), 1H-pyrazolo[4,3- 7.44 (d, J = 9.0 Hz, 2H), 7.26 – d]pyrimidin-1- 7.15 (m, 3H), 6.81 (s, 1H), 6.55 yl)phenyl)-2-(3,5- (brs, 2H), 5.22 (d, J = 4.8 Hz, difluorophenyl)-2- 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM43 A5 AR3 H1 LCMS (AM2): rt = 2.75 min, (457.39 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.23 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.85 - 7.81 rac-N-(4-(7- (m, 2H), 7.73 (t, J = 8.4 Hz, amino-3-methyl- 1H), 7.69 (d, J = 7.6 Hz, 1H), 1H-pyrazolo[4,3- 7.66 - 7.64 (m, 1H), 7.28 (d, J = d]pyrimidin-1-yl)- 8.4 Hz, 1H), 6.76 (d, J = 4.8 Hz, 3-methylphenyl)- 1H), 6.21 (brs, 1H), 5.30 (d, J = 2-hydroxy-2-(3- 4.8 Hz, 1H), 2.47 (s, 3H), 1.95 (trifluoromethyl)p (s, 3H) ppm. henyl)acetamide Purification Method: PM10 rac-N-(4-(7- A7 AR3 H1 LCMS (AM2): rt = 2.53 min, amino-3-methyl- (407.40 [M+H]+), 99.18% 1H-pyrazolo[4,3- purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 3-methylphenyl)- d6): δ 10.17 (s, 1H), 8.25 (s, 2-(3- 1H), 7.82 (d, J = 5.2 Hz, 1H), fluorophenyl)-2- 7.74 (s, 1H), 7.43 – 7.35 (m, hydroxyacetamide 3H), 7.28 (d, J = 8.6 Hz, 1H), 7.14 (t, J = 8.6 Hz,1H), 6.64 (d, J = 4.4 Hz, 1H), 5.19 (d, J = 4.4 Hz, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. Purification Method: PM5 A8 AR3 H1 LCMS (AM1): rt = 2.68 min, (389.3 [M+H]+), 99.91% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.14 (s, 1H), 8.25 (s, 1H), 7.83 (d, J = 3.8 Hz, 1H), rac-N-(4-(7- 7.77 - 7.73 (m, 1H), 7.55 - 7.53 amino-3-methyl- (m, 2H), 7.39 - 7.35 (m, 2H), 1H-pyrazolo[4,3- 7.32 - 7.26 (m, 2H), 6.49 (m, d]pyrimidin-1-yl)- 1H), 6.15 (brs, 1H), 5.14 (m, 3-methylphenyl)- 1H), 2.48 (s, 3H), 1.96 (s, 3H) 2-hydroxy-2- ppm. phenylacetamide Purification Method: PM10 A4 AR3 H1 LCMS (AM2): rt = 2.76 min, rac-N-(4-(7- (475.4 [M+H]+), 99.48% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.26 (s, 1H), 8.25 (s, d]pyrimidin-1-yl)- 1H), 7.82 - 7.70 (m, 4H), 7.68 - 3-methylphenyl)- 7.63 (m, 1H), 7.28 (d, J = 8.8 2-(3-fluoro-5- Hz, 1H), 6.93 (brs, 1H), 6.19 (trifluoromethyl)p (brs, 2H), 5.34 (s, 1H), 2.47 (s, henyl)-2- 3H), 1.96 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 A9 AR3 H1 LCMS (AM2): rt = 2.64 min, rac-N-(4-(7- (421.43 [M+H]+), 99.71% amino-3-methyl- purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.14 (s, 1H), 8.25 (s, 3-methylphenyl)- 1H), 7.81 (s, 1H), 7.73 (s, 1H), 2-(3-fluoro-4- 7.30 – 7.26 (m, 4H), 6.56 (d, J = methylphenyl)-2- 3.0 Hz, 1H), 6.18 (brs, 1H), 5.13 hydroxyacetamide (s, 1H), 2.47 (s, 3H), 2.21 (s, 3H), 1.96 (s, 3H) ppm. Purification Method: PM8 A10 AR3 H1 LCMS (AM1): rt = 2.77 min, (403.3 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.10 (s, 1H), 8.25 (s, rac-N-(4-(7- 1H), 7.83 (s, 1H), 7.75 (brs, 1H), amino-3-methyl- 7.35 – 7.18 (m, 4H), 7.12 (d, J = 1H-pyrazolo[4,3- 7.6 Hz, 1H), 6.44 (d, J = 4.6 Hz, d]pyrimidin-1-yl)- 1H), 6.16 (brs, 1H), 5.10 (d, J = 3-methylphenyl)- 4.5 Hz, 1H), 2.47 (s, 3H), 2.32 2-hydroxy-2-(m- (s, 3H), 1.96 (s, 3H) ppm. tolyl)acetamide Purification Method: PM10 A7 AR4 H1 LCMS (AM2): rt = 2.54 min, (411.40 [M+H]+), 99.17% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.43 (s, 1H), 8.26 (s, amino-3-methyl- 1H), 7.95 (dd, J = 12.8 Hz, 2.2 1H-pyrazolo[4,3- Hz, 1H), 7.72 (dd, J = 8.4 Hz, d]pyrimidin-1-yl)- 1.6 Hz, 1H), 7.49 – 7.34 (m, 3-fluorophenyl)-2- 4H), 7.17 – 7.12 (m, 1H), 6.75 (3-fluorophenyl)- (s, 1H), 6.55 (brs, 2H), 5.21 (s, 2- 1H), 2.46 (s, 3H) ppm. hydroxyacetamide Purification Method: PM7 A11 AR3 H1 LCMS (AM1): rt = 2.88 min, rac-N-(4-(7- (421.3 [M+H]+), 95.92% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.13 (s, 1H), 8.25 (s, d]pyrimidin-1-yl)- 1H), 7.82 (d, J = 6.2 Hz, 1H), 3-methylphenyl)- 7.74 (t, J = 7.2 Hz, 1H), 7.28 (d, 2-(3-fluoro-5- J = 8.6 Hz, 1H), 7.19 (s, 1H), methylphenyl)-2- 7.15 (d, J = 9.8 Hz, 1H), 6.97 (d, hydroxyacetamide J = 9.4 Hz, 1H), 6.60 (d, J = 4.1 Hz, 1H), 6.18 (brs, 1H), 5.13 (s, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 1.96 (s, 3H) ppm. Purification Method: PM10 A5 AR6 H1 LCMS (AM2): rt = 2.68 min, (443.04 [M+H]+), 98.78% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.30 (s, 1H), 8.28 (s, rac-N-(4-(7- 1H), 7.93 – 7.90 (m, 3H), 7.85 amino-3-methyl- (d, J = 7.6 Hz, 1H), 7.69 (d, J = 1H-pyrazolo[4,3- 7.8 Hz, 1H), 7.62 (t, J = 7.7 Hz, d]pyrimidin-1- 1H), 7.45 – 7.42 (m, 2H), 6.77 yl)phenyl)-2- (d, J = 4.8 Hz, 1H), 6.50 (brs, hydroxy-2-(3- 2H), 5.30 (d, J = 4.6 Hz, 1H), (trifluoromethyl)p 2.47 (s, 3H) ppm. henyl)acetamide Purification Method: PM7 A12 AR3 H1 LCMS (AM2): rt = 2.59 min, (425.07 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.17 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 5.6 Hz, 1H), rac-N-(4-(7- 7.73 (t, J = 6.8 Hz, 1H), 7.59 - amino-3-methyl- 7.54 (m, 1H), 7.47 - 7.36 (m, 1H-pyrazolo[4,3- 2H), 7.29 (d, J = 8.8 Hz, 1H), d]pyrimidin-1-yl)- 6.70 (d, J = 4.8 Hz, 1H, 6.17 3-methylphenyl)- (brs, 2H), 5.19 (d, J = 4.8 Hz, 2-(3,4- 1H), 2.47 (s, 3H), 1.96 (s, 3H) difluorophenyl)-2- ppm hydroxyacetamide Purification Method: PM10 A7 AR6 H1 LCMS (AM1): rt = 2.67 min, rac-N-(4-(7- (393.2 [M+H]+), 98.51% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.23 (s, 1H), 8.28 (s, d]pyrimidin-1- 1H), 7.91 (d, J = 9.2 Hz, 2H), yl)phenyl)-2-(3- 7.44 – 7.35 (m, 5H), 7.16 – 7.11 fluorophenyl)-2- (m, 1H), 6.65 (d, J = 2.0 Hz, hydroxyacetamide 1H), 6.51 (brs, 1H), 5.19 (s, 1H), 2.47 (s, 3H) ppm. Purification Method: PM10 A1 AR6 H1 LCMS (AM1): rt = 2.83 min, (409.2 [M+H]+), 99.24% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.24 (s, 1H), 8.28 (s, amino-3-methyl- 1H), 7.92 (d, J = 8.8 Hz, 2H), 1H-pyrazolo[4,3- 7.61 (s, 1H), 7.50 (d, J = 7.6 Hz, d]pyrimidin-1- 1H), 7.44 – 7.36 (m, 4H), 6.68 yl)phenyl)-2-(3- (s, 1H), 6.49 (brs, 1H), 5.19 (s, chlorophenyl)-2- 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM8 A13 AR3 H1 LCMS (AM2): rt = 2.71 min, (441.01 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.18 (s, 1H), 8.25 (s, 1H), 7.80 (d, J = 5.2 Hz, 1H), rac-N-(4-(7- 7.71 (t, J = 6.4 Hz, 1H), 7.62 – amino-3-methyl- 7.54 (m, 2H), 7.40 (dd, J = 8.4, 1H-pyrazolo[4,3- 2.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, d]pyrimidin-1-yl)- 1H), 6.75 (d, J = 4.8 Hz, 1H), 3-methylphenyl)- 6.19 (brs, 2H), 5.21 (d, J = 4.8 2-(4-chloro-3- Hz, 1H), 2.47 (s, 3H), 1.96 (s, fluorophenyl)-2- 3H) ppm. hydroxyacetamide Purification Method: PM25 rac-N-(4-(7- A14 AR3 H1 LCMS (AM2): rt = 2.83 min, amino-3-methyl- (475.06 [M+H]+), 98.99% purity 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.24 (s, 1H), 8.25 (s, 3-methylphenyl)- 1H), 7.83 - 7.80 (m, 2H), 7.74 - 2-(3-fluoro-4- 7.71 (m, 1H), 7.67 (d, J = 8.4 (trifluoromethyl)p Hz, 1H), 7.59 (d, J = 8.4 Hz, henyl)-2- 1H), 7.29 (d, J = 8.4 Hz, 1H), hydroxyacetamide 6.87 (d, J = 4.4 Hz, 1H), 6.21 (brs, 1H), 5.32 (s, 1H), 2.47 (s, 3H), 1.96 (s, 3H) ppm. Purification Method: PM10 A2 AR7 H1 LCMS (AM2): rt = 2.68 min, (429.19 [M+H]+), 97.24% purity. 1H NMR (400 MHz, DMSO- d6): δ = 9.83 (s, 1H), 8.30 (s, rac-N-(4-(7- 1H), 8.04 (t, J = 8.4 Hz, 1H), amino-3-methyl- 7.49 (dd, J = 11.6 Hz, 2.4 Hz, 1H-pyrazolo[4,3- 1H), 7.29 (dd, J = 8.4 Hz, 1.6 d]pyrimidin-1-yl)- Hz , 1H), 7.27 - 7.22 (m, 2H), 2-fluorophenyl)-2- 7.21 - 7.16 (m, 1H), 6.92 (brs, (3,5- 1H), 6.73 (brs, 2H), 5.33 (s, 1H), difluorophenyl)-2- 2.45 (s, 3H) ppm. hydroxyacetamide Purification Method:PM4 A5 AR7 H1 LCMS (AM2): rt = 2.78 min, (461.19 [M+H]+), 97.59% purity. 1H NMR (400 MHz, DMSO- d6): δ 9.87 (s, 1H), 8.29 (s, 1H), 8.08 - 8.02 (m, 1H), 7.90 (s, rac-N-(4-(7- 1H), 7.84 (d, J = 7.6 Hz, 1H), amino-3-methyl- 7.70 - 7.68 (m, 1H), 7.65 - 7.61 1H-pyrazolo[4,3- (m, 1H), 7.49 (dd, J = 2.0 Hz, d]pyrimidin-1-yl)- 2.4 Hz, 1H), 7.28 (d, J = 1.6 Hz, 2-fluorophenyl)-2- 1H), 6.89 (d, J = 4.8 Hz, 1H), hydroxy-2-(3- 6.71 (brs, 1H), 5.42 (d, J = 4.4 (trifluoromethyl)p Hz, 1H), 2.47 (s, 3H) ppm. henyl)acetamide Purification Method:PM10 rac-N-(4-(7- A7 AR7 H1 LCMS (AM1): rt = 2.79 min, amino-3-methyl- (411.2 [M+H]+), 97.10% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 9.79 (s, 1H), 8.30 (s, 1H), 2-fluorophenyl)-2- 8.08 (t, J = 8.4 Hz, 1H), 7.51 – (3-fluorophenyl)- 7.28 (m, 5H), 7.17 – 7.12 (m, 2- 1H), 6.81 (d, J = 4.8 Hz, 1H), hydroxyacetamide 6.71 (brs, 1H), 5.30 (d, J = 4.4 Hz, 1H), 2.46 (s, 3H) ppm. Purification Method:PM10 A1 AR7 H1 LCMS (AM2): rt = 2.72 min, (427.18 [M+H]+), 98.15% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ = 9.82 (brs, 1H), 8.30 (s, amino-3-methyl- 1H), 8.07 (t, J = 8.4 Hz, 1H), 1H-pyrazolo[4,3- 7.58 (s, 1H), 7.50 – 7.47 (m, d]pyrimidin-1-yl)- 2H), 7.43 – 7.37 (m, 2H), 7.30 2-fluorophenyl)-2- (d, J = 8.8 Hz, 1H), 6.72 (brs, (3-chlorophenyl)- 3H), 5.29 (s, 1H), 2.45 (s, 3H) 2- ppm. hydroxyacetamide Purification Method: PM4 A7 AR5 H1 LCMS (AM2): rt= 2.65 min, (429.11 [M+H]+), 98.73% rac-N-(4-(7- purity. amino-3-methyl-1H NMR (400 MHz, DMSO-d6: 1H-pyrazolo[4,3- 10.03 (s, 1H), 8.29 (s, 1H), 7.86 d]pyrimidin-1-yl)- - 7.80 (m, 1H), 7.46 - 7.34 (m, 2,3- 3H), 7.29 - 7.26 (m, 1H), 7.17 - difluorophenyl)-2- 7.13 (m, 1H), 6.80 (brs, 2H), (3-fluorophenyl)- 5.33 (d, J = 4.4 Hz, 1H), 2.47 (s, 2- 3H) ppm. hydroxyacetamide Purification Method: PM20 rac-N-(4-(7- A15 AR2 H1 LCMS (AM1): rt = 2.85 min, amino-3-methyl- (445.2 [M+H]+), 99.16% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.50 (brs, 1H), 8.25 (s, 3-chlorophenyl)-2- 1H), 8.20 (d, J = 11.6 Hz, 1H), (2,3- 7.88 (t, J = 9.6 Hz, 1H), 7.55 (d, difluorophenyl)-2- J = 8.8 Hz, 1H), 7.44 - 7.36 (m, hydroxyacetamide 2H), 7.27 - 7.24 (m, 1H), 6.91 (brs, 1H), 6.42 (brs, 2H), 5.45 (s, 1H), 2.46 (s, 3H) ppm. Purification Method: PM10 A11 AR2 H1 LCMS (AM2): rt = 2.67 min, (441.3 [M+H]+), 98.49% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.42 (brs, 1H), 8.25 (s, rac-N-(4-(7- 1H), 8.17 (dd, J = 2.3, 16.3 Hz, amino-3-methyl- 1H), 7.90 - 7.84 (m, 1H), 7.53 1H-pyrazolo[4,3- (d, J = 8.6 Hz, 1H), 7.19 (s, 1H), d]pyrimidin-1-yl)- 7.15 (dd, J = 2.4, 9.7 Hz, 1H), 3-chlorophenyl)-2- 6.98 - 6.96 (m, 1H), 6.75 (brs, (3-fluoro-5- 1H), 6.40 (brs, 1H), 5.14 (s, 1H), methylphenyl)-2- 2.46 (s, 3H), 2.33 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 A17 AR3 H1 LCMS (AM2): rt= 2.91 min, (491.19 [M+H]+), 99.65% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ = 10.25 (s, 1H), 8.25 (s, amino-3-methyl- 1H), 7.81 (d, J = 8.0 Hz, 1H), 1H-pyrazolo[4,3- 7.73 (t, J = 7.2 Hz, 1H), 7.45 – d]pyrimidin-1-yl)- 7.42 ( m, 2H), 7.34 (d, J = 8.4 3-methylphenyl)- Hz, 1H), 7.28 (d, J = 8.8 Hz, 2-(3-fluoro-5- 1H), 6.91 (brs, 1H), 6.20 (brs, (trifluoromethoxy) 2H), 5.27 (s, 1H), 2.47 (s, 3H), phenyl)-2- 1.96 (s, 3H) ppm. hydroxyacetamide Purification Method: PM8 rac-N-(4-(7- A18 AR3 H1 LCMS (AM2): rt = 2.81 min, amino-3-methyl- (437.21 [M+H]+), 99.35% 1H-pyrazolo[4,3- purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 3-methylphenyl)- d6): δ 10.14 (s, 1H), 8.24 (s, 2-(3-chloro-5- 1H), 7.82 (d, J = 7.0 Hz, 1H), methylphenyl)-2- 7.75 - 7.72 (t, J = 6.0 Hz, 1H), hydroxyacetamide 7.39 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 6.61 (s, 1H), 6.18 (brs, 1H), 5.12 (s, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 1.96 (s, 3H) ppm. Purification Method: PM10 A21 AR3 H1 LCMS (AM2): rt = 2.89 min, (471.22 [M+H]+), 99.60% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.23 (s, 1H), 8.24 (s, amino-3-methyl- 1H), 7.82 (d, J = 8.4 Hz, 1H), 1H-pyrazolo[4,3- 7.74 (m, 1H), 7.69 (s, 1H), 7.65 d]pyrimidin-1-yl)- (s, 1H), 7.50 (s, 1H), 7.28 (d, J = 3-methylphenyl)- 8.4 Hz, 1H), 6.76 (brs, 1H), 6.17 2-hydroxy-2-(3- (brs, 2H), 5.24 (s, 1H), 2.47 (s, methyl-5- 3H), 2.41 (s, 3H), 1.96 (s, 3H) (trifluoromethyl)p ppm. henyl)acetamide Purification Method: PM10 A19 AR3 H1 LCMS (AM1): rt = 2.87 min, (457.16 [M+H]+), 98.79% purity. 1H NMR : (400 MHz, DMSO- rac-N-(4-(7- d6): δ = 10.21 (s, 1H), 8.25 (s, amino-3-methyl- 1H), 7.81 (d, J = 6.8 Hz, 1H), 1H-pyrazolo[4,3- 7.75 - 7.71 (m, 1H), 7.58 - 7.57 d]pyrimidin-1-yl)- (m, 2H), 7.57 - 7.56 (m, 1H), 3-methylphenyl)- 7.28 (d, J = 8.8 Hz, 1H), 6.82 (s, 2-(3,5- 1H), 6.20 (s, 2H), 5.22 (s, 1H), dichlorophenyl)-2- 2.50 (s, 3H), 1.96 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 rac-N-(4-(7- A19 AR2 H1 LCMS (AM2): rt = 2.91 min, amino-3-methyl- (477.2 [M+H]+), 99.84% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.43 (s, 1H), 8.25 (s, 3-chlorophenyl)-2- 1H), 8.15 (dd, J = 18.4, 2.0 Hz, (3,5- 1H), 7.90 – 7.84 (m, 1H), 7.58 dichlorophenyl)-2- (s, 3H), 7.54 (d, J = 7.2 Hz, 1H), hydroxyacetamide 6.92 – 6.89 (m, 1H), 6.43 (brs, 2H), 5.25 (d, J = 4.7 Hz, 1H), 2.46 (s, 3H) ppm. Purification Method: PM5 A29 AR3 H1 LCMS (AM1): rt = 2.72 min, (425.2 [M+H]+), 99.80% purity. 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ 10.24 (brs, 1H), 8.25 (s, amino-3-methyl- 1H), 7.84 (brs, 1H), 7.74 (brs, 1H-pyrazolo[4,3- 1H), 7.41 - 7.37 (m, 1H), 7.31 - d]pyrimidin-1-yl)- 7.27 (m, 1H), 7.26 - 7.20 (m, 3-methylphenyl)- 2H), 6.82 (brs, 1H), 6.17 (brs, 2-(2,5- 1H), 5.39 (s, 1H), 2.47 (s, 3H), difluorophenyl)-2- 1.97 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 A11 AR4 H1 LCMS (AM1): rt = 2.99 min, (425.2 [M+H]+), 100% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.41 (s, 1H), 8.26 (s, 1H), 7.94 (dd, J = 12.8 Hz, 2.0 rac-N-(4-(7- Hz, 1H), 7.72 (d, J = 8.8 Hz, amino-3-methyl- 1H), 7.47 (t, J = 8.8 Hz, 1H), 1H-pyrazolo[4,3- 7.19 (s, 1H), 7.14 (d, J = 9.6 Hz, d]pyrimidin-1-yl)- 1H), 6.97 (d, J = 10.0 Hz, 1H), 3-fluorophenyl)-2- 6.72 (s, 1H), 6.55 (s, 2H), 5.15 (3-fluoro-5- (s, 1H), 2.46 (s, 3H), 2.33 (s, methylphenyl)-2- 3H) ppm. hydroxyacetamide Purification Method: PM27 A19 AR4 H1 LCMS (AM1): rt = 2.16 min, rac-N-(4-(7- (461.2 [M+H]+), 100% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.46 (brs, 1H), 8.26 (s, d]pyrimidin-1-yl)- 1H), 7.93 (dd, J = 12.8, 2.0 Hz, 3-fluorophenyl)-2- 1H), 7.71 (d, J = 8.8 Hz, 1H), (3,5- 7.58 (s, 3H), 7.48 (t, J = 8.6 Hz, dichlorophenyl)-2- 1H), 6.93 (brs, 1H), 6.55 (brs, hydroxyacetamide 2H), 5.24 (s, 1H), 2.46 (s, 3H) ppm. Purification Method: PM10 A18 AR4 H1 LCMS (AM1): rt = 3.05 min, (441.2 [M+H]+), 99.05% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.41 (brs, 1H), 8.26 (s, rac-N-(4-(7- 1H), 7.95 (dd, J = 2.0, 12.8 Hz, amino-3-methyl- 1H), 7.72 (dd, J = 1.2, 8.8 Hz, 1H-pyrazolo[4,3- 1H), 7.47 (t, J = 8.4 Hz, 1H), d]pyrimidin-1-yl)- 7.39 (s, 1H), 7.30 (s, 1H), 7.21 3-fluorophenyl)-2- (s, 1H), 6.73 (brs, 1H), 6.55 (brs, (3-chloro-5- 2H), 5.14 (s, 1H), 2.46 (s, 3H), methylphenyl)-2- 2.32 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 A18 AR2 H1 LCMS (AM1): rt = 3.10 min, (457.2 [M+H]+), 99.45% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.40 (s, 1H), 8.25 (s, rac-N-(4-(7- 1H), 8.17 (dd, J = 2.0, 16.8 Hz, amino-3-methyl- 1H), 7.91 - 7.84 (m, 1H), 7.53 1H-pyrazolo[4,3- (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), d]pyrimidin-1-yl)- 7.30 (s, 1H), 7.21 (s, 1H), 6.72 3-chlorophenyl)-2- (brs, 1H), 6.41 (brs, 2H), 5.14 (s, (3-chloro-5- 1H), 2.46 (s, 3H), 2.32 (s, 3H) methylphenyl)-2- ppm. hydroxyacetamide Purification Method: PM28 rac-N-(4-(7- A29 AR2 H1 LCMS (AM2): rt = 2.63 min, amino-3-methyl- (445.11 [M+H]+), 100% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.52 (brs, 1H), 8.25 (s, 3-chlorophenyl)-2- 1H), 8.18 (d, J = 8.8 Hz, 1H), (2,5- 7.88 (t, J = 8.8 Hz, 1H, 7.55 (d, difluorophenyl)-2- J = 8.8 Hz, 1H), 7.39 (m, 1H), hydroxyacetamide 7.29 - 7.23 (m, 2H), 6.94 (brs, 1H), 6.43 (brs, 1H), 5.40 (s, 1H), 2.47 (s, 3H) ppm. Purification Method: PM10 A4 AR2 H1 LCMS (AM1): rt = 2.17 min, (495.2 [M+H]+), 99.82% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 10.54 (s, 1H), 8.25 (s, 1H-pyrazolo[4,3- 1H), 8.16 (dd, J = 20.0, 2.4 Hz, d]pyrimidin-1-yl)- 1H), 7.90 – 7.83 (m, 1H), 7.78 3-chlorophenyl)-2- (s, 1H), 7.71 – 7.65 (m, 2H), (3-fluoro-5- 7.54 (d, J = 8.8 Hz, 1H), 7.09 (trifluoromethyl)p (brs, 1H), 6.42 (brs, 2H), 5.36 (s, henyl)-2- 1H), 2.46 (s, 3H) ppm. hydroxyacetamide Purification Method: PM5 A28 AR3 H1 LCMS (AM1): rt = 2.23 min, (491.2 [M+H]+), 99.87% purity. rac-N-(4-(7-1H NMR : (400 MHz, DMSO- amino-3-methyl- d6): δ 10.25 (s, 1H), 8.24 (s, 1H-pyrazolo[4,3- 1H), 7.90 (d, J = 16.2 Hz, 2H), d]pyrimidin-1-yl)- 7.80 – 7.75 (m, 2H), 7.73 – 7.71 3-methylphenyl)- (m, 1H), 7.28 (d, J = 8.8 Hz, 2-(3-chloro-5- 1H), 6.91 (d, J = 4.0 Hz, 1H), (trifluoromethyl)p 6.17 (brs, 2H), 5.32 (s, 1H), 2.50 henyl)-2- (s, 3H), 1.96 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 A21 AR2 H1 LCMS (AM1): rt = 3.22 min, (491.2 [M+H]+), 99.03% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 10.45 (s, 1H), 8.25 (s, 1H-pyrazolo[4,3- 1H), 8.17 (dd, J = 18.8, 2.4 Hz, d]pyrimidin-1-yl)- 1H), 7.91 – 7.85 (m, 1H), 7.70 3-chlorophenyl)-2- (s, 1H), 7.65 (s, 1H), 7.54 – 7.51 hydroxy-2-(3- (m, 2H), 6.82 – 6.79 (m, 1H), methyl-5- 6.41 (brs, 2H), 5.26 (d, J = 4.0 (trifluoromethyl)p Hz, 1H), 2.46 (s, 3H), 2.41 (s, henyl)acetamide 3H) ppm. Purification Method: PM5 A28 AR4 H1 LCMS (AM1): rt = 2.21 min, (495.2 [M+H]+), 99.90% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 10.50 (s, 1H), 8.26 (s, 1H-pyrazolo[4,3- 1H), 7.95 - 7.88 (m, 3H), , 7.84 d]pyrimidin-1-yl)- (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 3-fluorophenyl)-2- 7.48 (t, J = 8.7 Hz, 1H), 7.01 (d, (3-chloro-5- J = 4.8 Hz, 1H), 6.56 (brs, 2H), (trifluoromethyl)p 5.36 (d, J = 4.5 Hz, 1H) 2.46 (s, henyl)-2- 3H) ppm. hydroxyacetamide Purification Method: PM30 A28 AR2 H1 LCMS (AM1): rt = 3.37 min, rac-N-(4-(7- (511.2 [M+H]+), 99.64% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.51 (brs, 1H), 8.24 (s, d]pyrimidin-1-yl)- 1H), 8.18 (dd, J = 2.4 Hz, 1H), 3-chlorophenyl)-2- 7.91 – 7.82 (m, 4H), 7.53 (d, J (3-chloro-5- = 8.8 Hz, 1H), 7.04 (brs, 1H), (trifluoromethyl)p 6.46 (brs, 2H), 5.36 (s, 1H), 2.46 henyl)-2- (s, 3H) ppm. hydroxyacetamide Purification Method: PM30 A15 AR3 H1 LCMS (AM1): rt = 2.46 min, (425.4 [M+H]+), 99.64% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 10.26 (brs, 1H), 8.25 (s, 1H-pyrazolo[4,3- 1H), 7.85 (brs 1H), 7.76 (brs, d]pyrimidin-1-yl)- 1H), 7.38 - 7.37 (m, 2H), 7.31 - 3-methylphenyl)- 7.25 (m, 2H), 6.88 (brs, 1H), 2-(2,3- 6.20 (brs, 2H), 5.44 (s, 1H), 2.47 difluorophenyl)-2- (s, 3H), 1.97 (s, 3H) ppm. hydroxyacetamide Purification Method: PM10 rac-N-(4-(7- A21 AR4 H1 amino-3-methyl- LCMS (AM2): rt = 2.96 min, 1H-pyrazolo[4,3- (475.18 [M+H]+), 99.36% d]pyrimidin-1-yl)- purity. 3-fluorophenyl)-2-1H NMR (400 MHz, DMSO- hydroxy-2-(3- d6): δ 10.46 (brs, 1H), 8.26 (s, methyl-5- 1H), 7.94 (dd, J = 12.7, 2.2 Hz, (trifluoromethyl)p 1H), 7.72 – 7.70 (m, 2H), 7.65 henyl)acetamide (s, 1H), 7.51 (s, 1H), 7.47 (t, J = 8.8 Hz, 1H), 6.81 (s, 1H), 6.55 (brs, 2H), 5.26 (s, 1H), 2.46 (s, 3H).2.41 (s, 3H) ppm. Purification Method: PM31 A30 AR3 H1 LCMS (AM2): rt = 2.69 min, rac-N-(4-(7- (455.19 [M+H]+), 100% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.17 (s, 1H), 8.25 (s, d]pyrimidin-1-yl)- 1H), 7.82 (d, J = 4.4 Hz, 1H), 3-methylphenyl)- 7.75 - 7.74 (m, 1H), 7.45 – 7.04 2-(3- (m, 6H), 6.64 (brs, 1H), 6.17 (difluoromethoxy) (brs, 2H), 5.18 (s, 1H), 2.47 (s, phenyl)-2- 3H), 1.96 (s, 3H) ppm. hydroxyacetamide Purification Method: PM32 A3 AR5 H1 LCMS (AM2): rt = 2.89 min, (463.12 [M+H]+), 98.44% rac-N-(4-(7- purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.08 (s, 1H), 8.29 (s, d]pyrimidin-1-yl)- 1H), 7.82 - 7.78 (m, 1H), 7.48 2,3- (s, 1H), 7.41 - 7.35 (m, 2H), difluorophenyl)-2- 7.30 - 7.26 (m, 1H), 6.93 (brs, (3-chloro-5- 1H), 6.78 (brs, 2H), 5.36 (s, 1H), fluorophenyl)-2- 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM33 rac-N-(4-(7- A17 AR5 H1 LCMS (AM1): rt = 2.17 min, amino-3-methyl- (513.3 [M+H]+), 99.89% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.12 (s, 1H), 8.29 (s, 2,3- 1H), 7.80 – 7.76 (m, 1H), 7.46 – difluorophenyl)-2- 7.43 (m, 2H), 7.36 (d, J = 8.8 (3-fluoro-5- Hz, 1H), 7.28 (t, J = 7.6 Hz, (trifluoromethoxy) 1H), 6.99 (s, 1H), 6.79 (brs, 2H), phenyl)-2- 5.42 (s, 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM28 rac-N-(4-(7- A28 AR5 H1 LCMS (AM1): rt = 2.26 min, amino-3-methyl- (513.2 [M+H]+), 99.87% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.16 (s, 1H), 8.29 (s, 2,3- 1H), 7.92 (s, 1H), 7.89 (s, 1H), difluorophenyl)-2- 7.85 (s, 1H), 7.78 (t, J = 7.6 Hz, (3-chloro-5- 1H), 7.28 (t, J = 7.6 Hz, 1H), (trifluoromethyl)p 7.03 (s, 1H), 6.79 (s, 2H), 5.47 henyl)-2- (s, 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM28 A11 AR5 H1 LCMS (AM1): rt = 3.03 min, (443.2 [M+H]+), 98.44% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO- amino-3-methyl- d6): δ 9.98 (s, 1H), 8.29 (s, 1H), 1H-pyrazolo[4,3- 7.84 (t, J = 7.2 Hz, 1H), 7.28 (t, d]pyrimidin-1-yl)- J = 7.2 Hz, 1H), 7.20 (s, 1H), 2,3- 7.14 (d, J = 9.6 Hz, 1H), 6.98 (d, difluorophenyl)-2- J = 9.6 Hz, 1H), 6.77 (brs, 2H), (3-fluoro-5- 5.26 (s, 1H), 2.47 (s, 3H), 2.33 methylphenyl)-2- (s, 3H) ppm. hydroxyacetamide Purification Method: PM18 A18 AR5 H1 LCMS (AM1): rt = 3.18 min, rac-N-(4-(7- (459.2 [M+H]+), 100% purity. amino-3-methyl-1H NMR (400 MHz, DMSO- 1H-pyrazolo[4,3- d6): δ 10.00 (s, 1H), 8.29 (s, d]pyrimidin-1-yl)- 1H), 7.84 (t, J = 7.8 Hz, 1H), 2,3- 7.39 (s, 1H), 7.31 – 7.26 (m, difluorophenyl)-2- 2H), 7.22 (s, 1H), 6.78 (s, 3H), (3-chloro-5- 5.27 (s, 1H), 2.47 (s, 3H), 2.33 methylphenyl)-2- (s, 3H) ppm. hydroxyacetamide Purification Method: PM34 A19 AR5 H1 LCMS (AM2): rt = 3.00 min, rac-N-(4-(7- (479.18 [M+H]+), 99.23% amino-3-methyl- purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.10 (brs, 1H), 8.29 (s, 2,3- 1H), 7.81 (brs, 1H), 7.58 (s, 3H), difluorophenyl)-2- 7.28 (t, J = 7.4 Hz, 1H), 6.93 (3,5- (brs, 1H), 6.78 (brs, 2H), 5.36 (s, dichlorophenyl)-2- 1H), 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM22 A10 AR5 H1 LCMS (AM1): rt= 2.94 min, (425.2 [M+H]+), 99.86% purity. rac-N-(4-(7-1H NMR (400 MHz, DMSO-d6) amino-3-methyl- δ: 9.91 (s, 1 H), 8.29 (s, 1H), 1H-pyrazolo[4,3- 7.90 – 7.85 (m, 1H), 7.33 – 7.24 d]pyrimidin-1-yl)- (m, 4H), 7.11 (d, J = 7.2Hz, 2,3- 1H), 6.79 (brs, 1H), 6.65 (brs, difluorophenyl)-2- 1H), 5.23 (s, 1H), 2.47 (s, 3H), hydroxy-2-(m- 2.32 (s, 3H) ppm. tolyl)acetamide Purification Method: PM15 rac-N-(4-(7- A4 AR5 H1 LCMS (AM2): rt = 2.91 min, amino-3-methyl- (497.4 [M+H]+), 100% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.15 (s, 1H), 8.29 (s, 2,3- 1H), 7.79 – 7.76 (m, 2H), 7.71 – difluorophenyl)-2- 7.65 (m, 2H), 7.28 (t, J = 8 Hz, (3-fluoro-5- 1H), 7.02 (brs, 1H), 6.79 (brs, (trifluoromethyl)p 2H), 5.48 (d, J = 4.4 Hz, 1H), henyl)-2- 2.47 (s, 3H) ppm. hydroxyacetamide Purification Method: PM35 rac-N-(4-(7- A20 AR2 H1 LCMS (AM1): rt = 2.06 min, amino-3-methyl- (507.2 [M+H]+), 100% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.46 (s, 1H), 8.24 (s, 3-chlorophenyl)-2- 1H), 8.16 (dd, J = 16.7, 2.3 Hz, hydroxy-2-(3- 1H), 7.90 - 7.83 (m, 1H), 7.53 methoxy-5- (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), (trifluoromethyl)p 7.41 (s, 1H), 7.19 (s, 1H), 6.86 henyl)acetamide (brs, 1H), 6.41 (brs, 2H), 5.27 (s, 1H), 3.85 (s, 3H), 2.46 (s, 3H) ppm. Purification Method: PM15 rac-N-(4-(7- A21 AR5 H1 LCMS (AM1): rt = 2.17 min, amino-3-methyl- (493.2 [M+H]+), 99.74% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.07(s, 1H), 8.29 (s, 1H), 2,3- 7.84 - 7.80 (m, 1H), 7.69 (s,1H), difluorophenyl)-2- 7.65 (s, 1H), 7.52 (s, 1H), 7.29 - hydroxy-2-(3- 7.26 (m, 1H), 6.86 (brs, 1H), methyl-5- 6.79 (brs, 1H), 5.38 (s, 1H), 2.47 (trifluoromethyl)p (s, 3H), 2.41 (s, 3H) ppm. henyl)acetamide Purification Method: PM15 A22 AR2 H1 LCMS (AM1): rt= 3.06 min, (471.0 [M-H]-), 99.24% purity. 1H NMR (400 MHz, DMSO- d6): δ 10.40 (s, 1H), 8.24 (s, 1H), 8.18-8.14 (dd, J = 2.12, rac-N-(4-(7- 14.5 Hz, 1H), 7.89 -7.84 (m, amino-3-methyl- 1H), 7.54-7.52 (d, J = 8.4 Hz, 1H-pyrazolo[4,3- 1H), 7.17 (s, 1H), 7.09 (s, 1H), d]pyrimidin-1-yl)- 6.98-6.97 (m, 1H), 6.75-6.72 (m, 3-chlorophenyl)-2- 1H), 6.41 (m,2H), 5.16-5.15 (d, (3-chloro-5- J = 4.12 Hz, 1H),3.78(s, 3H), methoxyphenyl)-2- 2.46 (s, 3H) ppm. hydroxyacetamide Purification Method: PM36 rac-N-(4-(7- A3 AR1 H1 LCMS (AM1): rt = 2.09 min, amino-3-methyl- (463.1 [M+H]+), 100% purity. 1H-pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 9.95 (s, 1H), 8.28 (s, 1H), 2,5- 8.10 (dd, J = 11.7, 6.9 Hz, 1H), difluorophenyl)-2- 7.65 (dd, J = 10.7, 7.0 Hz, 1H), (3-chloro-5- 7.47 (s, 1H), 7.41-7.35 (m, 2H), fluorophenyl)-2- 6.98 (s, 2H), 5.38 (s, 1H), 2.46 hydroxyacetamide (s, 3H) ppm. Purification Method: PM37 rac-N-(4-(7- A4 AR1 H1 amino-3-methyl- LCMS (AM1): rt = 2.18 min, 1H-pyrazolo[4,3- (497.2 [M+H]+), 99.6% purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 2,5- d6): δ = 10.04 (brs, 1H), 8.28 (s, difluorophenyl)-2- 1H), 8.05 - 8.09 (m, 1H), 7.78 (3-fluoro-5- (s, 1H), 7.71 - 7.63 (m, 3H), (trifluoromethyl)p 7.06 (brs, 1H), 6.76 (brs, 2H), henyl)-2- 5.50 (s, 1H), 2.46 (s, 3H) ppm. hydroxyacetamide Purification Method: PM59 A5 AR5 H2 LCMS (AM2): rt = 2.71 min, rac-N-(4-(7- (493.4 [M+H]+), 96.0% purity. amino-3,5-1H NMR (400 MHz, DMSO- dimethyl-1H- d6): δ 10.09 (s, 1H), 7.90 (s, pyrazolo[4,3- 1H), 7.86 – 7.77 (m, 2H), 7.71 – d]pyrimidin-1-yl)- 7.62 (m, 2H), 7.23 (t, J = 7.8 2,3- Hz, 1H), 6.90 (d, J = 4.8 Hz, difluorophenyl)-2- 1H), 6.69 (brs, 2H), 5.43 (d, J = hydroxy-2-(3- 4.8 Hz, 1H), 2.44 (s, 3H), 2.43 (trifluoromethyl)p (s, 3H) ppm. henyl)acetamide Purification Method: PM24 rac-N-(4-(7- A4 AR5 H2 amino-3,5- dimethyl-1H- LCMS (AM1): rt = 2.19 min, pyrazolo[4,3- (509.0 [M-H]-), 99.20% purity. d]pyrimidin-1-yl)-1H NMR (400 MHz, DMSO- 2,3- d6): δ 10.13 (s, 1H), 7.78 - 7.74 difluorophenyl)-2- (m, 2H), 7.70 - 7.64 (m, 2H), (3-fluoro-5- 7.27 - 7.22 (m, 1H), 7.02 (brs, (trifluoromethyl)p 1H), 6.69 (brs, 2H), 5.46 (s, 1H), henyl)-2- 2.43 (m, 6H) ppm. hydroxyacetamide Purification Method: PM38 A5 AR4 H2 LCMS (AM1): rt = 2.18 min, (475.2 [M+H]+), 97.86% purity 1H NMR (400 MHz, DMSO- rac-N-(4-(7- d6): δ = 10.47 (brs, 1H), 7.94 (d, amino-3,5- J = 1.6 Hz, 2H), 7.84 (d, J = 7.6 dimethyl-1H- Hz, 1H), 7.71 - 7.62 (m, 2H), pyrazolo[4,3- 7.62 - 7.60 (m, 1H), 7.41 - 7.46 d]pyrimidin-1-yl)- (m, 1H), 6.85 (d, J = 4 Hz, 1H), 3-fluorophenyl)-2- 6.45 (brs, 2H), 5.31 (d, J = 1 Hz, hydroxy-2-(3- 1H), 2.43 (s, 3H), 2.42 (s, 3H) (trifluoromethyl)p ppm. henyl)acetamide Purification Method: PM60 A4 AR4 H2 LCMS (AM2): rt = 2.76 min, rac-N-(4-(7- (493.4 [M+H]+), 98.73% purity. amino-3,5-1H NMR (400 MHz, DMSO- dimethyl-1H- d6): δ 10.48 (s, 1H), 7.92 (dd, J pyrazolo[4,3- = 12.8, 2.8 Hz, 1H), 7.78 (s, d]pyrimidin-1-yl)- 1H), 7.70 – 7.65 (m, 3H), 7.45 3-fluorophenyl)-2- (t, J = 8.6 Hz, 1H), 7.00 (d, J = (3-fluoro-5- 4.8 Hz, 1H), 6.47 (brs, 2H), 5.36 (trifluoromethyl)p (d, J = 4.4 Hz, 1H), 2.44 (s, 3H), henyl)-2- 2.43 (s, 3H) ppm. hydroxyacetamide Purification Method: PM39 rac-N-(4-(7- A2 AR5 H2 LCMS (AM2): rt = 2.63 min, amino-3,5- (461.16 [M+H]+), 98.21% dimethyl-1H- purity. pyrazolo[4,3-1H NMR (400 MHz, DMSO- d]pyrimidin-1-yl)- d6): δ 10.05 (brs, 1H), 7.82 - 2,3- 7.76 (m, 1H), 7.26 - 7.16 (m, difluorophenyl)-2- 4H), 6.96 (brs, 1H), 6.69 (brs, (3,5- 2H), 5.36 (d, J = 4.8 Hz, 1H), difluorophenyl)-2- 2.43 (s, 3H), 2.45 (s, 3H) ppm. hydroxyacetamide Purification Method: PM30 rac-N-(4-(7- A6 AR5 H2 amino-3,5- LCMS (AM2): rt = 2.80 min, dimethyl-1H- (509.4 [M+H]+), 97.56% purity. pyrazolo[4,3-1H NMR (400 MHz, DMS...

Claims

Claimsor (b) is a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, wherein: - X is selected from C(R4E) and N; - R1 is selected from hydrogen, methyl, NH2 and NHCH3; - R2 is selected from: (a) C1-C6 alkyl, (b) hydrogen, (c) -(CH2)n-N(RN)2 in which n is an integer selected from 0 to 6 and each RNis independently selected from hydrogen and C1-C6alkyl, (d) -(CH2)m-(C3-C6cycloalkyl) in which m is an integer selected from 0 to 6, and (e) -(CH2)p-(4- to 7-membered heterocyclyl) in which p is an integer selected from 0 to 6; in which groups (a) and (c) are optionally substituted with at least one R2aand in which groups (d) and (e) are optionally substituted with at least one R2b; - each instance of R2a is independently selected from F, OH and methoxy, provided that any single carbon atom is substituted with no more than one group selected from OH and methoxy;- each instance of R2b is independently selected from F, OH, methoxy, methyl and =O, provided that any single carbon atom is substituted with no more than one group selected from OH and methoxy; - R3A, R3B, R3C and R3D are independently selected from hydrogen, F, Cl, and methyl; and - R4A, R4B, R4C, R4Dand R4Eare independently selected from hydrogen, F, Cl, Br, CN, C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy, hydroxy-C1-C3 alkyl, and O- cyclopropyl, wherein the C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy, hydroxy-C1-C3 alkyl and O-cyclopropyl are optionally substituted with at least one F.

2. The compound according to claim 1, wherein X is C(R4E).

3. The compound according to claim 1 or 2, wherein R1is hydrogen or methyl.

4. The compound according to claim 3, wherein R1is hydrogen.

5. The compound according to any one of the preceding claims, wherein R2is methyl.

6. The compound according to any one of the preceding claims, which (a) is of formula (Ia):or (b) is a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof.

7. The compound according to any one of the preceding claims, wherein R3A is selected from F, Cl, and methyl.

8. The compound according to any one of the preceding claims, wherein at least two of R3A, R3B, R3C and R3D are hydrogen.

9. The compound according to any one of claims 1 to 6, wherein: - R3A is selected from F, Cl, and methyl; - one of R3B and R3C is hydrogen, and the other of R3B and R3C is selected from hydrogen, F, Cl, and methyl; and - R3Dis hydrogen.

10. The compound according to claim 9, wherein one of R3Band R3Cis hydrogen, and the other of R3Band R3Cis selected from hydrogen and F.

11. The compound according to any one of the preceding claims, wherein R4B, R4C, R4D and R4Eare independently selected from hydrogen, F, Cl, CN, C1-C3alkyl, C1-C3alkoxy and hydroxy-C1-C3 alkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy and hydroxy-C1-C3 alkyl are optionally substituted with at least one F.

12. The compound according to any one of the preceding claims, wherein at most one of R4B, R4C, R4D and R4E is a group other than hydrogen.

13. The compound according to any one of the preceding claims, wherein R4Ais selected from F, Cl, methyl, cyclopropyl and methoxy, wherein the methyl, cyclopropyl and methoxy are optionally substituted with at least one F.

14. The compound according to any one of claims 1 to 10, wherein: - R4A is selected from F, Cl, methyl, cyclopropyl and methoxy, wherein the methyl, cyclopropyl and methoxy are optionally substituted with at least one F; - X is C(R4E); and- either (a) all of R4B, R4C, R4D and R4E are hydrogen, or (b) three of R4B, R4C, R4D and R4Eare hydrogen and the remaining one of R4B, R4C, R4Dand R4Eis selected from F, Cl, CN, C1-C3 alkyl, C1-C3 alkoxy and hydroxy-C1-C3 alkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy and hydroxy-C1-C3 alkyl are optionally substituted with at least one F.

15. The compound according to claim 14, wherein: - R4A is selected from F, Cl, CF3, CHF2, OCF3 and OCHF2; - R4B, R4Dand R4Eare hydrogen; and - R4C is selected from hydrogen, F, Cl, CF3, CHF2, OCF3 and OCHF2.

16. The compound according to claim 15, wherein: - R4Ais selected from F, Cl, CF3and OCF3; and - R4C is selected from hydrogen and F.

17. The compound according to claim 1, wherein the formula (I) is selected from: N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluoro-phenyl]-2-(3,5- difluorophenyl)-2-hydroxy-acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-hydroxy-2- (3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methyl-phenyl]-2-(3,5- difluorophenyl)-2-hydroxy-acetamide;N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-hydroxy- 2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-fluoro- 5-(trifluoromethyl)phenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3-chloro- 5-fluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; and N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide.

18. The compound according to claim 6, wherein the formula (Ia) is selected from:(2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluoro-phenyl]-2- (3,5-difluorophenyl)-2-hydroxy-acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-[4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methyl-phenyl]-2- (3,5-difluorophenyl)-2-hydroxy-acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- (3,5-difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyacetamide;(2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-methylphenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2-(3- chloro-5-fluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-chlorophenyl)-2-(3,5- difluorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)-2- (3-chlorophenyl)-2-hydroxyacetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethyl)phenyl)acetamide; (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3-fluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; (2R)-N-(4-(7-amino-3-methyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,5-difluorophenyl)-2- hydroxy-2-(3-(trifluoromethoxy)phenyl)acetamide; and (2R)-N-(4-(7-amino-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-2,3-difluorophenyl)- 2-(3-chlorophenyl)-2-hydroxyacetamide.

19. A pharmaceutical composition comprising a compound according to any one of the preceding claims in association with one or more pharmaceutically acceptable carriers.

20. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use as a medicament.

21. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in a method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity.

22. The use of a compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for the manufacture of a medicament for use in a method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity.

23. A method of treating and / or preventing a disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity in a patient, the method comprisingadministering a compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, to the patient.

24. The compound or pharmaceutical composition for use according to claim 21, use according to claim 22, or method according to claim 23, wherein the disease associated with dysregulated protein kinase RNA-like ER kinase (PERK) activity is selected from cancers, cellular proliferative disorders, viral infections, autoimmune and neurodegenerative disorders, pre-cancerous syndromes, ocular diseases, Type 1 diabetes, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, obesity, and inflammatory diseases.

25. The compound or pharmaceutical composition for use, use, or method according to claim 24, wherein the disease is cancer.

Images