TYK2 inhibitors

Abstract

This disclosure relates to compounds of formula (I), or pharmaceutically acceptable salts thereof: Formula (i); in which all of the variables are as defined in the application. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The disclosure further provides methods of preparing the compounds of the disclosure, and methods for their therapeutic use.

Description

[0001] TYK2 INHIBITORS RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 599,185, filed on November 15, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference. TECHNICAL FIELD Provided are certain agents that target the inhibition of Tyrosine kinase 2 (TYK2), and methods of making and using such agents BACKGROUND Cytokines are small secreted proteins released by cells and have a specific effect on the interactions and communications between cells. Cytokine pathways mediate a broad range of biological functions including many aspects of inflammation and immunity through mostly extracellular signaling. Tyrosine kinase 2 (TYK2) is a member of Janus kinases (JAK) that are cytoplasmic protein kinases associated with cytokine receptors and play a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; and Yamaoka et al. Genome Biology 2004, 5, 253). The JAK family also includes JAK1, JAK2 and JAK3. More specifically, cytokine’s engagement with cognate receptors triggers activation of receptors associate with JAK, which leads to JAK mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately transcriptional activation of specific gene sets (Schindler et al, 2007, J. Biol. Chem.282: 20059-63). Numerous cytokines known to activate the JAK family include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN- omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp) 130 family (IL-6, IL-11, OSM, LlF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), the gamma C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), the single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupled receptors (AT1). TYK2 is important in the signaling of the type I interferons (e.g., IFN-alpha), IL-6, IL-10, IL-12 and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18,5, 571-580; Kisseleva et al., 2002, Gene 285:1-24; and Watford, W.T. & O’Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL-10, IL-12 and IL-23 signaling. TYK2 signals with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2. Studies have shown that inappropriate JAK activities can arise from mutation, over- expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines, and therefore trigger a variety of biological cellular responses relating to cell growth, cell differentiation, cell function, survival, apoptosis, and cell mobility. The inappropriate JAK activities are implicated in many diseases that include but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. To date, all known small molecule JAK inhibitors that have progressed into development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (also referred to as the JH1 or Janus Homology 1 domain) of the JAK protein, which prevents catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signal transduction (Bryan et al., J. Med. Chem.2018, 61, 9030−9058). Because of the high homology of the ATP active site across the kinome and especially within the JAK family, it is a significant challenge to achieve high selectivity for a specific JAK family member while also maintaining selectivity within the kinome. As a result, many JAK inhibitors that have been developed are pan-JAK inhibitors or are modestly selective for one or more JAK family members. While these inhibitors have shown encouraging results in treating autoimmune diseases, undesirable side effects leading to a narrow therapeutic index have been observed and suggest the need for improved treatments. TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory disease and autoimmune disease including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory conditions. There remains a need for potent compounds that demonstrate high selectivity for TYK2 over other members of the JAK family. SUMMARY In a first aspect, the present disclosure relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R1is C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, -C(O)R1c, -SO2R1c, phenyl, 5-or 6- membered monocyclic heteroaryl, or 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein the C1-6alkyl and C2-6alkenyl are each optionally substituted by one or more R1a, and wherein the C3-10cycloalkyl, phenyl, 5-or 6-membered monocyclic heteroaryl, and 4- to 10- membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R1b; each R1ais, independently, halo, cyano, OR1d, C3-6cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, halo, C1-3alkyl, C1-3alkyl-C1-3alkoxy, -OH, -NH2, -N(C1-3alkyl)2, C1-3alkoxy, C1-3haloalkoxy, -C(O)R1c, or cyano; R1cis H, C1-3alkyl, C1-3haloalkyl, –OH, C1-3alkoxy, or C3-6cycloalkyl; R1dis H, C1-3haloalkyl, or C1-3alkyl optionally substituted by phenyl; R2is H, -OR2a, C1-3alkyl, C3-6cycloalkyl, or C1-3haloalkyl, wherein the C1-3alkyl is optionally substituted by OR2a,cyano, or C3-4cycloalkyl; each R2ais, independently, H, C1-3alkyl, or C1-3haloalkyl; Ring A is 5- or 6-membered monocyclic heteroaryl substituted by 1 to 3 R3; each R3is, independently, C1-6alkyl, C1-6haloalkyl, cyano, -C(O)R3b, -OR3a, -N(R3c)2, C3-6cycloalkyl, 4- to 10- membered monocyclic or bicyclic heterocyclyl, phenyl, or 5- to 6- membered monocyclic heteroaryl, wherein the C1-6alkyl and C1-6haloalkyl are each optionally substituted by one or more R4, and wherein the C3-6cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl, phenyl, and 5- or 6-membered monocyclic heteroaryl are each optionally substituted by one or more R5; R3ais, independently, C1-3alkyl, C1-3haloalkyl, C1-3alkyl-C1-3alkoxy, C3-6cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R5; R3bis H, C1-3alkyl, C1-3haloalkyl, -OH, or C1-3alkoxy; each R3cis, independently, H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyC1-3alkyl, or C3-6cycloalkyl, wherein the C3-6cycloalkyl is optionally substituted by one or more R5; each R4is, independently, C1-3alkoxy, or –OH; and each R5is, independently, cyano, C1-3alkyl, C1-3haloalkyl, halo, C1-3alkoxy, or –OH. provided that: (i) when the 4- to 10-membered monocyclic or bicyclic heterocyclyl represented by R3is substituted then Ring A is a 5-membered monocyclic heteroaryl; (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl; (iii) when R3is a cyano substituted cyclopropyl then ring A is pyrimidinyl. In one aspect, the present disclosure is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some aspects, the present disclosure is a method of treating a disease or disorder responsive to inhibition of TYK2 in a subject comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. The present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition described herein, for the manufacture of a medicament for inhibiting TYK2 activity. Also included is the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition described herein, for the manufacture of a medicament for treating a disease or disorder responsive to inhibition of TYK2. The disclosure also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in inhibiting TYK2 activity. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease or disorder responsive to inhibition of TYK2. In some aspects, the compounds of the present disclosure have low efflux ratio, especially in comparison to similar compounds known in the art. Compounds with low efflux ratios may have good brain penetrant properties and are suitable for treating CNS disorders. Other features or advantages will be apparent from the following detailed description of several embodiments, and also from the appended claims. DETAILED DESCRIPTION The compounds or pharmaceutically acceptable salts thereof described herein demonstrate high potency against TYK2. In addition, the compounds or pharmaceutically acceptable salts thereof of the present disclosure have high selectivity for inhibiting TYK2 over other members of JAK family, such as JAK1 and JAK2. I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the relevant art. The termsa and an do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g.,such as), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. As used herein, the term alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, the alkyl comprises 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, an alkyl comprises from 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl. When indicated as being optionally substituted, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls). As used herein, the term alkoxy refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a --O-- C1-4 alkyl group wherein C1-4 alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like. Preferably, alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons. As used herein the term alkoxy-alkly (i.e. C1-3alkoxyC1-3alkyl) refers to an alkyl group substituted with an alkoxy group. As used herein, the number of carbon atoms in a group is specified herein by the prefix Cx-xx, wherein x and xx are integers. For example, C1-4 alkyl is an alkyl group which has from 1 to 4 carbon atoms As used herein, the term aryl refers to a carbocyclic (all carbon) aromatic monocyclic or bicyclic ring system containing 6-10 carbon atoms. Examples of 6-10 membered aryl groups include phenyl and naphthyl. In some embodiments, the aryl is phenyl. The term cycloalkyl refers to completely saturated monocyclic or bicyclic or spiro hydrocarbon groups of 3-7 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms. In some embodiments, cycloalkyl is a 3- to 6-membered monocyclic cycloalkyl. As used herein, the terms carbocycle, carbocyclyl and carbocyclic ring refer to saturated or partially unsaturated (i.e., non-aromatic) monocyclic or bicyclic hydrocarbon groups of, for example, 3-10, 3-8, 3-7, 3-5, 3-6, 4-6, 5-7 or 7-10 carbon atoms. Halogen or halo may be fluoro, chloro, bromo or iodo. As used herein, the term haloalkyl or halo-substituted alkyl or refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The haloalkyl group can be monohalo-alkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhaloalkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl group refers to an alkyl group having all hydrogen atoms replaced with halo atoms. As used herein, the term heteroaryl refers to an aromatic 5- to 6-membered monocyclic or an 8- to 10- membered bicyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Examples of 5- to 6- membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, and the like. Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to, imidazolthiazolyl, imidazopyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2^2-isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl and thieno[3,2-b]pyridinyl. As used herein, the term heterocyclyl refers to a saturated or unsaturated, monocyclic or bicyclic (e.g., fused, bridged or spiro ring systems) ring system which has from 3- to 14- ring members, or in particular 3- to 8-ring members, 3- to 7-ring members, 3- to 6- ring members, 5- to 7- ring members, 4- to 10-ring members, 4- to 7- ring members or 4- to 6-ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. The heterocyclyl group can be attached to the rest of a compound of the invention at a heteroatom or a carbon atom. The term azacyclic refers to a non-aromatic heterocyclyl, which has at least one nitrogen ring atom. The examples of azacyclic include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and morpholine. Fully saturated heterocyclyl groups include heterocycloalkyl groups. Examples of 3- to 7-membered monocyclic heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, thirranyl, oxaziridinyl, oxazepanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. In one embodiment, a heterocyclyl is a 5-to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated). Examples include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, oxazepanyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. In one embodiment, a heterocyclyl is a 4 to 6-membered saturated monocyclic heterocyclyl. Examples include, but are not limited to, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, and piperdinyl. In one embodiment, a heterocyclyl is a 5- or 6-membered saturated monocyclic or bicyclic heterocyclyl. Examples include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, and 2- oxabicyclo[2.1.1]hexanyl. The term bicyclic heterocycle refers to a bicyclic ring which is partially or fully saturated and contains 1 to 2 heteroatoms, independently selected from sulfur, oxygen and / or nitrogen. The term partially or fully saturated heterocycle refers to a nonaromatic ring that is either partially or fully saturated and may exist as a single ring, bicyclic ring (including fused heterocyclic rings) or a spiro ring. Unless specified otherwise, the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. As used herein Hydroxyl or Hydroxy refers to the group -OH. The term fused ring system, as used herein, is a ring system that has two ring structures sharing two adjacent ring atoms. In one embodiment, a fused ring system have from 8 to 12 ring members. The term bridged ring system, as used herein, is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, and S. In one embodiment, a bridged ring system have from 6 to 8 ring members. The term spiro ring system, as used herein, is a ring system that has two ring structures having one ring atom in common. In one embodiment, spiro ring systems have from 5 to 8 ring members. As used herein, the phrase optionally substituted is used interchangeably with the phrase substituted or unsubstituted. In general the term optionally substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. The term oxo (=O) refers to an oxygen atom connected to a carbon or sulfur atom by a double bond. Examples include carbonyl, sulfinyl, or sulfonyl groups (--C(O)--, --S(O)-- or --S(O)2--) such as, a ketone, aldehyde, or part of an acid, ester, amide, lactone, or lactam group and the like. Unless specified otherwise, the term compounds of the present disclosure refers to compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), or (IIe-1) as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts. Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967- 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). The protection of functional groups by protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999, in The Peptides; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in Methoden der organischen Chemie (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, and in H.-D. Jakubke and H. Jeschkeit, Aminosauren, Peptide, Proteine (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by enzymatic cleavage). The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms salt or salts refers to an acid addition or base addition salt of a compound of the disclosure. Salts include in particular pharmaceutical acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Salts of compounds of the present disclosure having at least one salt-forming group may be prepared in a manner known to those skilled in the art. For example, acid addition salts of compounds of the present disclosure are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Salts can be converted into the free compounds in accordance with methods known to those skilled in the art. Acid addition salts can be converted, for example, by treatment with a suitable basic agent. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfornate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). In some embodiments, the disclosure provides deuterated compounds in which any or more positions occupied by hydrogen can include enrichment by deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions at its natural abundance. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term an optical isomer or a stereoisomer refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization. For those compounds containing an asymmetric carbon atom, the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures. Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a commercially available chiral HPLC column. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In accordance with the present disclosure any structure that does not designate the stereochemistry is to be understood as embracing all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase). In some embodiment, the compounds described herein are isolated stereoisomers wherein each of the compounds has one stereocenter and the stereoisomer is in the R configuration. In other embodiment, the compounds described herein are isolated stereoisomers wherein each of the compounds has one stereocenter and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers wherein each of the compounds has two stereocenters and the stereoisomer is in the R R configuration. In one embodiment, the compounds described herein are isolated stereoisomers wherein each of the compounds has two stereocenters and the stereoisomer is in the R S configuration. In one embodiment, the compounds described herein are isolated stereoisomers stereoisomer wherein each of the compounds has two stereocenters and the stereoisomer is in the S R configuration. In one embodiment, the compounds described herein are isolated stereoisomers stereoisomer wherein each of the compounds has two stereocenters and the stereoisomer is in the S S configuration. In one embodiment, the compounds described herein each have one or two stereocenters and are racemic mixtures. When a particular stereoisomer of a compound is depicted by name or structure, the stereochemical purity^ of the compounds is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. Stereochemical purity means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer). It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms. As used herein, the term an optical isomer or a stereoisomer refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound. Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present disclosure, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)); a single stereoisomer with known relative configuration but unknown absolute configuration is designated with stars (e.g., (1R*,2R*)); and a racemate with two letters (e.g, (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)). Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers / diastereomers via chiral HPLC. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless specified otherwise, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAKRTMand CHIRALCELRTMavailable from DAICEL Corp. using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included. The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. All such forms are embraced within the scope of the disclosure. In addition, some compounds may exhibit polymorphism. The term tautomer or tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine- enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. II. COMPOUNDS OF THE DISCLOSURE In a first embodiment, the compound of the present disclosure is represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables are as described in the first aspect above. In an alternative first embodiment, the compound of the present disclosure is represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R1is C1-3alkyl, C3-6cycloalkyl, -C(O)R1c, -SO2R1c, phenyl, 5-or 6-membered monocyclic heteroaryl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C1-3alkyl is optionally substituted by one or more R1a, and wherein the C3-6cycloalkyl, phenyl, 5-or 6- membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R1b; each R1ais, independently, halo, cyano, C1-3alkoxy, or –OH; each R1bis, independently, halo, C1-3alkyl, -OH, -NH2, -N(C1-3alkyl)2, C1-3alkoxy, - C(O)R1c, or cyano; R1cis H, C1-3alkyl, C1-3haloalkyl, –OH, or C1-3alkoxy; R2is H, -OR2a, C1-3alkyl or C1-3haloalkyl; each R2ais, independently, H, C1-3alkyl, or C1-3haloalkyl; Ring A is 5- or 6-membered monocyclic heteroaryl substituted by 1 to 3 R3; each R3is, independently, C1-6alkyl, C1-6haloalkyl, cyano, -C(O)R3b, -OR3a, -N(R3c)2, C3-6cycloalkyl, 4- to 10- membered monocyclic or bicyclic heterocyclyl, phenyl, or 5- to 6- membered monocyclic heteroaryl, wherein the C1-6alkyl is optionally substituted by one or more R4, the C3-6cycloalkyl is optionally substituted by one or more halo, and the 4- to 10- membered monocyclic or bicyclic heterocyclyl, phenyl, and 5- or 6-membered monocyclic heteroaryl are each optionally substituted by one or more R5; each R3ais, independently, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; R3bis H, C1-3alkyl, C1-3haloalkyl, –OH, or C1-3alkoxy; each R3cis, independently, H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; each R4is, independently, C1-3alkoxy, or –OH; and each R5is, independently, C1-3allkyl, C1-3haloalkyl, halo, C1-3alkoxy, or –OH. provided that: (i) when the 4- to 10-membered monocyclic or bicyclic heterocyclyl represented by R3is substituted then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl. In a second embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, R2is C1-3alkyl; and the remaining variables are as described in the first embodiment. In an alternative second embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, R2is -CH3, -CH2OH, -CH2-cyclopropyl, - CH2OCH3, -CH2CH2OCH3, -CH2CH2CN, or cyclopropyl; and the remaining variables are as described in the first embodiment. In another alternative second embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, R2is -CH3; and the remaining variables are as described in the first embodiment. In a third embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a 6-membered monocyclic heteroaryl comprising at least one N atom, or Ring A is a 5-membered monocyclic heteroaryl comprising at least one S atom and one or more N atoms; and the remaining variables are as described in the first or second embodiment. In an alternative third embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, Ring A is a 6-membered monocyclic heteroaryl comprising at least one N atom, or Ring A is a 5-membered monocyclic heteroaryl comprising one or more N atoms and optionally one S atom; and the remaining variables are as described in the first or second embodiment. In a fourth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, Ring A is pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which are substituted with 1 to 3 R3; and the remaining variables are as described in the first, second, or third embodiment. In an alternative fourth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, Ring A is pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which are substituted with 1 to 3 R3; and the remaining variables are as described in the first, second, or third embodiment. In a fifth embodiment, for the compounds of formula (I), or a pharmaceutically or 2 R3; and the remaining variables are as described in the fourth embodiment. In an alternative fifth embodiment, for the compounds of formula (I), or a pharmaceutically R3; and the remaining variables are as described in the fourth embodiment. In a sixth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, Ring A is: ,

[0002] the remaining variables are as described in the fifth embodiment. In an alternative sixth embodiment, for the compounds of formula (I), or a pharmaceutically the remaining variables are as described in the fifth embodiment. In a seventh embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, each R3is, independently, C1-3alkyl, C1-3haloalkyl, -OR3a, -N(R3c)2, C3-6cycloalkyl, 5- or 6-membered monocyclic or bicyclic heterocyclyl, wherein the C1-3alkyl and C1-3haloalkyl are each optionally substituted by -OH or C1-3alkoxy, and wherein the C3- 6cycloalkyl and 5- and 6-membered monocyclic or bicyclic heterocyclyl are optionally substituted by 1 to 3 R5; R3ais C1-3alkyl, C1-3haloalkyl, C1-3alkyl-C1-3alkoxy, or C3-4cycloalkyl, or 4-to 5-membered monocyclic heterocyclyl, wherein the C3-4cycloalkyl and 4- to 5-membered monocyclic heterocyclyl are optionally substituted by 1 or 2 R5; each R3cis, independently, H, C1-3alkyl, C1-3alkoxyC1-3alkyl, or C3-4cycloalkyl, wherein the C3-4cycloalkyl is optionally substituted by 1 or 2 R5; each R5is, independently, halo, C1-3alkoxy, cyano, or C1-3alkyl; provided that: (i) when R3is a substituted 5- or 6-membered monocyclic or bicyclic heterocyclyl, then Ring A is a 5-membered monocyclic heteroaryl; (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl; or (iii) when R3is a cyano substituted cyclopropyl then ring A is pyrimidinyl; and the remaining variables are as described in the first, second, third, fourth, fifth, or sixth embodiment. In an alternaitve seventh embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, each R3is, independently, C1-3alkyl, C1-3haloalkyl, -OR3a, C3-4cycloalkyl, 5- or 6- membered monocyclic or bicyclic heterocyclyl, wherein the C1-3alkyl is optionally substituted by C1-3alkoxy, wherein the C3-4cycloalkyl is optionally substituted by 1 or 2 halo, and the 5- or 6-membered monocyclic or bicyclic heterocyclyl is optionally substituted by 1 or 2 C1-3alkoxy; R3ais C1-3alkyl or C3-4cycloalkyl, provided (i) when R3is a substituted 5- or 6-membered monocyclic or bicyclic heterocyclyl , then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl; and the remaining variables are as described in the first, second, third, fourth, fifth, or sixth embodiment. In an eighth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CF2CH2OH, - CH2OCH3, CH(OH)CH3, -CH(CH3)2, -CF(CH3)2, -OCH3, -CF2CH2CH3, -CF2CH2OCH3, - OCH3, -OCHF2, -OCH(CH3)2, -OCH2CH2OCH3, -O-cyclopropyl, -NHCH3, -NHCH2CH3, - NHCH(CH3)2, -N(CH3)2, -NHCH2CH2OCH3, -NH-cyclopropyl, -NH-cyclobutyl, -O- oxetanyl, -O-pyrrolidinyl, cyclopropyl, cyclobutyl, bicyclopentanyl, tetrahydrofuranyl, tetrahydropyranyl, or 2-oxabicyclohexanyl, wherein the cyclopropyl, cyclobutyl, bicyclopentanyl, tetrahydrofuranyl, tetrahydropyranyl, and 2-oxabicyclohexanyl represented by R3or as part of an R3group are each optionally substituted by 1 or 2 groups selected from -OCH3, -OCH2CH3, cyano, -CH3, and -F, provided that: (i) when R3is tetrahydrofuranyl, substituted tetrahydropyranyl, or oxabicyclohexanyl, then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R3is a cyano substituted cyclopropyl then ring A is pyrimidinyl; and the remaining variables are as described in the seventh embodiment. In an alternative eighth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CH2OCH3, - CF(CH3)2, -OCH3, -O-cyclopropyl, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, or 2- oxabicyclo[2.1.1]hexanyl, wherein the cyclopropyl is optionally substituted by 1 or 2 halo, and the tetrahydrofuranyl is optionally substituted by –OCH3, provided that when R3is tetrahydrofuranyl, substituted tetrahydropyranyl, or 2-oxabicyclo[2.1.1]hexanyl, then Ring A is a 5-membered monocyclic heteroaryl; and the remaining variables are as described in the seventh embodiment. In a ninth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CF2CH2OH, - CH2OCH3, -CH(OH)CH3, -CH(CH3)2, -CF(CH3)2, -CF2CH2CH3, -CF2CH2OCH3, -OCH3, - OCHF2, -OCH(CH3)2, -OCH2CH2OCH3, -O-cyclopropyl, -NHCH3, -NHCH2CH3, - NHCH(CH3)2, -N(CH3)2, -NHCH2CH2OCH3, -NH-cyclopropyl, -NH-cyclobutyl, membered monocyclic heteroaryl; or (ii) when R3is then Ring A is pyrimidinyl.; and the remaining variables are as described in the first, second, third, fourth, fifth, or sixth embodiment. In an alternative ninth embodiment, for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, each R3is, independently, -CH3, CH2CH3, - Ring A is a 5-membered monocyclic heteroaryl; and the remaining variables are as described in the first, second, third, fourth, fifth, or sixth embodiment. In a tenth embodiment, the compound of the present disclosure is represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y1, Y3, and Y5are each N or CH; Y2is CRY1; Y4is N or CRY2; provided that no more than 2 of Y1, Y2, Y4, and Y5are N; RY1is C1-3haloalkyl or C3-4cycloalkyl substituted by one or more halo; RY2is H, C1-3alkyl, -ORY2a, or 5-or 6-membered monocyclic heterocyclyl, wherein the C1-3alkyl is optionally substituted by C1-3alkoxy, provided that RY2is not tetrahydrofuranyl; RY2ais C1-3alkyl or C3-4cycloalkyl; R1is C1-3alkyl, C3-6cycloalkyl, -C1-3alkyl-C1-3alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, C1-3alkyl, C1-3alkoxy, or cyano; and the remaining variables are as described in the first embodiment. In an eleventh embodiment, the compound of the present disclosure is represented by (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh): or a pharmaceutically acceptable salt thereof, wherein the variables RY1, RY2, R1, and X are as defined in the tenth embodiment. In an eleventh embodiment, the compound of the present disclosure is represented by (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh): or a pharmaceutically acceptable salt thereof, wherein the variables RY1, RY2, R1, and X are as defined in the tenth embodiment. In a twelfth embodiment, for the compounds of formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), or (IIh), or a pharmaceutically acceptable salt thereof, RY1is -CF2CH3, - ; and the remaining variables are as described in the tenth or eleventh embodiment. In a thirteenth embodiment, for the compounds of formula (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), or (IIh), or a pharmaceutically acceptable salt thereof, RY2is H, -CH3, CH2CH3, -CH2OCH3, -OCH3, -O-cyclopropyl, or tetrahydropyranyl; and the remaining variables are as described in the tenth, eleventh, or twelfth embodiment. In a fourteenth embodiment, the compound of the present disclosure is represented by Formula (III): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Z1, Z2, Z3, and Z4are each independently N, S, CH, or CR3; provided that no more than 2 of Z1, Z2, Z3, and Z4are N and no more than 1 of Z1, Z2, Z3, and Z4are S; each R3is, independently, C1-3alkyl, C1-3haloalkyl, -OR3a, C3-6cycloalkyl, 5- or 6- membered monocyclic or bicyclic heterocyclyl, wherein the C3-6cycloalkyl is optionally substituted by 1 or 2 halo, and the 5- or 6-membered monocyclic or bicyclic heterocyclyl is optionally substituted by 1 or 2 C1-3alkoxy or halo; R3ais C1-3alkyl or C3-4cycloalkyl; R1is C1-3alkyl, C3-6cycloalkyl, C1-3alkyl-C1-3alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, C1-3alkyl, C1-3alkoxy, or cyano; and the remaining variables are as described in the first embodiment. In a fifteenth embodiment, the compound of the present disclosure is represented by (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), or (IIIi):

[0003] or a pharmaceutically acceptable salt thereof, wherein the variables R1and R3are as described in the fourteenth embodiment. In an alternative fifteenth embodiment, the compound of the present disclosure is represented by (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh):

[0004] or a pharmaceutically acceptable salt thereof, wherein the variables R1and R3are as described in the fourteenth embodiment. In a sixteenth embodiment, for the compounds of formula (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), or (IIIi), or a pharmaceutically acceptable salt thereof, R3is -CF2CH3, -CF(CH3)2, , tetrahydrofuranyl, tetrahydropyranyl, or 2- oxabicyclo[2.1.1]hexanyl, wherein the tetrahydrofuranyl is optionally substituted with – OCH3 or -F; and the remaining variables are as described in the fifteenth embodiment. In a seventeenth embodiment, for the compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), or (IIIi), or a pharmaceutically acceptable salt thereof, R1is C1-4alkyl, C2-6alkenyl, -C(O)R1c, - SO2R1c, C3-10cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, or 5- to 6- membered monocyclic heteroaryl, wherein the C1-4alkyl and C2-6alkenyl are optionally substituted by one to three R1a, and the C3-10cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 or 2 R1b; each R1ais, independently, halo, cyano, OR1d, C3-5cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-5cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, halo, C1-3alkyl, C1-3alkyl-C1-3alkyoxy, C1-3alkoxy, C1-3haloalkoxy, -N(C1-3alkyl)2, or cyano; R1cis C3-4cycloalkyl; R1dis H or C1-3alkyl optionally substituted by phenyl; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment. In an alternative seventeenth embodiment, for the compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh), or a pharmaceutically acceptable salt thereof, R1is C1-3alkyl, C3-6cycloalkyl, -C1-3alkyl-C1-3alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, C1-3alkyl, C1-3alkoxy, or cyano; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment. In an eighteenth embodiment, for the compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh), or a pharmaceutically acceptable salt thereof, R1is -CH3, -CH2CH3, -CHF2, -CF3, -CH(CH3)2, - CH2CH2OCH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(CH3)CH2OCH3, -CH2CH2OH, - CH(CH3)CHF2, -CH(CH3)CH2F,-CH2CH2OCH3, -CH2CH2CN, -CH2CH=C(CH3)2, -CH2- cyclopropyl, -CH2-oxetanyl, -CH(CH3)-oxetanyl, -CH2-spiropentanyl, -C(O)-cyclopropyl, - SO2-cyclopropyl, , , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl, spirohexanyl, spiropentanyl, oxaspiroheptanyl, spiroheptanyl, or pyrazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl spirohexanyl, spiropentanyl, oxaspiroheptanyl, spiroheptanyl, and pyrazolyl represented by R1or as part of an R1group are each optionally substituted by 1 or 2 R1b; each R1bis, independently, -F, -CH3, -CH2CH3, -CH(CH3)2, -CH2OCH3, -OCH3, -OCH2CH3, - OCH(CH3)2, -OCHF2, -N(CH3)2, or cyano; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment. In an alternative eighteenth embodiment, for the compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh), or a pharmaceutically acceptable salt thereof, R1is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3, cyclopropyl, cyclobutyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, or piperdinyl, wherein the cyclobutyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, and piperdinyl are each optionally substituted by 1 R1b; each R1bis, independently, -CH3, -OCH3, or cyano; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment. In a nineteenth embodiment, for the compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh), or a pharmaceutically acceptable salt thereof, R1-CH3, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, - CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(CH3)CH2OCH3, -CH2CH2OH, -CH(CH3)CHF2, - CH(CH3)CH2F,-CH2CH2OCH3, -CH2CH2CN, -CH2CH=C(CH3)2, -CH2-cyclopropyl, -C(O)- cyclopropyl, -SO2-cyclopropyl, cyclopropyl, cyclobutyl, , , , the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment. In an alternative nineteenth embodiment, for the compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh), or a pharmaceutically acceptable salt thereof, R1is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3, cyclopropyl, cyclobutyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment. In a twentieth embodiment, the compound of the present disclosure is represented by Formula (IIe-1): or a pharmaceutically acceptable salt thereof, wherein: R1is C1-3alkyl or C3-4cycloalkyl; RY1is C1-3haloalkyl; and RY2is C1-3alkyl; and the remaining variables are as described in the first embodiment. In a twenty-first embodiment, for the compound of Formula (IIe-1), or a pharmaceutically acceptable salt thereof, R1is -CH2CH3or cyclopropyl; and the remaining variables are as described in the twentieth embodiment. In a twenty-second embodiment, for the compound of Formula (IIe-1), or a pharmaceutically acceptable salt thereof, RY1is -CF2CH3; and the remaining variables are as described in the twentieth or twenty-first embodiment. In a twenty-third embodiment, for the compound of Formula (IIe-1), or a pharmaceutically acceptable salt thereof, RY2is -CH2CH3; and the remaining variables are as described in the twentieth, twenty-first, or twenty-second embodiment. In a twenty-fourth embodiment, the compound of present disclosure is any one of compounds of Examples 1-222, or a pharmaceutically acceptable salt thereof. In an alternative twenty-fourth embodiment, the compound of present disclosure is any one of compounds of Examples 1-46, or a pharmaceutically acceptable salt thereof. The disclosure also includes both the neutral form and pharmaceutically acceptable salts of the compounds illustrated in the exemplification. III. PHARMACEUTICAL COMPOSITIONS In one aspect, the present disclosure is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The phrase pharmaceutically acceptable indicates that the substance, composition or dosage form must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith. As used herein, the term pharmaceutically acceptable carrier includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present disclosure or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product. The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration. For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art. Suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, or contain about 1-50%, of the active ingredient. The effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be 10 μg -500 mg. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal comprises any suitable delivery method. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound described herein, or a pharmaceutically acceptable salt thereof. Thus, a compound or pharmaceutically acceptable salt thereof as described herein, may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the compound or pharmaceutically acceptable salt thereof as described herein may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent. The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the compounds or pharmaceutically acceptable salts thereof as described herein can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Useful dosages of a compound or pharmaceutically acceptable salt thereof as described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949, which is incorporated by reference in its entirety. The amount of a compound or pharmaceutically acceptable salt thereof as described herein, required for use in treatment can vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and can be ultimately at the discretion of the attendant physician or clinician. In general, however, a dose can be in the range of from about 0.1 to about 10 mg / kg of body weight per day. The compound or pharmaceutically acceptable salt thereof as described herein can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg / kg or less can be suitable. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals. IV. USE OF COMPOUNDS AND COMPOSITIONS OF THE DISCLOSURE The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease or inhibit the activity of TYK2 or to otherwise affect the properties and / or behavior of TYK2, e.g., stability, phosphorylation, kinase activity, interactions with other proteins, etc. Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some aspect, the present disclosure is a method of treating a disease or disorder responsive to inhibition of TYK2 in a subject comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. The present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition described herein for the manufacture of a medicament for inhibiting TYK2 activity. Also included is the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition described herein for the manufacture of a medicament for treating a disease or disorder responsive to inhibition of TYK2. The disclosure also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in inhibiting TYK2 activity. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in treating a disease or disorder responsive to inhibition of TYK2. As used herein, the term inhibit, inhibition or inhibiting refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term subject and patient may be used interchangeably, and means a mammal in need of treatment, e.g., human, companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment. As used herein, a subject is in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human). As used herein, the term treat, treating or treatment refers to obtaining desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome. As used herein the term co-administer refers to the presence of two active agents in the blood of an individual. Active agents that are co-administered can be concurrently or sequentially delivered. The term combination therapy or in combination with or pharmaceutical combination refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co- administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent being administered prior to, concurrent with, or sequentially to each other with no specific time limits. In each case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. In some embodiment, the method described herein treats the disease or disorder responsive to inhibition of TYK2, wherein the disease or disorder includes inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction , thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration , glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis and sunburn. The term autoimmune disorders includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis. The term inflammatory disorders includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. The term cancer includes diseases or disorders involving abnormal cell growth and / or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g. small- cell lung carcinoma, non-small-cell lung carcinoma), gastric carcinoma, gastrointestinal stromal tumors, pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal cell carcinoma, lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g. microsatellite instability-high colorectal cancer). The disclosed method can include a kit comprising a compound or pharmaceutically acceptable salt thereof as described herein and instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject. This should be construed to include other embodiments of kits that are known to those skilled in the art, such as a kit comprising a (such as sterile) solvent for dissolving or suspending a compound or pharmaceutically acceptable salt thereof as described herein or composition prior to administering a compound or pharmaceutically acceptable salt thereof as described herein or composition to a cell or a subject. In some embodiments, the subject can be a human. EXEMPLIFICATIONS For illustrative purposes, the syntheses described below provide routes for synthesizing the compounds of the present disclosure as well as key intermediates. Although specific starting materials and reagents are illustrated in the synthetic protocols below, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the procedures described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. Abbreviations: Aq. means aqueous; Bn means benzyl; Boc means tert-butoxy carbonyl; Boc2O means di-tert-butyl dicarbonate br means broad; t-BuOH means tertiary butanol n-BuLi means n-butyl lithium; d means doublet; dd means double doublet; DCM means dichloromethane; DEA means diethylamine DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMA means N,N-dimethylacetamide; DMF means N,N-dimethylformamide; DMSO means Dimethylsulfoxide; DMSO-d6 means hexadeuterodimethyl sulfoxide; Et means ethyl; EtOH means ethanol; EtOAc means ethyl acetate; Eq. means equivalent; HPLC means high pressure liquid chromatography; IPA means 2-propanol LCMS means liquid chromatography mass spectrometry; LDA means lithium diisopropylamide; m means multiplet; Me means methyl; MeCN means acetonitrile; MeI means iodomethane MeOH means methanol; MeOH-d4 means deutero-methanol; MS m / z means mass spectrum peak; MsCl means methanesulfonyl chloride; NBS means N-bromosuccinimide; NOE means nuclear Overhauser effect spectroscopy; PE means petroleum ether; Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium (0); Pd(dppf)Cl2 means [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdCl2(PPh3)2 means bis(triphenylphosphine)palladium(II) dichloride; Pd / C means palladium on charcoal; q means quartet; rt means room temperature; s means singlet; sat. means saturated; SFC means supercritical fluid chromatography; soln. means solution; t means triplet; TBME means tert-butyl methyl ether; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; TLC means thin layer chromatography; TsCl means para-toluenesulfonyl chloride; TsOH means para-toluenesulfonic acid; and RuPhos Pd G3 means (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate. Schemes Scheme 1 (a) : Pd Ligand, bis(pinacolato)diboron, base (b) : Pd Ligand, base (c) : EtOH at 130℃, or hexafluoroisopropanol at 70℃, or acid at rt (d) : R1-Br, I,OMs,OTf or SO2Ph and base (e) : oxirane, base (f) : ClCF2CO2Na, base at 100℃ (i) : 1,10-phenanthroline, Iridium catalst, HBPin Scheme 3

[0005] (j): Pd Ligand, base, bis(pinacolato)diboron (k): Pd ligand, base Scheme 4 (k): NIS, HBF4(l) : hexa(C1-C4)alkyltin, Pd ligand (m) : CuI, Pd ligand Scheme 6 (o): Compound (I) may be converted to an alternative compound (I), using standard chemical transformations, known to those skilled in the art. Examples of these transformations include, but are not limited to: reductive amination of an aldehyde with a primary or secondary amine to provide respectively, a secondary or tertiary amine fluorination of an alcohol to provide an alkyl fluoride fluorination of an alkyl bromide to provide an alkyl fluoride amination of a heteroaryl chloride to provide a heteroaryl amine It will be appreciated by those skilled in the art that it may be necessary to utilise a suitable protecting group strategy for the preparation of compounds of Formula (I). Typical protecting groups may comprise, carbamate and preferably Boc for the protection of amines. Preparation 1 4-Chloro-N,6-dimethoxy-N-methylpicolinamide A mixture of N,O-dimethylhydroxylamine hydrochloride (4.8 g, 49 mmol), 4-chloro-6- methoxypicolinic acid (7.1 g, 38 mmol), HATU (22 g, 57 mmol), and TEA (26 mL 189 mmol) in DCM (100 mL) and DMF (30 mL) was stirred at 20 °C under N2 atmosphere. After 12 h, the mixture was concentrated under reduced pressure to give a residue that was purified with silica gel column chromatography (petroleum ether / EtOAc = 5 / 1) to afford 4-chloro- N,6-dimethoxy-N-methylpicolinamide (8.2 g, 94 % yield) as a yellow oil.1H NMR (400MHz, CDCl3) δ (ppm) 7.29 (s, 1H), 6.85 (d, J = 1.6 Hz, 1H), 3.98 (s, 3H), 3.82 (s, 3H), 3.42 (s, 3H). Preparation 2 1-(4-Chloro-6-methoxypyridin-2-yl)ethan-1-one To a solution of 4-chloro-N,6-dimethoxy-N-methylpicolinamide (Preparation 1, 8.2 g, 36 mmol) in THF (100 mL) was added 3 M methyl magnesium bromide in THF (15 mL, 46 mmol) slowly at -60 °C under N2 atmosphere. Upon complete addition, the mixture was stirred at 0 °C for 2 h under N2atmosphere. The reaction mixture was quenched by addition of saturated, aqueous NH4Cl solution then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to give a residue that was purified with silica gel column chromatography (petroleum ether / EtOAc= 15 / 1) to afford 1-(4-chloro-6-methoxypyridin-2-yl)ethan-1-one as a white solid (6.1 g, 92 % yield).1H NMR (400MHz, DMSO-d6) δ (ppm) 7.54 (d, J = 1.6 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H), 2.62 (s, 3H). Preparation 3 4-Chloro-2-(1,1-difluoroethyl)-6-methoxypyridine To a flask containing 1-(4-chloro-6-methoxypyridin-2-yl)ethan-1-one (Preparation 2, 6.1 g, 33 mmol) was added DAST (60 mL, 454 mmol) carefully. Upon complete addition of DAST, the mixture was carefully heated to 50 °C for 12 h. The reaction mixture was added to ice water (500 mL) dropwise then extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to give a residue that was purified with silica gel column chromatography (100 % petroleum ether) to afford a yellow liquid as 4-chloro-2-(1,1-difluoroethyl)-6-methoxypyridine (5.0 g, 70 % yield).1H NMR (400MHz, CDCl3) δ (ppm) 7.23 (d, J = 1.2 Hz, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 1.98 (t, J = 18.8 Hz, 3H). Preparation 4 2-(1,1-difluoroethyl)pyrimidine-4,6-diol To a solution of malonamide (15.0 g, 147 mmol) in EtOH (500 mL) was added t-BuONa (49.4 g, 514.24 mmol) and the solution was stirred at 25 °C for 30 mins. Ethyl 2,2- difluoropropanoate (50.7 g, 367.32 mmol) was added and the reaction stirred under reflux at 100°C for 16 h. The reaction was cooled, 4N HCl (75 mL) was added and the mixture concentrated. The resulting solid was collected and concentrated to give 2-(1,1- difluoroethyl)pyrimidine-4,6-diol (20.0 g, 77.3% yield) as a yellow solid. LCMS m / z = 177 [M+H]+Preparation 5 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine A solution of 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (Preparation 4, 20 g, 114 mmol) in POCl3 (200 mL, 2.2 mol) was stirred at 100 °C for 8 h. The mixture was evaporated to dryness, the residue diluted with DCM (150 mL) and added slowly into water. The mixture was extracted with DCM (200 mL x 3), the combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (EtOAc in PE 0% to 10%) to give 4,6-dichloro-2-(1,1- difluoroethyl)pyrimidine (23.0 g, 95% yield) as a yellow liquid. LCMS m / z = 213 [M+H]+Preparation 6 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine To a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 5, 75 g, 352 mmol) in THF (750 mL) and NMP (75 mL) at 23°C was added Fe(acac)3(12 g, 35 mmol). The mixture was purged with N2, then cooled to -20°C. To the cooled solution, CH3MgBr (3 M, 117 mL) was added dropwise, maintaining the internal temperature at between -20 and - 10°C during addition. The resulting mixture was stirred at -20℃ for 2 h. The mixture was poured into sat. aq. NH4Cl (1.5 L) and extracted with MTBE (1.0 L). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated. The resulting reddish-brown liquid was purified by Prep-HPLC (Method F, Gradient: 40%-58%). The desired fractions were evaporated in vacuo to remove MeCN. The mixture was extracted with MTBE (500 mL), the organic phase was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 4-chloro-2-(1,1-difluoroethyl)-6- methylpyrimidine as a yellow liquid. LCMS m / z = 193 [M+H]+. Preparation 7 4-chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine To a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 5, 1.5 g, 7 mmol) in water (3 mL) and dioxane (15 mL) was added ethylboronic acid (520 mg, 7 mmol), K2CO3 (1.46 g, 10.6 mmol) and Pd(dppf)Cl2 (515 mg, 0.70 mmol) and the mixture was stirred at 100 °C for 16 h under N2. The mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (PE / EtOAc 1 / 0 to 10 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine (410 mg, 28.2% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ (ppm) 7.28 (s, 1H), 2.86 (q, J=7.5 Hz, 2H), 2.06 (t, J=18.5 Hz 3H), 1.34 (t, J=7.5 Hz, 3H). Preparation 8 4-chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine To a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 5, 300 mg, 1.41 mmol) in MeOH (5.0 mL) was added NaOMe (76.1 mg, 1.41 mmol) at 0 °C and the reaction was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE / EtOAc 15 / 1 to 5 / 1) to give 4- chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (260 mg, 89 % yield) as colourless oil.1H NMR: (400 MHz, CDCl3) δ ppm: 6.81 (s, 1H), 4.08 (s, 3H), 2.02 (t, J=18.5 Hz, 3H). Preparation 9 2-(4,6-dichloropyrimidin-2-yl)propan-2-ol To a solution of 4,6-dichloro-2-iodopyrimidine (1 eq) in toluene was added n-BuLi (2.5 M, 1.5 eq) slowly at -70 °C over 30 mins under N2. Acetone (1.2 eq) was added slowly at -70 °C and the reaction then stirred for 3 h under N2. The mixture was poured into NH4Cl (sat.) and extracted with EtOAc (3 times). The organic phase was washed with brine, dried (Na2SO4), filtered and the filtrate was concentrated. The residue was purified by chromatography (PE / EtOAc = 20 / 1 to 3 / 1) on silica gel to give.2-(4,6-Dichloropyrimidin-2-yl)propan-2-ol was obtained as a yellow oil, (500 mg, 66% yield).1H NMR (500 MHz, CDCl3) δ (ppm) 7.30 (s, 1H), 3.92 (br s, 1H), 1.59 (s, 6H). Preparation 10 4,6-dichloro-2-(2-fluoropropan-2-yl)pyrimidine To a solution of 2-(4,6-dichloropyrimidin-2-yl)propan-2-ol (Preparation 9, 1eq) in DCM was added DAST (2 eq) and the reaction was stirred at 20 °C for 12 h. The mixture was quenched with aq. Na2CO3and extracted with DCM (twice). The combined organic phase was washed with brine dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE / EtOAc = 3 / 1) to give 4,6-Dichloro-2-(2-fluoropropan-2-yl)pyrimidine as a yellow oil.1H NMR (500 MHz, CDCl3) δ (ppm) 7.34 (s, 1H), 1.80 (s, 3H), 1.75 (s, 3H). Preparation 11 4-chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine 4-Chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine was obtained as a yellow oil, 720 mg, 79.8% yield from 4,6-dichloro-2-(2-fluoropropan-2-yl)pyrimidine (Preparation 10) and methyl boronic acid, following a similar procedure to that described in Preparation 7.1H NMR: (500 MHz, CDCl3) δ (ppm) 7.13 (s, 1H), 2.56 (s, 3H), 1.79 (s, 3H), 1.75 (s, 3H). Preparation 12 4-chloro-2-(2-fluoropropan-2-yl)-6-methoxypyrimidine A solution of NaOMe (1.12 g, 5.16 mmol, 1.18 mL, 25% purity) in MeOH was added to a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 10, 980 mg, 4.69 mmol) in dry MeOH (10 mL). A white precipitate forms upon addition. The mixture was stirred at 70 °C for 16 hours under a nitrogen atmosphere. The mixture was cooled to rt, diluted with H2O, and extracted with CH2Cl2(x 3). The combined organic phases were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give 4-chloro-2-(2-fluoropropan-2-yl)-6-methoxypyrimidine (800 mg, 4 mmol, 83 % yield) as a yellow oil. LCMS m / z = 205 [M+ H]+.1H NMR (500 MHz, CDCl3) δ (ppm) 6.60 (s, 1H), 3.94 (s, 3H), 1.74 - 1.69 (m, 3H), 1.68 - 1.61 (m, 3H). Preparation 13 4-chloro-6-ethyl-2-(2-fluoropropan-2-yl)pyrimidine 4-Chloro-6-ethyl-2-(2-fluoropropan-2-yl)pyrimidine was obtained as a colorless oil, 300 mg, crude, from 4,6-dichloro-2-(2-fluoropropan-2-yl)pyrimidine (Preparation 5) and ethyl boronic acid, following the procedure described in Preparation 7. LCMS m / z = 203 [M+H]+. Preparation 14 4-(benzyloxy)-2-chloropyrimidine Under N2, to a solution of 2,4-dichloro-6-methylpyrimidine (1 eq) in 1:1 THF:DMF was added t-BuOK (1 M, 1eq) and benzyl alcohol (2 eq) dropwise at -70 °C. The mixture was stirred at -70 °C for 2 h and the reaction was then quenched with NH4Cl (sat) and evaporated. The residue was extracted (EtOAc), washed (brine) and the organic layer was evaporated. The residue was purified by SiO2 (PE / EtOAc = 9 / 1) to afford 4-(Benzyloxy)-2- chloropyrimidine (4.8 g, 65 % yield) as a white solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.31 (d, J=5.6 Hz, 1H), 7.37-7.46 (m, 5H), 6.70 (d, J=5.6 Hz, 1H), 5.43 (s, 2H). Preparation 15 methyl 4-(benzyloxy)pyrimidine-2-carboxylate To a solution of 4-(benzyloxy)-2-chloropyrimidine (Preparation 14, 9.5 g, 21.5 mmol) in MeOH (100 mL) was added Pd(dppf)Cl2(315 mg, 0.4 mmol) and TEA (4.4 g, 43 mmol). The resulting mixture was stirred at 80 °C for 16 h under CO (50 psi). The mixture was concentrated and was purified by chromatography (PE / EtOAc = 3 / 1) on silica gel to give methyl 4-(benzyloxy)pyrimidine-2-carboxylate (3.6 g, 68.5% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ (ppm) 8.59 (d, J=5.6 Hz, 1H), 7.42-7.50 (m, 2H), 7.35-7.41 (m, 3H), 6.91 (d, J=6.0 Hz, 1H), 5.53 (s, 2H), 4.05 (s, 3H). Preparation 16 1-(4-(benzyloxy)pyrimidin-2-yl)ethan-1-one To a solution of methyl 4-(benzyloxy)pyrimidine-2-carboxylate (1 eq) in THF (10 mL) was added MeMgBr (3 M, 1.5 eq) slowly at 0 °C and the reaction stirred for 12 h at rt under N2. The reaction was concentrated and diluted with water and EtOAc. The organic phase was washed (brine), dried (Na2SO4) and evaporated. The residue was purified by SiO2 (PE / EtOAc = 3 / 1) to afford 1-(4-(benzyloxy)pyrimidin-2-yl)ethan-1-one (288 mg, 21%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ (ppm) 8.61 (d, 1H), 7.49-7.35 (m, 5H), 6.90 (d, 1H), 5.52 (s, 2H), 2.75 (s, 3H). Preparation 17 4-(benzyloxy)-2-(1,1-difluoroethyl)pyrimidine 4-(Benzyloxy)-2-(1,1-difluoroethyl)pyrimidine was obtained as a yellow oil, 537 mg, 76%, from 1-(4-(benzyloxy)pyrimidin-2-yl)ethan-1-one (Preparation 16) following a similar procedure to that described in Preparation 10.1H NMR (500 MHz, CDCl3) δ (ppm) 8.52 (d, 1H), 7.48-7.35 (m, 5H), 6.81 (d, 1H), 5.48 (s, 2H), 2.03 (t, 3H). Preparation 18 2-(1,1-difluoroethyl)pyrimidin-4-ol A solution of 4-(benzyloxy)-2-(1,1-difluoroethyl)pyrimidine (Preparation 17, 537 mg, 2.2 mmol) in TFA (4.5 g, 39 mmol) was stirred at 100 °C for 12 h. The mixture was purified by prep-HPLC-D (0-20% MeCN) to give 2-(1,1-difluoroethyl)pyrimidin-4-ol as a white solid (230 mg, 67%).1H NMR (400 MHz, CDCl3) δ: 7.99 (d, 1H), 6.55 (d, 1H), 2.03 (t, 3H). Preparation 19 4-chloro-2-(1,1-difluoroethyl)pyrimidine A solution of 2-(1,1-difluoroethyl)pyrimidin-4-ol (Preparation 18, 100 mg, 0.63 mmol) in POCl3 (2 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated, the residue diluted with H2O (10 mL) and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na2SO4) and concentrated to give 4-chloro-2-(1,1- difluoroethyl)pyrimidine as a yellow oil (85 mg, 76%).1H NMR (400 MHz, CDCl3) δ (ppm) 8.74 (d, 1H), 7.44 (d, 1H), 2.07 (t, 3H). Preparation 20 1-(2-chloro-6-methylpyrimidin-4-yl)ethan-1-one To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (985 mg, 5.3 mmol) in THF (10 mL) was added MeMgBr (3 M, 1.8 mL) at 0°C under N2. The reaction mixture was stirred for 5 h, then quenched with H2O (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (PE / EtOAc 5 / 1) to afford 1-(2-chloro-6-methylpyrimidin-4- yl)ethan-1-one (147 mg, 16% yield) as white solid.1H NMR: (400 MHz, CDCl3) δ (ppm) 7.69 (s, 1H), 2.70 (s, 3H), 2.63 (s, 3H). Preparation 21 2-chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine 2-Chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine was obtained as a yellow oil, 114 mg, 84% yield, from 1-(2-chloro-6-methylpyrimidin-4-yl)ethan-1-one (Preparation 20) and DAST following the procedure described in Preparation 10.1H NMR: (500 MHz, CDCl3) δ (ppm) 7.42 (s, 1H), 2.62 (s, 3H), 1.98 (t, J=19.0 Hz, 3H). Preparation 22 1-fluorocyclopropanecarboxamide To a solution of 1-fluorocyclopropanecarboxylic acid (2 g, 19 mmol) in DCM (20 mL) under nitrogen was added oxalyl chloride (2 M, 12 mL) and DMF (74 uL). Stirred at rt for 1h. the reaction mixture was concentrated under vacuo. The residue was dissolved in DCM (20 mL), cooled to 0°C. ammonia (7 M, 27 mL) was added slowly. The mixture was then stirred at rt for 2h. The solid formed (inorganic salt) was filtered off. The filtrate was concentrated and diluted with acetonitrile, the solid formed was collected by filtration (repeat the process for several times) to give 1-fluorocyclopropanecarboxamide (1.15 g, 58% yield) as a white solid.1H NMR (METHANOL-d4, 400 MHz) δ (ppm) 1.3-1.4 (m, 1H), 1.2-1.3 (m, 3H). Preparation 23 2-(1-fluorocyclopropyl)-4-methyl-1H-pyrimidin-6-one A mixture of NaOMe (25wt% in MeOH, 3.56mL) in n-Butanol (4.0 mL) was heated to 105°C in a sealed vial (pierced with a needle open to air) while the solvent was removed. To this was portion wise added a solution of methyl (E)-3-aminobut-2-enoate (400 mg, 3.5 mmol) and 1-fluorocyclopropanecarboxamide (Preparation 22, 1.1 g, 10.4 mmol) in MeOH (20mL), after the addition, raised the temperature to 110°C while the removal of the solvent continued. Continue heating for another 2h (the needle can be removed when the gas release calmed down). Cooled down, the reaction mixture was neutralized with conc. HCl. The formed organic salt was filtered off, and the filtrate was concentrated under a reduced pressure. The filtrate was then concentrated. The residue was diluted with acetonitrile. The solid formed was collected by filtration, the filtrate was then concentrated and treated with acetonitrile to collect more solid. The same process was repeated for several times. The collected solid was dried to give 2-(1-fluorocyclopropyl)-4-methyl-1H-pyrimidin-6-one (247 mg, 42% yield) as a white solid. LCMS m / z = 169 [M+H]+.1H NMR (400 MHz, CDCl3) δ (ppm) 7.29 (s, 1H), 6.1-6.3 (m, 1H), 2.25 (s, 3H), 1.63 (dd, 1H, J=2.3, 4.0 Hz), 1.6-1.6 (m, 3H). Preparation 24 4-chloro-2-(1-fluorocyclopropyl)-6-methyl-pyrimidine To a solution of 2-(1-fluorocyclopropyl)-4-methyl-1H-pyrimidin-6-one (Preparation 23, 240 mg, 1.4 mmol) in DCM (2 mL) was added POCl3 (3.3 g, 21.4 mmol, 2.00 mL), followed by two drops of DMF. After 2h at rt, the reaction was evaporated. To the residue was added aq.NaHCO3 and ice, extracted with EtOAc (2x). The organic layer was then separated, dried, and concentrated to give 4-chloro-2-(1-fluorocyclopropyl)-6-methyl-pyrimidine (88 mg, 33% yield) as a brownish oil which was used as is in the next step without further purifications. LCMS m / z = 187 [M+H]+. Preparation 25 4-chloro-6-ethyl-2-(1-fluorocyclopropyl)pyrimidine 4-chloro-6-ethyl-2-(1-fluorocyclopropyl)pyrimidine is made similar to Preparation 24 using (E)-3-aminopent-2-enoate. LCMS m / z = 201 [M+H]+. Preparation 26 tert-butyl 5-acetamido-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate A flask containing tert-butyl 5-acetamido-3-bromo-pyrrolo[2,3-c]pyridine-1-carboxylate (2 g, 5.65 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (2.94 g, 11.58 mmol), KOAc (2.50 g, 25.52 mmol), and XPhos Pd G3 (477 mg, 564 μmol) in anhydrous dioxane (40 mL) was degassed then backfilled with nitrogen then carefully heated to 95 °C for 3h. The mixture was diluted with EtOAc, washed with brine. The organic layer was separated, the aqueous layer was extracted with more EtOAc (2x). The combine organics was dried and concentrated to give crude tert-butyl 5-acetamido- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate as a yellow solid which was used as is in the next step without further purifications. LCMS m / z = 320 [M+H]+ (corresponding boronic acid). Preparation 27 N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (500 mg, 2.9 mmol) in THF (10 mL) was added NaH (137 mg, 3.4 mmol, 60% purity), the mixture was stirred for 30 min. Then CH3I (486 mg, 3.4 mmol, 213 μL) was added to the mixture. After 3 h at rt, the reaction mixture was concentrated. The residue was taken up in water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford compound N-(1-methyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (500 mg, 93% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm:8.38 (s, 2H), 8.27 (br s, 1H), 7.18 (d, J=2.8 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 3.85 (s, 3H), 2.21 (s, 3H) Preparation 28 N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a solution of N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 27) (500 mg, 2.6 mmol) in Dioxane (10 mL) was added 1,10-Phenanthroline (48 mg, 264 μmol), [Ir(COD)(OMe)]2 (175.2 mg, 264.25 μmol) and 1,3,2-Dioxaborolane (1.0 g, 7.9 mmol, 1.2 mL). The mixture was stirred at 90 °C for 2 hours under microwave. The mixture was concentrated and the residue was purified by SiO2 ((Petroleum ether / EtOAc=1 / 1) to give N- (1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide (300 mg, 36% yield) as a yellow solid. LCMS m / z = 316 [M+H]+ Preparation 29 3-bromo-5-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridine A flask containing 3-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (731 mg, 3.0 mmol) in anhydrous 2-MeTHF (12 mL) was cooled in an ice water bath to <5 °C then sodium hydride (60 % in mineral oil) (167 mg, 4.2 mmol, 60% purity) was added carefully in portions. After 15 minutes, ethyl iodide (698 mg, 4.5 mmol, 360 μL) was added carefully dropwise to the cooled reaction mixture. Upon complete addition of ethyl iodide, the reaction was warmed to 23 °C and monitored with LCMS. After 22 hours, the reaction was carefully quenched with slow addition of cold water. The mixture was extracted (EtOAc), dried (Na2SO4), evaporated and purified by SiO2 (15- 75 % ethyl acetate in heptane) to afford 3-bromo-5-chloro-1-ethyl- pyrrolo[2,3-c]pyridine (681 mg, 2.6 mmol, 86% yield) as a white solid. LCMS m / z = 258.9 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) = 8.49 (d, J = 0.9 Hz, 1H), 7.83 (s, 1H), 7.80 (d, J = 0.9 Hz, 1H), 4.23 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 7.3 Hz, 3H). Preparation 30 3-bromo-5-chloro-1-ethyl-1H-pyrazolo[3,4-c]pyridine To a stirring solution of 3-bromo-5-chloro-1H-pyrazolo[3,4-c]pyridine (700 mg, 3.0 mmol) dissolved in DMF (10 mL) was added iodoethane (564 mg, 3.6 mmol, 291 μL). The resulting mixture was cooled to 0°C and to this was added sodium hydride (132 mg, 3.3 mmol, 60% purity) portion wise over 30 mins. The reaction was gradually warmed to 23 °C. After 1h reaction was cooled to 0°C and quenched carefully with water. The aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, evaporated and used directly for the next step as a mixture of regioisomers. LCMS (m / z) = 260 [M+ H]+Preparation 31 5-Chloro-3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4- c]pyridine A vial containing 4-chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine (Preparation 11) (235 mg, 1.2 mmol), 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridine (244 mg, 990 umol), Bis(pinacolato)diboron (674 mg, 2.7 mmol), cesium fluoride (902 mg, 5.9 mmol), cataCXium A (130 mg, 364 umol), and Pd2dba3 (158 mg, 172 umol) in water (0.3 mL), methanol (2 mL), and 2-MeTHF (2 mL) was degassed then backfilled with nitrogen then carefully heated to 60 °C. After 17 h, the mixture was cooled to room temperature then filtered through a celite plug. After rinsing the plug with EtOAc, the organics were pooled then concentrated under reduced pressure. The residue was loaded onto a silica gel column and purified with (30- 100 % EtOAc in heptane.) afford 5-chloro-3-(2-(2-fluoropropan-2-yl)- 6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridine (241 mg) a yellow film. LCMS m / z = 320.0 [M+ H]+. Preparation 32 5-chloro-3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3- c]pyridine Prepared in a similar manner as described in Preparation 31 starting with 4-chloro-6-ethyl-2- (1-fluorocyclopropyl)pyrimidine (Preparation 25) (254 mg, 1.27 mmol) and 3-bromo-5- chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine to afford 5-chloro-3-(6-ethyl-2-(1- fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (65 mg, 196 umol, 20 % yield) as a white solid . LCMS m / z = 331.0 [M+ H]+.1H NMR (500 MHz, CDCl3) δ (ppm) 8.34 (d, J = 0.6 Hz, 1H), 8.05 (d, J = 0.9 Hz, 1H), 7.80 (s, 1H), 7.04 (s, 1H), 3.82 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 1.51 (td, J = 4.9, 3.2 Hz, 2H), 1.48 (s, 2H), 1.24 (t, J = 7.6 Hz, 3H). Preparation 33 N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide To tert-butyl 5-acetamido-3-bromo-pyrrolo[2,3-c]pyridine-1-carboxylate (838 mg, 2.37 mmol) in a 10-20 mL microwave tube was added EtOH (10 mL). It was heated with microwave irritation at 110^C for 1h. After release the internal pressure, the reaction tube was re-capped and heated at 120^C for 1h. After cooling down to rt, the solid was filtered and washed with MeCN to get N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (410 mg, 68% yield) as an off-white solid. The filtrate was concentrated to get additional 185 mg light brown solid, which is used for next step without further purification. Total yield 99% (595 mg). LCMS m / z = 256 [M+H]+. Preparation 34 N-[3-bromo-1-(oxetan-3-yl)pyrrolo[2,3-c]pyridin-5-yl]acetamide To a mixture of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 33, 183 mg, 0.7 mmol), cesium carbonate (375 mg, 1.2 mmol) in DMF (3 mL) in a reaction vial was added 3-iodooxetane (212 mg, 101 mL, 1.2 mmol). The mixture was heated at 100^C for 1h, and let it stir at rt overnight. Added EtOAc (50 mL) and water (30 mL), the organic phase was isolated, washed with water (x3), dried over MgSO4, filtered and concentrated. Triturated with MeCN to get N-[3-bromo-1-(oxetan-3-yl)pyrrolo[2,3-c]pyridin-5-yl]acetamide (110 mg, 49% yield) as a light brown solid. LCMS m / z = 312 [M+H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 8.72 (d, J = 1.0 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 5.80 (tt, J = 7.5, 5.8 Hz, 1H), 5.21 (t, J = 7.0 Hz, 2H), 5.03 (dd, J = 7.3, 6.3 Hz, 2H), 2.21 (s, 3H). Preparation 35 N-(1-(bromodifluoromethyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 200 mg, 0.604 mmol) in DMF (5 mL) was added NaH (29.0 mg, 0.724 mmol, 60% purity), tetrabutylammonium bromide (77.8 mg, 0.241 mmol) and dibromodifluoromethane (633 mg, 3.02 mmol) at 0°C. The reaction mixture was stirred at 20°C for 16 h, then concentrated and purified by column chromatography on silica gel (PE / EtOAc 20 / 1 to 1 / 1) to give N-(1-(bromodifluoromethyl)-3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (35.0 mg, 12.6% yield) as a yellow solid. LCMS m / z = 460 [M+H]+. Preparation 36 1,3-dioxoisoindolin-2-yl 2-fluorocyclopropane-1-carboxylate To a solution of 2-fluorocyclopropane-1-carboxylic acid (1 g, 9.61 mmol) in DCM (100 mL) was added N-hydroxyphthalimide (1.7 g, 10.43 mmol), 4-(dimethylamino)pyridine (117.4 mg, 0.96 mmol) and finally N,N′-dicyclohexylcarbodiimide (2.2 g, 10.57 mmol) at 0℃. The reaction was stirred at 25 °C for 48 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE / EtOAc = 2 / 1) to afford 1,3-dioxoisoindolin-2-yl 2-fluorocyclopropane-1-carboxylate (1.2 g, 50.1% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ: 7.79-7.90 (m, 4H), 4.90-5.08 (m, 1H), 2.41-2.48 (m, 1H), 1.75-1.81 (m, 1H), 1.54-1.59 (m, 1H). Preparation 37 2-(2-fluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1,3-dioxoisoindolin-2-yl 2-fluorocyclopropane-1-carboxylate (Preparation 36, 1.2 g, 4.82 mmol) in EtOAc (20 mL) was added bis(pinacolato)diboron (2.5 g, 9.63 mmol) and tert-butyl pyridine-4-carboxylate (345.2 mg, 1.93 mmol). The reaction was stirred at 90 °C for 16 h under N2. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE / EtOAc=5 / 1) to give 2-(2-fluorocyclopropyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (200 mg, 22.3% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ: 4.57-4.76 (m, 1H), 1.21 (s, 12H), 1.12-1.15 (m, 1H), 0.70-0.73 (m, 1H), 0.39-0.44 (m, 1H). Preparation 38 tert-butyl (3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-1-yl)cyclobutyl)carbamate To a solution of tert-butyl (3-iodocyclobutyl)carbamate (807.1 mg, 2.72 mmol) and N-(3-(2- (1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 34, 300 mg, 0.91 mmol) in DMF (8 mL) was added Cs2CO3(885.1 mg, 2.72 mmol) at 25 °C and the mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated and purified by silica gel column chromatography (EtOAc in PE from 20% to 80%) to give tert-butyl (3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1H-pyrrolo[2,3-c]pyridin-1-yl)cyclobutyl)carbamate (300 mg, 66.2% yield) as a yellow solid. LCMS m / z = 501 [M+H]+ Preparation 39 N-(1-(3-aminocyclobutyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of tert-butyl (3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1H-pyrrolo[2,3-c]pyridin-1-yl)cyclobutyl)carbamate (Preparation 38, 290 mg, 0.579 mmol) in DCM (5 mL) was added TFA (660.6 mg, 5.79 mmol) and the reaction mixture was stirred at 25 °C for 3 h. The mixture was concentrated, the residue partitioned between water (20 mL) and DCM (10 mL) and the pH adjusted to 9-10 using aq NaOH. The mixture was extracted with DCM (30 mL x 3) and the combined organic phase was concentrated to give N-(1-(3-aminocyclobutyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (160 mg, crude) as a yellow solid. LCMS m / z = 401 [M+H]+ Preparation 40 tert-butyl 3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-1-yl)azetidine-1-carboxylate To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 500.0 mg, 1.51 mmol) in DMF (8.0 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (854.5 mg, 3.02 mmol) and Cs2CO3 (983.4 mg, 3.02 mmol) and the reaction mixture was stirred at 110 °C for 16 h. The mixture was poured into H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (PE / EtOAc = 20 / 1 to 0 / 1) to give tert-butyl 3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)azetidine-1-carboxylate (550 mg, 74.9% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm: 9.12 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.16 (br s, 1H), 7.54 (s, 1H), 5.24-5.25 (m, 1H), 4.57-4.61 (m, 2H), 4.36- 4.39 (m, 2H), 2.66 (s, 3H), 2.27 (s, 3H), 2.20 (t, J=18.8 Hz, 3H), 1.51 (s, 9H). Preparation 41 N-(1-(azetidin-3-yl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide trifluoroacetate To a solution of tert-butyl 3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1H-pyrrolo[2,3-c]pyridin-1-yl)azetidine-1-carboxylate (Preparation 40, 550.0 mg, 1.13 mmol) in DCM (5.0 mL) was added TFA (1.0 mL, 13.06 mmol) and the resulting mixture was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give N- (1-(azetidin-3-yl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide trifluoroacetate (520.0 mg, crude) as a yellow solid. LCMS m / z = 387 [M+H]+Preparation 42 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-hydroxycyclopropyl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 120.0 mg, 0.362 mmol) in DMF (3.0 mL) was added 1-(phenylsulfonyl)cyclopropan-1-ol (143.6 mg, 0.724 mmol) and K2CO3 (100.1 mg, 0.724 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The reaction was concentrated and the residue was purified by chromatography on silica gel (PE / EtOAc = 20 / 1 to 0 / 1) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-hydroxycyclopropyl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (110.5 mg, 78.8% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ ppm: 8.80 (s, 1H), 8.65 (s, 1H), 8.12 (s, 2H), 7.32 (s, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 2.19 (t, J=18.8 Hz, 3H), 1.56-1.58 (m, 2H), 1.37-1.40 (m, 2H). Preparation 43 6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-ol To a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 5, 1.5 g, 7.04 mmol) in water (3 mL) and dioxane (3 mL) was added HCl (12 M, 8.80 mL) and the reaction was stirred at 85 °C for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with water (15 mL) and concentrated. The crude was purified by column chromatography on silica gel (EtOAc in PE from 0% to 25%) to give 6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-ol (150 mg, 11.0% yield) as a white solid. LCMS m / z = 195 [M+H]+ Preparation 44 4-chloro-2-(1,1-difluoroethyl)-6-(difluoromethoxy)pyrimidine To a solution of 6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-ol (Preparation 43, 100 mg, 0.514 mmol) and sodium 2-chloro-2,2-difluoroacetate (195.9 mg, 1.28 mmol) in DMF (8 mL) was added Cs2CO3(167.5 mg, 0.514 mmol) and the reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (15 mL) and concentrated. The crude was purified by column chromatography on silica gel (EtOAc in PE from 0% to 5%) to give 4- chloro-2-(1,1-difluoroethyl)-6-(difluoromethoxy)pyrimidine (70 mg, 55.7% yield) as colorless oil. LCMS m / z = 245 [M+H]+ Preparation 45 N-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 33, 3.3 g, 13.0 mmol) in MeCN (100 mL) was added Cs2CO3(8.5 g, 26.0 mmol) and dimethyl sulfate (6.6 g, 52.0 mmol) and the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated, the residue was diluted with water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc= 0 / 1) to give N-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (2.56 g, 73.5% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ ppm: 8.37 (s, 1H), 8.32 (s, 1H), 8.13 (br s, 1H), 7.20 (s, 1H), 3.86 (s, 3H), 2.23 (s, 3H). Preparation 46 tert-butyl 5-acetamido-3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate To a mixture of tert-butyl 5-acetamido-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-c]pyridine-1-carboxylate (Preparation 26, 7.5 g, 16.82 mmol), 4,6-dichloro-2- (1,1-difluoroethyl)pyrimidine (Preparation 5, 3.76 g, 17.66 mmol) and K3PO4(8.93 g, 42.05 mmol) in dioxane (100 mL) and H2O (20 mL) was added Pd(dppf)Cl2.DCM (1.37 g, 1.68 mmol) under N2 and the reaction mixture was stirred at 90 °C for 0.5 h under N2. The mixture was concentrated to remove dioxane, then EtOAc (200 mL) and water (200 mL) were added to the crude material. The mixture was stirred at 20 °C for 0.5 h, filtered and the filter cake was washed with MTBE and EtOAc and concentrated. The crude material was suspended in MTBE / EtOAc / DCM / MeOH (25 mL / 25 mL / 10 mL / 2 mL) and stirred at 20 °C for 0.5 h. After filtration, the filtrate was concentrated to give a residue, which was suspended in MTBE / EtOAc (25 mL / 10 mL) and stirred at 20 °C for 0.5 h. After filtration, the filter cake was washed with MTBE and PE and concentrated to give tert-butyl 5-acetamido-3-(6-chloro- 2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (5.8 g, 75.4% yield) as an off-white solid. LCMS m / z = 452 [M+H]+ Preparation 47 N-(3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide A solution of tert-butyl 5-acetamido-3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridine-1-carboxylate (Preparation 46, 1.0 g, 2.21 mmol) in hexafluoroisopropanol (10.0 mL) was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give N-(3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (720.0 mg, crude) as a white solid. LCMS m / z = 352 [M+H]+ Preparation 48 N-(3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a solution of N-(3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Preparation 47, 350.0 mg, 1.0 mmol) in DMSO (8.0 mL) was added 2-iodopropane (186.1 mg, 1.09 mmol) and K2CO3(412.6 mg, 3.0 mmol) and the reaction mixture was stirred at 70 °C for 1 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica column chromatography (PE / EtOAc = 1 / 0 to 0 / 1) to give N-(3-(6-chloro-2-(1,1- difluoroethyl)pyrimidin-4-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (135.0 mg, 34.5% yield) as a yellow solid. LCMS m / z = 394 [M+H]+ Preparation 49 Tert-butyl 3-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate DIEA (0.73 mL, 4.19 mmol) and DMAP (25.8 mg, 0.211 mmol) were added to a solution of 3-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (471.3 mg, 2.04 mmol) and Boc anhydride (495.4 mg, 2.27 mmol) in anhydrous 2-MeTHF (8 mL) and the reaction mixture stirred at rt for 3 h. The mixture was diluted with water then extracted with EtOAc (3 x). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was suspended in EtOAc and sonicated. The heterogeneous mixture was filtered to afford a white solid as tert-butyl 3-bromo-5-chloro-pyrrolo[2,3-c]pyridine-1-carboxylate (597 mg, 88 % yield).1H NMR (500 MHz, DMSO-d6) δ = 9.06 (br s, 1H), 8.28 (s, 1H), 7.63 (s, 1H), 1.64 (s, 9H). Preparation 50 5-Chloro-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine A mixture of tert-butyl 3-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Preparation 49, 333 mg, 1.01 mmol), 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 6, 245 mg, 1.27 mmol), bis(pinacolato)diboron (707 mg, 2.78 mmol), cesium fluoride (933 mg, 6.14 mmol), CataCXium A (129 mg, 0.359 mmol), and Pd2dba3 (154 mg, 0.169 mmol) in water (0.4 mL), MeOH (3 mL) and 2-MeTHF (3 mL) was degassed and backfilled with N2then carefully heated to 60 °C. After 18 h, the mixture was cooled to rt and filtered through Celite®, washing through with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column (10- 55 % 3:1 EtOAc: EtOH in heptane.) to give 5-chloro-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridine (90 mg, 29 % yield) as a white solid. LCMS m / z = 309 [M+H]+. Preparation 51 5-Chloro-1-(cyclopropylsulfonyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridine A mixture of 5-chloro-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine (Preparation 50, 90 mg, 0.292 mmol) in anhydrous 2-MeTHF (3 mL) was cooled in an ice water bath to <5 °C then DIEA (0.15 mL, 0.861 mmol) and DMAP (4 mg, 34 μmol) were added. After 15 min, cyclopropanesulfonyl chloride (0.06 mL, 0.589 mmol) was added dropwise and the reaction was warmed to 23 °C and stirred for 22 h. The reaction was diluted with water and the mixture was extracted with EtOAc (3x). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10- 60 % 3:1 EtOAc: EtOH in heptane) to afford a white solid as 5-chloro-1-cyclopropylsulfonyl-3-[2-(1,1-difluoroethyl)-6- methyl-pyrimidin-4-yl]pyrrolo[2,3-c]pyridine (84 mg, 70% yield).1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.07 - 9.03 (m, 2H), 8.61 (s, 1H), 8.28 (s, 1H), 3.50 - 3.45 (m, 1H), 2.60 (s, 3H), 2.11 (br t, J = 18.9 Hz, 3H), 1.46 - 1.42 (m, 2H), 1.22 (br d, J = 7.6 Hz, 2H). Preparation 52 2-(1,1-difluoroethyl)-4-(trimethylstannyl)pyrimidine To a solution of 4-chloro-2-(1,1-difluoroethyl)pyrimidine (Preparation 19, 150 mg, 0.84 mmol) and hexamethylditin (550.4 mg, 1.68 mmol) in dioxane (3 mL) was added Pd(PPh3)4(97.1 mg, 0.084 mmol) and the reaction was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to give 2-(1,1-difluoroethyl)-4- (trimethylstannyl)pyrimidine (210 mg, crude) as brown oil. LCMS m / z = 309 [M+H]+ Preparation 53 N-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide To a solution of 5-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (1 g, 4.72 mmol) in dioxane (8 mL) was added acetamide (557.1 mg, 9.43 mmol), Brettphos-Pd-G3(427.5 mg, 0.472 mmol) and Cs2CO3 (3.07 g, 9.43 mmol) and the reaction mixture was stirred at 90 °C for 2 h under N2. The mixture was concentrated and the residue was purified by chromatography on silica gel (PE / EtOAc = 0 / 1) to give N-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (435 mg, 48.5% yield) as a solid.1H NMR (400 MHz, CDCl3) δ: 8.61 (s, 1H), 8.50 (s, 1H), 8.10 (br s, 1H), 7.99 (s, 1H), 4.15 (s, 3H), 2.23 (s, 3H). Preparation 54 N-(3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide To a solution of N-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (Preparation 53, 400 mg, 2.10 mmol) in MeCN (5 mL) was added NIS (567.8 mg, 2.52 mmol) and HBF4 (1.92 g, 10.52 mmol, 48% purity) at 25 °C and the reaction mixture was stirred at 80 °C for 2 h. The mixture was diluted with aq NaHCO3 (10 mL) and water (20 mL), then extracted with DCM (40 mL x 3). The combined organic phase was washed with water (15 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel column (EtOAc in PE from 20% to 80%) to give N-(3-iodo-1-methyl-1H-pyrazolo[3,4- c]pyridin-5-yl)acetamide (160 mg, 23.2% yield) as a red solid. LCMS m / z = 317 [M+H]+ Preparation 55 N-(1-methyl-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide To a solution of N-(3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (Preparation 54, 1.0 g, 3.16 mmol) in dioxane (20.0 mL) was added hexamethylditin (2.1 g, 6.33 mmol) and Pd(PPh3)2Cl2 (222.1 mg, 0.316 mmol). The reaction was stirred at 100 °C for 2 h under N2. The mixture was concentrated, the residue diluted with EtOAc, then the mixture was filtered and concentrated to give N-(1-methyl-3-(trimethylstannyl)-1H-pyrazolo[3,4- c]pyridin-5-yl)acetamide (2.4 g, crude) as a black solid. LCMS m / z = 353 [M+H]+ Example 1 tert-butyl 5-acetamido-3-[4-(1,1-difluoroethyl)thiazol-2-yl]pyrrolo[2,3-c]pyridine-1- A mixture of 2-bromo-4-(1,1-difluoroethyl)thiazole (100 mg, 439 μmol), tert-butyl 5- acetamido-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-c]pyridine-1- carboxylate (Preparation 26, 422 mg, 526 μmol), K3PO4 (1.5 M in water, 877 μL), XPhos Pd G3 (37 mg, 43.85 μmol) in 2-Methyltetrahydrofuran (5 mL) was degassed with N2, then heated at 100°C for 1h. The reaction was cooled down, filter off the solid, the filtrate was diluted with EtOAc, washed with aq.NaHCO3, the organic layer was separated, dried and concentrated. The crude was purified by chromatography on silica gel (0-100%EtOAc in heptane) to give tert-butyl 5-acetamido-3-[4-(1,1-difluoroethyl)thiazol-2-yl]pyrrolo[2,3- c]pyridine-1-carboxylate (78 mg, 42% yield) as a white powder. LCMS m / z = 423 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.57 (s, 1H), 9.1-9.2 (m, 1H), 9.04 (d, 1H, J=0.8 Hz), 8.5- 8.6 (m, 1H), 8.0-8.2 (m, 1H), 2.1-2.2 (m, 6H), 1.7-1.7 (m, 9H). Example 2 N-[3-[4-(1,1-difluoroethyl)thiazol-2-yl]-1H-pyrrolo[2,3-c]pyridin-5-yl]acetamide A mixture of tert-butyl 5-acetamido-3-[4-(1,1-difluoroethyl)thiazol-2-yl]pyrrolo[2,3- c]pyridine-1-carboxylate (Example 1, 70 mg, 166 μmol) in EtOH (2 mL) was heated in a sealed vial at 130°C for 30min. The solvent was removed under vacuum to give N-[3-[4-(1,1- difluoroethyl)thiazol-2-yl]-1H-pyrrolo[2,3-c]pyridin-5-yl]acetamide (54 mg, 95% yield) as a white powder. LMCS m / z = 323 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 12.1-12.3 (m, 1H), 10.2-10.4 (m, 1H), 8.90 (s, 1H), 8.55 (d, 1H, J=1.0 Hz), 8.34 (s, 1H), 7.8-8.0 (m, 1H), 2.0-2.2 (m, 6H). Example 3 N-(3-(4-(1,1-difluoroethyl)thiazol-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide To a mixture of N-[3-[4-(1,1-difluoroethyl)thiazol-2-yl]-1H-pyrrolo[2,3-c]pyridin-5- yl]acetamide (Example 2, 40 mg, 124 μmol) and Cs2CO3 (81 mg, 248 μmol) in DMF (1.5 mL) was added iodomethane (15 μL 248 μmol). After 30 min at rt, the mixture was diluted (EtOAc), washed (H2O x 3, then brine). The organic layer was then separated, dried and concentrated. The residue was purified by SiO2 (10-90%EtOAc-EtOH 3:1 with 2%NH4OH in heptane) to afford N-(3-(4-(1,1-difluoroethyl)thiazol-2-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (30 mg, 71% yield) as a white solid. LCMS m / z = 337 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.2-10.5 (m, 1H), 8.90 (s, 1H), 8.68 (d, 1H, J=1.0 Hz), 8.35 (s, 1H), 7.89 (s, 1H), 3.9-4.0 (m, 3H), 2.0-2.2 (m, 6H). Example 4 N-(3-(2-(1,1-difluoroethyl)thiazol-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide ( The title compound was prepared in the same way as described in Example 3 started from 4- bromo-2-(1,1-difluoroethyl)thiazole and tert-butyl 5-acetamido-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrrolo[2,3-c]pyridine-1-carboxylate. LCMS m / z = 337 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.2-10.4 (m, 1H), 8.8-9.0 (m, 1H), 8.64 (d, 1H, J=1.0 Hz), 8.1-8.2 (m, 1H), 7.8-7.9 (m, 1H), 3.93 (s, 3H), 2.25 (t, 3H, J=19.0 Hz), 2.10 (s, 3H). Example 5 N-(3-(4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared in the same way as described in Example 2 from tert-butyl 5-acetamido-3-(4- (1,1-difluoroethyl)-5-methylthiazol-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate. LCMS m / z = 337 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 12.0-12.2 (m, 1H), 10.2-10.4 (m, 1H), 8.90 (s, 1H), 8.53 (d, 1H, J=1.0 Hz), 8.22 (s, 1H), 2.5-2.6 (m, 3H), 2.1-2.2 (m, 6H); Example 6 N-(3-(4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide N-(3-(4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide compound was prepared in the same way as described in Example 3 from N-(3- (4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide (Example 5). LCMS m / z = 351 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.3-10.4 (m, 1H), 8.89 (s, 1H), 8.66 (d, 1H, J=1.0 Hz), 8.23 (s, 1H), 3.93 (s, 3H), 2.5-2.6 (m, 3H), 2.1-2.2 (m, 6H). Example 7 N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared in the same way as described in Example 2 from tert-butyl 5-acetamido-3-(6-(2- fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate. LCMS m / z = 314 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 11.9-12.2 (m, 1H), 10.22 (s, 1H), 9.2-9.2 (m, 1H), 9.13 (s, 1H), 8.5-8.6 (m, 2H), 8.5-8.5 (m, 1H), 2.1-2.1 (m, 3H), 1.8-1.9 (m, 6H). Example 8 N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide was prepared in the same way as described in Example 3 from N-(3-(6-(2- fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide. LCMS m / z = 328 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.2-10.4 (m, 1H), 9.19 (s, 1H), 9.04 (s, 1H), 8.67 (d, 1H, J=0.8 Hz), 8.52 (s, 1H), 8.5-8.5 (m, 1H), 3.96 (s, 3H), 2.1-2.1 (m, 3H), 1.86 (s, 6H). Example 9 N-(1-methyl-3-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5- The title compound was prepared in the same way as described in Example 3 from N-(3-(4- (tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide to afford N-(1- methyl-3-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (3.5 mg, 10% yield) as a brown solid. LCMS m / z = 343 [M+H]+ 1H NMR (400 MHz, CDCl3) δ (ppm) 8.91 (s, 1H), 8.41 (s, 1H), 7.98 (br s, 1H), 7.83 (s, 1H), 6.89 (s, 1H), 4.17-4.22 (m, 1H), 4.06-4.08 (m, 1H), 3.90-3.97 (m, 5H), 3.66-3.69 (m, 1H), 2.27-2.42 (m, 2H), 2.23 (s, 3H). Example 10 rac-(R)-N-(1-methyl-3-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide The title compound was prepared in the same way as described in Example 3 from rac-(R)-N- (3-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide to give rac-(R)-N-(1-methyl-3-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (6.6 mg, 24.48% yield) as a yellow solid. LCMS m / z = 357 [M+H]+.1H NMR (500 MHz, CHLOROFORM-d) δ (ppm) 8.90 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 4.11-4.17 (m, 2H), 3.98-4.01 (m, 1H), 3.88-3.93 (m, 4H), 3.53- 3.57 (m, 1H), 2.43 (s, 3H), 2.37-2.42 (m, 1H), 2.27-2.29 (m, 1H), 2.24 (s, 3H). ([M+H] = 357.2). Example 11 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a solution of N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Preparation 28, 61.1 mg) in Dioxane (3 mL), H2O (0.5 mL) was added 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 6, 100 mg, 317 μmol), K2CO3(88 mg, 635 μmol), Pd(dppf)Cl2.DCM (26 mg, 32 μmol). The mixture was stirred at 90 °C for 16 hours under N2. The mixture was concentrated and purified by prep-HPLC (Column: Phenomenex Gemini NX 150*30mm*5um; Condition: water(NH4HCO3)-ACN; Begin B: 25; End B: 55; Gradient Time (min): 11; 100%B Hold Time (min): 2.5; Flow Rate (ml / min): 25; Detection wavelength: 220 nm) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (14 mg, 12% yield, 100% purity) as a yellow solid. LCMS m / z = 346 [M+H]+.1H NMR (400 MHz, CDCl3) δ (ppm) 9.05 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.98 (br s, 1H), 7.51 (s, 1H), 3.96 (s, 3H), 2.64 (s, 3H), 2.15-2.26 (m, 6H). Example 12 N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- To a solution of N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Preparation 28, 200 mg, 381 μmol) in Dioxane (5 mL)，H2O (1 mL) was added 4-chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine (Preparation 7, 79 mg, 381 μmol), Pd(dppf)Cl2.DCM (31 mg, 38 μmol), K2CO3(105 mg, 762 μmol). The mixture was stirred at 90 °C for 3 hours under N2. The mixture was concentrated and purified by prep-HPLC (Column: Phenomenex Gemini NX 150*30mm*5um; Condition: water (NH4HCO3)-ACN; Begin B: 28; End B: 58; Gradient Time (min): 11; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to give N-(3-(2-(1,1-difluoroethyl)-6- ethylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (45 mg, 32% yield, 100% purity) as a yellow solid. LCMS m / z = 360 [M+H]+.1H NMR (400 MHz, CDCl3) δ (ppm) 9.06 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 8.03 (br s, 1H), 7.52 (s, 1H), 3.96 (s, 3H), 2.91 (q, J=7.6 Hz, 2H), 2.15-2.26 (m, 6H), 1.40 (t, J=7.6 Hz, 3H). Example 13 N-(3-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a solution of N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Preparation 28, 100 mg, 317.28 μmol) and 2-chloro-4-(1,1- difluoroethyl)pyrimidine (85 mg, 476 μmol) in Dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2.DCM (25.91 mg, 31.73 μmol) and K2CO3 (131.55 mg, 951.85 μmol). The reaction mixture was stirred at 90oC for 2 h under N2. The mixture was concentrated and purified by prep-HPLC (Column: Phenomenex Gemini NX 150×30mm,5μm; Condition: water (NH4HCO3)-ACN; Begin B: 32; End B: 62; Gradient Time(min): 11; 100%B Hold Time(min): 2.5; Flow Rate(mL / min): 25; Detection wavelength: 220) to give N-(3-(4-(1,1- difluoroethyl)pyrimidin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (8 mg, 23 μmol, 7% yield, 99% purity) as a yellow solid. LCMS m / z = 332 [M+H]+ 1H NMR (400 MHz, MeOD) δ (ppm) 9.11 (s, 1H), 8.88 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 7.41 (d, J = 5.2 Hz, 1H), 4.00 (s, 3H), 2.13-2.23 (m, 6H). Example 14 N-(3-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a mixture of 2-chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 21, 90 mg, 467.31 µmol) and N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 28, 221 mg, 701 µmol) in dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)Cl2·DCM (38 mg, 47 μmol) and K2CO3(194 mg, 1.4 mmol) at 25 °C and the mixture was stirred at 90 °C for 2 h under N2. The reaction mixture was concentrated to give the residue, which was purified by prep-HPLC (Column: Phenomenex Gemini NX 150×30mm, 5μm; Condition: water (NH4HCO3)-ACN; Begin B: 34; End B: 64; Gradient Time (min): 11; 100%B Hold Time (min): 2.5; Flow Rate (mL / min): 25) to give N-(3-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (8 mg, 23 µmol, 5% yield, 100% purity) as a gray solid. LCMS m / z = 346 [M+H]+ 1H NMR (400MHz, CDCl3) δ (ppm) 9.40 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.24 (s, 1H), 3.96 (s, 3H), 2.64 (s, 3H), 2.27 (s, 3H), 2.21 (t, J=19.2 Hz, 3H) Example 15 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a suspension of N-(3-(2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 100 mg, 302 μmol) and Cesium carbonate (148 mg, 453 μmol) in dry DMF (2 mL) was added Ethyl iodide (47 mg, 302 μmol, 24 μL) and the resulting mixt was stirred at 100 °C for 1h. Cooled to rt, diluted with water and EtOAc, the layers separated and the aqueous one extracted with EtOAc (3x). The combined organic extracts were filtered through Celite with aid of EtOAc, washed with brine (3x), dried (MgSO4), filtered and concentrated in vacuum. The residue was purified by SiO2 (0-100% EtOAc in Hept) to afford N-[3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1-ethyl- pyrrolo[2,3-c]pyridin-5-yl]acetamide (71 mg, 187 μmol, 62% yield, 95% purity) as an off- white solid. LCMS m / z = 360 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.31 (s, 1 H), 9.19 (s, 1 H), 8.73 (d, J=1.2 Hz, 1 H), 8.68 (s, 1 H), 7.82 (s, 1 H), 4.37 (q, J=7.1 Hz, 2 H), 2.53 (s, 3 H), 2.21 (t, J=20.2 Hz, 3 H), 2.10 (s, 3 H), 1.49 (t, J=7.3 Hz, 3 H). Example 16 Rac-cis / trans-N-(1-((1s,3s)-3-cyanocyclobutyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin- 4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide A suspension of (rac-cis / trans-3-cyanocyclobutyl)methanesulfonate (52.88 mg, 301.82 μmol) , N-[3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1H-pyrrolo[2,3-c]pyridin-5- yl]acetamide (Example 34, 100 mg, 301 μmol) and CsCO3 (148 mg, 453 μmol) in dry DMF (2 mL) was stirred at 100 °C for 17h. Additional (3-cyanocyclobutyl) methanesulfonate (53 mg, 302 μmol) was added and stirred at 100 °C was continued for 24 h. Cooled to rt, diluted with water and EtOAc, the layers separated and the aqueous one extracted with EtOAc (3x). The combined organic extracts were filtered through Celite with aid of EtOAc, washed with brine (3x), dried (MgSO4), filtered and concentrated in vacuum. The residue was purified by SiO2 (0-100% EtOAc in Hep) to afford N-[1-(3-cyanocyclobutyl)-3-[2-(1,1-difluoroethyl)-6- methyl-pyrimidin-4-yl]pyrrolo[2,3-c]pyridin-5-yl]acetamide (32 mg, 75 μmol, 25% yield, 98% purity) as a pale yellow solid. LCMS m / z = 411 [M+H]+.1H NMR (500 MHz, DMSO- d6) δ ppm 10.33 (s, 1 H), 9.21 (s, 1 H), 8.91 (s, 1 H), 8.77 (d, J=1.2 Hz, 1 H), 7.91 (s, 1 H), 5.51 - 5.58 (m, 1 H), 3.52 - 3.59 (m, 1 H), 2.92 - 3.05 (m, 4 H), 2.54 (S, 3 H), 2.22 (t, J=15.0 Hz, 3 H), 2.10 (s, 3 H). Example 17 rac-(R)-N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(tetrahydrofuran-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide A suspension of [rac-(3R)-tetrahydrofuran-3-yl] methanesulfonate (73 mg, 439 μmol) , N-[3- [2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1H-pyrrolo[2,3-c]pyridin-5-yl]acetamide (Example 34, 65 mg, 146 μmol) and CsCO3 (238 mg, 731 μmol) in dry DMF (2 mL) was stirred at 100 °C for 17h. Cooled to rt, diluted with water and EtOAc, the layers separated and the aqueous one extracted with EtOAc (3x). The comb org extracts were filtered through Celite with aid of EtOAc, washed with brine (3x), dried (MgSO4), fitered and conc in vacuum. The residue was purified by SiO2 (0-4% MeOH in DCM). Desired product was obtained as a pale yellow solid, which was triturated with diethyl ether to provide N-[3-[2- (1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1-[rac-(3S)-tetrahydrofuran-3-yl]pyrrolo[2,3- c]pyridin-5-yl]acetamide (15 mg, 38 μmol, 26% yield) as an off-white solid. LCMS m / z = 402 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.45 (br s, 1 H), 9.16 (br s, 1 H), 8.82 (s, 1 H), 8.69 (s, 1 H), 7.98 (s, 1 H), 5.42 - 5.48 (m, 1 H), 4.18 (td, J=8.2, 6.6 Hz, 1 H), 3.98 - 4.08 (m, 2 H), 3.87 (td, J=8.6, 6.3 Hz, 1 H), 2.55 - 2.63 (m, 1 H), 2.53 (s, 3 H), 2.25 - 2.31 (m, 1 H), 2.21 (t, J=19.1 Hz, 3 H), 2.12 (s, 3 H). Example 18 N-(3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)acetamide A vial containing 5-chloro-3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H- pyrazolo[3,4-c]pyridine (Preparation 31, 137 mg, 427 umol), acetamide (105 mg, 1.8 mmol), cesium carbonate (371 mg, 1.1 mmol), and BrettPhos Pd G3 (75 mg, 82 umol) in anhydrous dioxane (3 mL) was degassed then backfilled with nitrogen then carefully heated to 85 °C. After 2.5 h, the mixture was cooled to room temperature then filtered through a celite plug. The plug was rinsed several times with EtOAc, then the organics were pooled and concentrated under reduced pressure. The residue was purified with (30-100 % 3:1 EtOAc: ethanol in heptane.) The desired fractions were pooled then concentrated under reduced pressure to afford a yellow solid that was dissolved in DMSO and few drops of water then filtered. The homogeneous solution was submitted for mass directed reverse phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 30 mm × 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 − 65 % B (0.2% NH4OH final v / v % modifier) with flow rate at 60 mL / min, affording N-(3-(2- (2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide (10 mg, 6 % yield) as a white solid. LCMS m / z = 343.0 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.55 (s, 1H), 9.24 (s, 1H), 9.05 (d, J = 1.5 Hz, 1H), 7.91 (s, 1H), 4.27 (s, 3H), 2.58 (s, 3H), 2.13 (s, 3H), 1.89 (s, 3H), 1.85 (s, 3H).19F NMR (471 MHz, DMSO-d6) δ (ppm) -137.09. Example 19 N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide Prepared in a similar manner to Example 18 starting with 2-chloro-6-(1-fluoro-1-methyl- ethyl)pyrazine to afford N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)acetamide (2 mg) as a white solid. LCMS m / z = 329.0 [M+ H]+.1H NMR (500 MHz, CD2Cl2) δ (ppm) 9.30 (s, 1H), 9.27 - 9.21 (m, 1H), 8.75 (d, J = 0.9 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.19 (br s, 1H), 4.23 (s, 3H), 2.22 (s, 3H), 1.92 (s, 3H), 1.88 (s, 3H).19F NMR (471 MHz, CD2Cl2) δ (ppm) = -146.61. Example 20 N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide Prepared in a similar manner to Example 18 starting with 4-chloro-6-ethyl-2-(1- fluorocyclopropyl)pyrimidine (Preparation 25) to afford N-(3-(6-ethyl-2-(1- fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (4 mg) as a white solid. LCMS m / z = 355 [M+ H]+.1H NMR (500 MHz, CD2Cl2) δ (ppm) 9.16 (s, 1H), 8.66 (d, J = 1.2 Hz, 1H), 8.15 (br s, 1H), 7.80 (s, 1H), 4.21 (s, 3H), 2.86 (q, J = 7.6 Hz, 2H), 2.22 (s, 3H), 1.77 - 1.72 (m, 2H), 1.65 - 1.59 (m, 2H), 1.36 (t, J = 7.6 Hz, 3H).19F NMR (471 MHz, CD2Cl2) δ (ppm) = -195.49. Example 21 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)propionamide Prepared in a similar manner to Example 18 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methyl-pyrimidine (Preparation 11) and N-ethylacetamide to afford N-(3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)propionamide (15 mg) as a white solid. LCMS m / z = 361 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.50 (s, 1H), 9.22 (s, 1H), 9.07 (d, J = 1.2 Hz, 1H), 8.08 (s, 1H), 4.29 (s, 3H), 2.62 (s, 3H), 2.43 (q, J = 7.6 Hz, 2H), 2.24 (t, J = 19.1 Hz, 3H), 1.11 (t, J = 7.6 Hz, 3H).19F NMR (471 MHz, DMSO-d6) δ (ppm) -90.29. Example 22 N-(3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide A vial containing 5-chloro-3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridine (149 mg, 467 umol) (prepared similar to Preparation 32 using 4- chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine (Preparation 11)), acetamide (112 mg, 1.9 mmol), cesium carbonate (404 mg, 1.2 mmol), and BrettPhos Pd G3 (80 mg, 89 umol) in anhydrous dioxane (3 mL) was degassed then backfilled with nitrogen then carefully heated to 85 °C. After 2.5 h, the mixture was cooled to room temperature then filtered through a celite plug. The plug was rinsed several times with EtOAc, then the organics were pooled and concentrated under reduced pressure. The residue was purified with (30-100 % 3:1 EtOAc: ethanol in heptane.) The desired fractions were pooled then concentrated under reduced pressure to afford a yellow solid that was dissolved in DMSO and few drops of water then filtered. The homogeneous solution was submitted for mass directed reverse phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 30 mm × 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 − 65 % B (0.2% NH4OH final v / v % modifier) with flow rate at 60 mL / min. The desired fractions were pooled then concentrated under reduced pressure to afford N-(3-(2-(2- fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide (49 mg, 29 % yield) as a white solid. LCMS m / z = 342 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.28 (s, 1H), 9.18 (s, 1H), 8.66 (d, J = 0.9 Hz, 1H), 8.53 (s, 1H), 7.61 (s, 1H), 3.96 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H), 1.86 (s, 3H), 1.81 (s, 3H).19F NMR (471 MHz, DMSO-d6) δ (ppm) -137.38. Example 23 N-(3-(2-(1,1-difluoroethyl)thiazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide Prepared in a similar manner to Example 22 starting with 5-bromo-2-(1,1- difluoroethyl)thiazole to afford N-(3-(2-(1,1-difluoroethyl)thiazol-5-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (2 mg) as a white solid. LCMS m / z = 337 [M+ H]+.1H NMR (500 MHz, CD2Cl2) δ (ppm) 8.61 (s, 1H), 8.46 (s, 1H), 8.13 (br s, 1H), 7.96 (t, J = 1.5 Hz, 1H), 7.51 (s, 1H), 3.90 (s, 3H), 2.20 (s, 3H), 2.15 (t, J = 18.5 Hz, 3H).19F NMR (471 MHz, CD2Cl2) δ (ppm) -81.00. Example 24 N-(3-(2-(1,1-difluoroethyl)-6-methoxypyridin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- Prepared in a similar manner to Example 22 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methoxypyridine (Preparation 3) to afford N-(3-(2-(1,1-difluoroethyl)-6-methoxypyridin-4- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (26 mg) as a white solid. LCMS m / z = 361 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.39 (s, 1H), 8.69 (s, 2H), 8.38 (s, 1H), 7.56 (d, J = 0.9 Hz, 1H), 7.13 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.10 (s, 3H), 2.02 (t, J = 19.1 Hz, 3H).19F NMR (471 MHz, DMSO-d6) δ -89.30. Example 26 N-(3-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide Prepared in a similar manner to Example 22 starting with 4-bromo-2-(1,1- difluoroethyl)pyridine to afford N-(3-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (7 mg) as a white solid. LCMS m / z = 331.0 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.40 (s, 1H), 8.75 - 8.69 (m, 2H), 8.66 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.75 (dd, J = 1.5, 5.2 Hz, 1H), 3.95 (s, 3H), 2.11 (s, 3H), 2.04 (t, J = 19.1 Hz, 3H).19F NMR (471 MHz, DMSO-d6) δ (ppm) -88.66. Example 26 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)propionamide Prepared in a similar manner to Example 22 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methyl-pyrimidine (Preparation 6) and N-Ethylacetamide to afford N-(3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)propionamide (51 mg) as a white solid. LCMS m / z = 360 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 10.24 (s, 1H), 9.16 (s, 1H), 8.68 (d, J = 0.9 Hz, 1H), 8.59 (s, 1H), 7.77 (s, 1H), 3.97 (s, 3H), 2.53 (s, 3H), 2.43 - 2.38 (m, 2H), 2.21 (t, J = 19.1 Hz, 3H), 1.10 (t, J = 7.6 Hz, 3H).19F NMR (471 MHz, DMSO-d6) δ (ppm) -90.19. Example 27 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)propionamide Prepared in a similar manner to Example 22 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methyl-pyrimidine (Preparation 6) and 1-methylurea to afford 1-(3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea (15 mg) as a white solid. LCMS m / z = 361 [M+ H]+.1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.09 (s, 1H), 8.58 (d, J = 0.9 Hz, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 7.74 (s, 2H), 3.93 (s, 3H), 2.74 (d, J = 4.6 Hz, 3H), 2.52 (s, 3H), 2.22 - 2.14 (m, 3H).19F NMR (471 MHz, DMSO-d6) δ (ppm) - 90.27. Example 28 N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner Example 22 using 5-chloro-3-(6-(1,1-difluoroethyl)pyridin-2- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 22 with 2-bromo-6-(1,1- difluoroethyl)pyridine, 55.6 mg, 181 umol) to afford the N-(3-(6-(1,1-difluoroethyl)pyridin- 2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (50 mg, 151 umol, 84 % yield). LCMS m / z = 331 [M+ H]+.1H NMR (500 MHz, CDCl3) δ (ppm) 9.02 (s, 1H), 8.73 (d, J = 5.2 Hz, 1H), 8.44 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.26 - 7.15 (m, 1H), 3.95 (s, 3H), 2.26 (s, 3H), 1.93 (br s, 3H). Example 29 N-(3-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner Example 22 using 5-chloro-3-(2-(1,1-difluoroethyl)-6- methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 32 using Preparation 8, 61 mg, 181 umol) to afford the title compound (18 mg, 50 umol, 28 % yield) as a white solid. LCMS m / z = 362 [M+ H]+.1H NMR (500 MHz, CDCl3) δ (ppm) 8.91 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 6.97 (s, 1H), 3.99 (s, 3H), 3.87 (s, 3H), 2.19 (s, 3H), 1.75 (br s, 3H). Example 30 N-(3-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)acetamide Prepared in a similar manner Example 20 using 5-chloro-3-(2-(1,1-difluoroethyl)-6- methoxypyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridine (Preparation 31 using 4- chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (Preparation 8), 336 mg, 990 umol) to afford the title compound N-(3-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1-methyl- 1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (7 mg, 2% yield over 2 steps). LCMS m / z = 363 [M+ H]+.1H NMR (500 MHz, chloroform-d) δ (ppm) 9.33 (s, 1H), 8.65 (s, 1H), 8.15 (br s, 1H), 7.48 (s, 1H), 4.24 (s, 3H), 4.11 (s, 3H), 2.37 - 2.22 (m, 6H).19F NMR (471 MHz, chloroform-d) δ (ppm) -92.49. Example 31 N-(3-(2-(2-fluoropropan-2-yl)-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide Prepared similar to Example 22 using 5-chloro-3-(2-(2-fluoropropan-2-yl)-6- methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 32 with 4-chloro- 2-(2-fluoropropan-2-yl)-6-methoxypyrimidine (Preparation 12)) to afford the title compound (40 mg, 112 umol, 61 % yield) as a white solid. LCMS m / z = 358 [M+ H]+.1H NMR (500 MHz, CDCl3) δ (ppm) 8.92 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 6.84 (s, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 2.18 (s, 3H), 1.82 (s, 3H), 1.78 (s, 3H). Example 32 N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner as described Example 18 but using 5-chloro-3-(6-ethyl-2-(1- fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 32 starting with 4-chloro-6-ethyl-2-(1-fluorocyclopropyl)pyrimidine (Preparation 25), 59.8 mg, 181 umol) to afford the title compound N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (9 mg, 25.5 umol, 14 % yield). LCMS m / z = 354 [M+ H]+.1H NMR (500 MHz, CDCl3) δ (ppm) 9.05 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.34 (s, 1H), 3.97 (s, 3H), 2.92 - 2.83 (m, 2H), 1.77 - 1.60 (m, 7H), 1.44 - 1.35 (m, 3H) Example 33 tert-Butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate Prepared in a similar manner as described Example 1 using tert-butyl 5-acetamido-3-bromo- pyrrolo[2,3-c]pyridine-1-carboxylate and 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 6) to afford the title compound tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (25 mg, 26% yield). LCMS m / z = 432 [M+ H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.26 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.74 (s, 1H), 7.99 (s, 1H), 2.66 (s, 3H), 2.16-2.34 (m, 6H), 1.77 (s, 9H) Example 33, alternative synthesis tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate To a stirring solution of 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine (Preparation 6, 333.3 mg, 1.73 mmol) and tert-butyl 5-acetamido-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Preparation 26, 500 mg, 0.872 mmol) in dioxane (5 mL) were added K3PO4(1.5 M, 1.74 mmol, 1.16 mL) and Pd(dppf)Cl2.CH2Cl2(71.23 mg, 87.2 μmol). The resulting mixture was degassed for 10 mins and then heated at 100°C for 3 h. The reaction mixture was filtered through Celite® and the filtrate evaporated to give tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate (87 mg, 23.1% yield) as an off-white solid. LCMS m / z = 432.0 [M+H]+Example 34 N-(3-(2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar to Example 2 but using tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)- 6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Example 33) to afford the title compound N-(3-(2-(1,1-Difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (13 mg, 81% yield). LCMS m / z = 332 [M+ H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.11 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 7.80 (s, 1H), 2.61 (s, 3H), 2.15-2.37 (m, 6H) Example 34, alternative synthesis N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide trifluoroacetate To a stirring solution of tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Example 33, 87 mg, 0.202 mmol) in anhydrous DCM (3 mL) was added TFA (344.9 mg, 3.02 mmol) and the reaction was stirred at rt for 16 h. The reaction mixture was evaporated, to give N-(3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide trifluoroacetate. LCMS m / z = 332.0 [M+H]+Example 35 tert-Butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate Prepared in a similar manner as described in Example 1 using 4-chloro-2-(1,1-difluoroethyl)- 6-ethylpyrimidine (Preparation 7) to afford the title compound tert-Butyl 5-acetamido-3-(2- (1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (6 mg, 25% yield). LCMS m / z = 468 [M+ Na]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.26 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.77 (s, 1H), 7.98 (s, 1H), 2.94 (q, J = 7.5 Hz, 2H), 2.17-2.33 (m, 6H), 1.77 (s, 9H), 1.41 (t, J = 7.8 Hz, 3H) Example 35, alternative synthesis tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate To a mixture of tert-butyl 5-acetamido-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-c]pyridine-1-carboxylate (Preparation 26, 33 g, 82.24 mmol), 4-chloro-2-(1,1- difluoroethyl)-6-ethylpyrimidine (Preparation 7, 20.39 g, 98.7 mmol) and K2CO3 (28.42 g, 205.6 mmol) in dioxane (500 mL) and H2O (100 mL) was added Pd(dppf)Cl2 DCM (3.36 g, 4.11 mmol) under N2. The reaction mixture was stirred at 90 °C for 4 h under N2. The mixture was concentrated then diluted with water (500 mL). The mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6- ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (30 g, 81.9% yield) as a yellow solid. LCMS m / z = 446 [M+H]+ Example 36 N-(3-(2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide Prepared in a similar manner as described (Example 2) but using tert-butyl 5-acetamido-3-(2- (1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Example 35) to afford the title compound N-(3-(2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (35 mg, 99% yield). LCMS m / z = 346 [M+ H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.10 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 7.78 (s, 1H), 2.89 (q, J = 7.5 Hz, 2H), 2.16-2.33 (m, 6H), 1.40 (t, J = 7.8 Hz, 3H) Example 36, alternative synthesis tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridine-1-carboxylate A mixture of tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridine-1-carboxylate (Example 35, 30 g, 67.35 mmol) in hexafluoroisopropanol (300 mL) was stirred at 70 °C for 16 h. The mixture was concentrated to give tert-butyl 5-acetamido-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridine-1-carboxylate (30 g, crude) as an off white solid. LCMS m / z = 346 [M+H]+ Example 37 N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner as described in Example 3 but using N-(3-(2-(1,1- difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 36) and 2-iodopropane to afford the title compound N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin- 4-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (22 mg, 98% yield). LCMS m / z = 388 [M+ Na]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.14 (s, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 7.82 (s, 1H), 4.92-5.01 (m, 1H), 2.89 (q, J = 7.5 Hz, 2H), 2.17-2.30 (m, 6H), 1.67 (d, J = 6.5 Hz, 6H), 1.40 (t, J = 7.5 Hz, 3H) Example 38 N-[1-cyclobutyl-3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]pyrrolo[2,3-c]pyridin-5- yl]acetamide To a mixture of N-[3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1H-pyrrolo[2,3- c]pyridin-5-yl]acetamide (Example 34, 21 mg, 0.063 mmol), cesium carbonate (31 mg, 0.095 mmol), iodocyclobutane (33 mg, 0.18 mmol) was added DMF (1 mL). The mixture was heated at 100oC for 1h. Added water and EtOAc. the organic phase was concentrated and triturated with small amount of MeCN to get N-[1-cyclobutyl-3-[2-(1,1-difluoroethyl)-6- methyl-pyrimidin-4-yl]pyrrolo[2,3-c]pyridin-5-yl]acetamide as an off-white solid (6 mg, 25% yield). LCMS m / z = 386 [M+ H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.12 (s, 1H), 8.64 (s, 1H), 8.62 (s, 1H), 7.83 (s, 1H), 5.08-5.19 (m, 1H), 2.57-2.75 (m, 7H), 2.17-2.30 (m, 6H), 2.05-2.11 (m, 2H) Example 39 N-(1-Cyclopentyl-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide Prepared in a similar manner as described in Example 38 but using iodocyclopentane to afford the title compound N-(1-Cyclopentyl-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (14 mg, 55% yield). LCMS m / z = 400 [M+ H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.00 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.69 (s, 1H), 4.88-5.00 (m, 1H), 2.48 (s, 3H), 2.20-2.34 (m, 2H), 2.04-2.18 (m, 6H), 1.69-2.02 (m, 6H) Example 40 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(oxetan-3-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a mixture of N-[3-bromo-1-(oxetan-3-yl)pyrrolo[2,3-c]pyridin-5-yl]acetamide (Preparation 34, 62 mg, 0.2 mmol), 4-chloro-2-(1,1-difluoroethyl)-6-methyl-pyrimidine (Preparation 6, 58 mg, 0.3 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (102 mg, 0.4 mmol) and CsF (152 mg, 1.00 mmol) in a microwave tube was added H20 (0.2 mL), MeOH (1 mL). Flushed with N2, and heated at 70^C for 5 min. At the meantime, in a separate reaction vial was added bis(1-adamantyl)- butyl-phosphane (29 mg, 0.08 mmol) diacetoxypalladium (9 mg, 0.04 mmol) and THF (1 mL), flushed with N2. The resulting light-yellow solution was added to the above reaction suspension (sealed tube with 70^C heating). The mixture was heated at 70oC for 1h. Added water (2 mL) and EtOAc (2 mL). The solid not dissolved in two phases was filtered off and washed with water and MeCN. The organic phase of the filtrate was separated, concentrated and purified by normal phase column (24g, EtOAc / EtOH 3 / 1 in heptane 50-100%), followed by trituration by MeCN to get N-[3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1- (oxetan-3-yl)pyrrolo[2,3-c]pyridin-5-yl]acetamide (16 mg, 20% yield) as a white solid. LCMS m / z = 388 [M+H]+.1H NMR (METHANOL-d4, 400 MHz) δ (ppm) 9.19 (s, 1H), 8.83 (s, 1H), 8.78 (s, 1H), 7.86 (s, 1H), 5.83-5.95 (m, 1H), 5.28 (t, J = 7.5 Hz, 2H), 5.13 (dd, J = 7.3, 6.3 Hz, 2H), 2.63 (s, 3H), 2.18-2.30 (m, 6H) Example 41 N-(3-(2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)-1-(oxetan-3-yl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide Prepared in a similar manner as described in Example 37 using N-(3-(2-(1,1-Difluoroethyl)- 6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 36) and 3- iodooxetane to afford the title compound N-(3-(2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)- 1-(oxetan-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (181 mg, 29% yield). LCMS m / z = 402 [M+ 1]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.26 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.77 (s, 1H), 7.98 (s, 1H), 2.94 (q, J = 7.5 Hz, 2H), 2.17-2.33 (m, 6H), 1.77 (s, 9H), 1.41 (t, J = 7.8 Hz, 3H) Example 42 Rac-N-(3-(2-(1,1-Difluoroethyl)-6-ethylpyrimidin-4-yl)-1-(tetrahydrofuran-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide Prepared in a similar manner as described in Example 37 but using N-(3-(2-(1,1- difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 36) and 3-iodotetrahydrofuran to afford the title compound rac-N-(3-(2-(1,1-Difluoroethyl)-6- ethylpyrimidin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (7 mg, 29% yield). LCMS m / z = 416 [M+ H]+.1H NMR (METHANOL-d4, 400 MHz): δ (ppm) 9.02 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 5.28 (tt, J = 5.4, 2.6 Hz, 1H), 4.07-4.23 (m, 2H), 3.98 (dd, J = 10.3, 5.8 Hz, 1H), 3.85 (td, J = 8.6, 6.8 Hz, 1H), 2.77 (q, J = 7.5 Hz, 2H), 2.58 (dtd, J = 13.8, 8.1, 6.0 Hz, 1H), 2.18-2.31 (m, 1H), 2.03-2.17 (m, 6H), 1.28 (t, J = 7.5 Hz, 3H) Example 43 N-(1-ethyl-3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a stirring solution of 5-chloro-1-ethyl-3-[2-(1-fluoro-1-methyl-ethyl)-6-methyl-pyrimidin- 4-yl]pyrrolo[2,3-c]pyridine (Preparation 32 starting with 3-bromo-5-chloro-1-ethyl-1H- pyrrolo[2,3-c]pyridine (Preparation 29) and 4-chloro-2-(2-fluoropropan-2-yl)-6- methylpyrimidine (Preparation 11), 185 mg, 555.89 μmol) and acetamide (136.01 mg, 2.30 mmol) dissolved in dioxane (6 mL) were added cesium carbonate (482.54 mg, 1.48 mmol) and BrettPhos Pd G3 (97.26 mg, 107.30 μmol). The resulting mixture was degassed for 10 mins, heated at 90°C and monitored with LCMS. After 5h, the reaction mixture was cooled to room temperature, filtered through celite plug, and evaporated. The crude product was purified using 0-100% heptane-ethyl acetate / ethanol (3:1) to obtain N-[1-ethyl-3-[2-(1- fluoro-1-methyl-ethyl)-6-methyl-pyrimidin-4-yl]pyrrolo[2,3-c]pyridin-5-yl]acetamide (96 mg, 270.11 μmol, 49% yield) as pale white solid. LCMS m / z = 356 [M+ H]+.1H NMR (500 MHz, DMSO) δ 10.46 (s, 1H), 9.44 (d, J = 1.1 Hz, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 4.23 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 1.82 (s, 3H), 1.78 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H);19F NMR (471 MHz, DMSO) δ -137.57. Example 44 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-ethyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide To a stirring solution of 5-chloro-3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1-ethyl- pyrazolo[3,4-c]pyridine (Preparation 30 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methylpyrimidine (Preparation 6), 200 mg, 592.15 μmol) and acetamide (144.88 mg, 2.45 mmol) dissolved in dioxane (6 mL) were added cesium carbonate (514.02 mg, 1.58 mmol) and BrettPhos Pd G3 (103.61 mg, 114.29 μmol) . The resulting mixture was degassed for 10 mins, heated at 90°C and monitored with LCMS. After 12 h, the reaction mixture was cooled to room temperature, filtered through celite plug, and evaporated. The crude product was purified with (0-100 % 3:1 EtOAc: ethanol in heptane.) The desired fractions were pooled then concentrated under reduced pressure that was dissolved in DMSO and was submitted for mass directed reverse phase HPLC purification. Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 30 mm × 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 − 60 % B (0.2% NH4OH final v / v % modifier) with flow rate at 60 mL / min. To afford N-[3-[2-(1,1-difluoroethyl)-6-methyl- pyrimidin-4-yl]-1-ethyl-pyrazolo[3,4-c]pyridin-5-yl]acetamide (24 mg, 65 μmol, 11% yield) as white solid. LCMS m / z = 361 [M+ H]+.1H NMR (500 MHz, DMSO) δ 10.57 (s, 1H), 9.21 (s, 1H), 9.10 (s, 1H), 8.06 (s, 1H), 4.66 (q, J = 7.2 Hz, 2H), 2.62 (s, 3H), 2.23 (t, J = 19.1 Hz, 3H), 2.13 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H).19F NMR (471 MHz, DMSO) δ -90.24. Example 45 N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared similar to Example 2 from tert-butyl 5-acetamido-3-(6-(1,1- difluoroethyl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate using 2-chloro-6-(1,1- difluoroethyl)pyrazine like Example 1. LCMS m / z = 318 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 12.1-12.3 (m, 1H), 10.26 (s, 1H), 9.33 (s, 1H), 9.1-9.2 (m, 1H), 8.66 (s, 1H), 8.64 (s, 1H), 8.5-8.6 (m, 1H), 2.2-2.3 (m, 3H), 2.10 (s, 3H);. Example 46 N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared similarly to Example 3, from N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 45). LCMS m / z = 332 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.2-10.4 (m, 1H), 9.2-9.3 (m, 1H), 9.1-9.2 (m, 1H), 8.69-8.7 (m, 1H), 8.66 (s, 1H), 8.60 (s, 1H), 3.98 (s, 3H), 2.21-2.31 (m, 3H), 2.11 (s, 3H). Example 47 N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide To a solution of compound N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 36, 10 g, 28.96 mmol) and K2CO3 (10.0 g, 72.39 mmol) in DMF (100 mL) was added ethyl iodide (6.32 g, 40.54 mmol) and the reaction was stirred at 100 °C for 2 h. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with H2O (100 mL x 3), brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was dissolved in H2O (140 mL) and 5% wt H2SO4(56 mL) and the mixture stirred at 25oC for 30 min, then filtered.3 wt% APDTC was added, the solution stirred for 1 h, then extracted with EtOAc (50 mL x 2). The aqueous solution was adjusted to pH 6 using saturated NaHCO3at 25 °C, the solution heated to 70 °C and the pH adjusted further to 7 and the mixture stirred for 2 h. The mixture was filtered to give N-(3-(2-(1,1-difluoroethyl)-6- ethylpyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (4.7 g, 43.5% yield) as an off yellow solid. LCMS m / z = 374 [M+H]+1H NMR (400MHz, CDCl3) δ ppm: 9.00 (s, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.46 (s, 1H), 4.24 (q, J = 7.6 Hz, 2H), 2.84 (q, J = 7.6 Hz, 2H), 2.06-2.22 (m, 6H), 1.53 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.6 Hz, 3H). Example 48 N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide (Example 36, 70 mg, 0.203 mmol) and Cs2CO3(198 mg, 0.608 mmol) in DMF (3 mL) was added oxirane (44.6 mg, 1.01 mmol) at 20°C. The reaction mixture was stirred at 90°C for 2 h, then concentrated and purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, Condition: water (NH4HCO3)-MeCN, 22%~52%, Flow Rate (mL / min): 25) to give the title compound (16.1 mg, 20% yield) as a white solid. LMCS m / z = 390 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ: 10.28 (s, 1H), 9.17 (s, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 7.81 (s, 1H), 5.01-5.05 (m, 1H), 4.37-4.40 (m, 2H), 3.79-3.84 (m, 2H), 2.77- 2.84 (m, 2H), 2.21 (t, 3H), 2.10 (s, 3H), 1.31 (t, 3H). Example 49 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(difluoromethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 100 mg, 0.302 mmol) and sodium 2-chloro-2,2- difluoroacetate (59.8 mg, 0.392 mmol) in DMF (5 mL) was added Cs2CO3 (148 mg, 0.453 mmol) at 25°C. The reaction mixture was stirred at 100°C for 2.5 h, then hydrolysed with water (20 mL) and extracted with EtOAc (35 mL x 2). The organic phase was washed with water (15 mL) and concentrated. The crude was purified by prep-HPLC (Column:Welch Xtimate C18150*25mm*5µm; Condition: water (NH4HCO3)-MeCN; Begin B: 27; End B: 57; Gradient Time (min): 11; 100%B Hold Time (min): 2.5; Flow Rate (mL / min): 25) to give the title compound (23.7 mg, 21% yield) as a white solid. LMCS m / z = 382 [M+H]+.1H NMR (CDCl3, 400 MHz) δ : 9.14 (s, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H), 7.34 (t, 1H), 2.68 (s, 3H), 2.27 (s, 3H), 2.20 (t, 3H). Example 50 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(trifluoromethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of N-(1-(bromodifluoromethyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 35, 55.0 mg, 0.120 mmol) in sulfolane (2.0 mL) was added tetramethylammonium fluoride (5.6 mg, 60 μmol). The reaction mixture was stirred at 60°C for 16 h, then purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um; Condition: water (NH3.H2O)-MeCN; Begin B: 35; End B: 65; Gradient Time (min): 11; 100%B Hold Time (min): 2.5; Flow Rate (mL / min): 60) to give the title compound (25.8 mg, 53.8% yield) as a white solid. LCMS m / z = 400 [M+H]+.1H NMR (CDCl3, 400 MHz) δ: 9.18 (s, 1H), 8.66 (s, 1H), 8.24 (s, 1H), 8.05 (br s, 1H), 7.59 (s, 1H), 2.70 (s, 3H), 2.27 (s, 3H), 2.22 (t, 3H). Example 51 N-(1-cyclopropyl-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 350 mg, 0.95 mmol) and cyclopropylboronic acid (163.5 mg, 1.90 mmol) in DMF (1.0 mL) was added 2-(2-pyridyl)pyridine (148.6 mg, 0.95 mmol), Na2CO3(201.7 mg, 1.90 mmol), copper (II) acetate (172.8 mg, 0.95 mmol) and TEA (192.6 mg, 1.90 mmol) and the resulting mixture was stirred at 100 °C for 17 h. The mixture was concentrated under reduced pressure and the residue purified by column chromatography (PE / EtOAc = 1 / 1 to DCM / MeOH = 10 / 1) to give a yellow solid. This solid was triturated with EtOAc (1.5 mL) and the mixture stirred at 25 °C for 30 mins. The resulting precipitate was collected by filtration, washed with EtOAc (1.0 mL) and dried in vacuo to give N-(1- cyclopropyl-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide (193 mg, 54.6% yield) as a white solid. LCMS m / z = 372 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.29 (s, 1H), 9.19 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 7.90 (s, 1H), 3.70-3.74 (m, 1H), 2.52 (s, 3H), 2.10-2.25 (m, 6H), 1.12-1.17 (m, 4H). Example 52 rac-N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1R,2R)-2-fluorocyclopropyl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 80 mg, 0.241 mmol) in DMF (2 mL) was added 2-(2- fluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 37, 100 mg, 0.538 mmol), 2-(2-pyridyl)pyridine (75.4 mg, 0.483 mmol), copper (II) acetate (21.9 mg, 1.21 mmol), TEA (1.45 g, 14.35 mmol) and Na2CO3 (51.2 mg, 0.483 mmol). The reaction was stirred at 90 °C for 16 h. The mixture was concentrated and purified by prep-HPLC (Column: Phenomenex Gemini NX 150*30mm*5um; Condition: water (NH4HCO3)-MECN; Begin B: 29; End B: 49; Gradient Time (min): 11; Flow Rate (mL / min): 25;) to give rac-N-(3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1R,2R)-2-fluorocyclopropyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (27.6 mg, 28.7% yield) as a white solid. LCMS m / z = 390 [M+H]+1H NMR: (400 MHz, CDCl3) δ ppm: 8.95 (br s, 1H), 8.56 (br s, 1H), 7.98 (s, 1H), 7.90 (br s, 1H), 7.41 (s, 1H), 4.81-4.99 (m, 1H), 3.78-3.85 (m, 1H), 2.55 (s, 3H), 2.16 (s, 3H), 2.09 (t, J = 18.8 Hz, 3H), 1.75-1.81 (m, 1H), 1.51 - 1.53 (m, 1H). Example 53 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-methyl-1H-pyrazol-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 60.0 mg, 0.181 mmol) in DMF (1 mL) was added 1- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75.4 mg, 0.362 mmol), copper (II) acetate (32.9 mg, 0.181 mmol), TEA (36.7 mg, 0.362 mmol) and 2-(2- pyridyl)pyridine (28.3 mg, 0.181 mmol), Na2CO3 (38.4 mg, 0.362 mmol). The mixture was stirred at 100 °C for 3 h. The mixture was concentrated and purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um; Condition: water (NH4HCO3)-MeCN; Begin B: 23; End B: 63; Gradient Time (min): 9; Flow Rate (mL / min): 30) to give N-(3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (20.0 mg, 26.7% yield) as a white solid. LCMS m / z = 412 [M+H]+1H NMR (400 MHz, CDCl3) δ ppm: 9.19 (br s, 2H), 8.43 (s, 1H), 8.05 (br s, 1H), 7.59 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.00 (s, 3H), 2.67 (s, 3H), 2.28 (s, 3H), 2.24 (t, J=18.8 Hz, 3H). Example 54 N-(1-cyclopropyl-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide To a mixture of N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide (Example 36, 18 g, 52.12 mmol) in DMF (400 mL) were added cyclopropyl boronic acid (9.40 g, 109.5 mmol), copper (II) acetate (10.41 g, 57.33 mmol), TEA (10.55 g, 104.24 mmol), 2-(2-pyridyl) pyridine (8.14 g, 52.12 mmol) and Na2CO3(11.05 g, 104.24 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 16 h. The mixture was concentrated and then water (500 mL) was added. The mixture was extracted with EtOAc (350 mL x 3), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 0 / 1). The product was suspended in H2O (500 mL) H2SO4 (100 mL, 5 %) was added slowly at 20 °C and the mixture stirred for 30 min. The mixture was filtered and the filtrate extracted with EtOAc (50 mL x 2). The filtrate was adjusted to pH 6, then 7 with aq. NaHCO3slowly and the mixture was stirred at 70 °C for 2 h. The precipitate was filtered and dried in vacuo to give N-(1-cyclopropyl-3-(2-(1,1- difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (5.1 g, 25.3% yield) as a white solid. LCMS m / z = 386 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ ppm: 9.07 (s, 1H), 8.66 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.53 (s, 1H), 3.51-3.54 (m, 1H), 2.89 (q, J = 7.6 Hz, 2H), 2.16-2.26 (m, 6H), 1.41 (t, J = 7.6 Hz, 3H), 1.15-1.24 (m, 4H). Example 55 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1r,3r)-3- (dimethylamino)cyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide And Example 56 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1s,3s)-3- (dimethylamino)cyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(1-(3-aminocyclobutyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 39, 150 mg, 0.375 mmol) and (CH2O)n(89.87 mg, 0.075 mmol) in MeOH (6 mL) was added NaBH3CN (94.2 mg, 1.50 mmol) and the reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with DCM (35 mL x 2). The combined organic phase was washed with water (15 mL) and concentrated. The crude product was separated by SFC (Column: Phenomenex-Cellulose-2 (250mm*30mm, 10µm; Condition: CO2-MeOH (0.1%NH3·H2O) 45% isocratic gradient at 130 mL / min and Column temp: 35 °C) to give Peak 1, Example 55 (18.2 mg, 51.9% yield) and Peak 2, Example 56 (29.5 mg, 81.3% yield) both as white solids. Example 55 LCMS m / z = 429 [M+H]+1H NMR (400 MHz, CDCl3) δ ppm: 9.04 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 5.09-5.14 (m, 1H), 3.01-3.06 (m, 1H), 2.71-2.81 (m, 2H), 2.60-2.68 (m, 5H), 2.29 (s, 6H), 2.26 (s, 3H), 2.20 (t, J=18.8 Hz, 3H). Example 56 LCMS m / z = 429 [M+H]+1H NMR: (400 MHz, CDCl3) δ ppm: 9.08 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 7.93 (s, 1H), 7.51 (s, 1H), 4.62-4.70 (m, 1H), 2.87-2.94 (m, 2H), 2.67-2.73 (m, 1H), 2.64 (s, 3H), 2.38-2.44 (m, 2H), 2.17-2.27 (m, 12H). Example 57 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-methylazetidin-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide To a solution of N-(1-(azetidin-3-yl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide trifuoroacetate (Preparation 41, 100.0 mg, 0.20 mmol) in MeOH (3.0 mL) was added NaBH3CN (62.9 mg, 1.0 mmol) and (CH2O)n (240.2 mg, 0.20 mmol) and the reaction was stirred at 25 °C for 16 h. The mixture was concentrated and purified by prep-HPLC (Column: Phenomenex C18150mm*30mm*5μm; Condition: Water (NH4HCO3)-MeCN; Begin B: 23; End B:63; Gradient Time (min): 9; Flow Rate (mL / min): 30) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-methylazetidin-3-yl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (7.5 mg, 9.4% yield) as a white solid. LCMS m / z = 401 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 9.09 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 8.01 (br s, 1H), 7.54 (s, 1H), 5.09-5.12 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 3.58 (t, J=6.8 Hz, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 2.26 (s, 3H), 2.22 (t, J=18.8 Hz, 3H). Example 58 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-ethylazetidin-3-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of N-(1-(azetidin-3-yl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide trifluoroacetate (Preparation 41, 200.0 mg, 0.40 mmol) in MeOH (5.0 mL) was added CH3CHO (441.0 mg, 4.0 mmol, 40% purity) and NaBN3CN (125.8 mg, 2.0 mmol). The reaction was stirred at 25 °C for 3 h. The mixture was concentrated and purified by prep-HPLC (Column: Boston Prime C18150*30mm*5um; Condition: Water (NH4HCO3)-MeCN; Begin B: 18; End B: 48; Gradient Time (min): 8; Flow Rate (mL / min): 50) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-ethylazetidin-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (53.0 mg, 31.9% yield) as a white solid. LCMS m / z = 415 [M+H]+1H NMR: (400 MHz, CDCl3) δ ppm: 9.08 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.01 (br s, 1H), 7.54 (s, 1H), 5.10-5.14 (m, 1H), 3.94 (t, J=8.0 Hz, 2H), 3.52 (t, J=7.2 Hz, 2H), 2.65- 2.69 (m, 5H), 2.26 (s, 3H), 2.21 (t, J=18.4 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H). Example 59 N-(1-(cyclopropanecarbonyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide Cyclopropanecarboxylic acid (12.22 mg, 0.142 mmol) was dissolved in anhydrous DMF (1 mL). DIEA (95.43 mg, 0.738 mmol) was added and the mixture was cooled to 0°C. HATU (70.19 mg, 0.185 mmol) was added portion wise, then N-(3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide trifluoroacetate (Example 34, 89 mg, 0.269 mmol) in anhydrous DMF (0.5 mL) was added dropwise and the reaction was warmed to rt and stirred for 16 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3x 20 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using 0-100% heptane-EtOAc / EtOH (3:1) to obtain N-(1-(cyclopropanecarbonyl)-3-(2- (1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (34 mg, 54.0% yield) as white solid. LCMS m / z = 400 (M+H)+.1H NMR (500 MHz, DMSO) δ 10.53 (d, J = 2.6 Hz, 1H), 9.47 (d, J = 4.3 Hz, 1H), 9.34 (d, J = 3.2 Hz, 1H), 9.28 – 9.25 (m, 1H), 8.18 (d, J = 5.4 Hz, 1H), 2.92 – 2.84 (m, 1H), 2.60 (s, 3H), 2.25 (t, J = 19.2 Hz, 3H), 2.12 (s, 3H), 1.26 – 1.20 (m, 4H). Example 60 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-fluorocyclopropyl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide formate To a solution of N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1- hydroxycyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 42, 80.0 mg, 0.207 mmol) in DCM (3.0 mL) was added Deoxy-Flour (228.5 mg, 1.03 mmol) at 25 °C for 2 h. The mixture was purified by prep-HPLC (Column: Welch Xtimate C18 150*25mm*5um; Condition: water (FA)-MeCN; Begin B: 13; End B: 53; Gradient Time (min): 9; Flow Rate (mL / min): 60) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1-(1-fluorocyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide formate (10.0 mg, 11.4% yield) as a yellow solid. LCMS m / z = 390 [M+H]+1H NMR: (400 MHz, MeOHd4) δ ppm: 9.20 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 2.62 (s, 3H), 2.18-2.27 (m, 6H), 1.83-1.88 (m, 2H), 1.61-1.64 (m, 2H). Example 61 N-(3-(2-(1,1-difluoroethyl)-6-(difluoromethoxy)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of 4-chloro-2-(1,1-difluoroethyl)-6-(difluoromethoxy)pyrimidine (Preparation 44, 65.68 mg, 0.269 mmol), N-(3-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 45, 60 mg, 0.224 mmol) and bis(pinacolato)diboron (113.7 mg, 0.448 mmol) in MeOH (3 mL), H2O (3 mL) and 2-MeTHF (3 mL) was added CsF (88.75 mg, 1.34 mmol), cataCXium A (32.1 mg, 0.090 mmol), Pd2(dba)3 (20.5 mg, 0.022 mmol) and the mixture was stirred at 65 °C for 2 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (35 mL x 2). The combined organic phase was washed with water (15 mL) and concentrated. The crude was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5µm; Condition: water (NH4HCO3)-MeCN; Begin B: 33; End B: 33; Gradient Time (min): 11; Flow Rate (mL / min): 25) to give N-(3-(2-(1,1-difluoroethyl)-6- (difluoromethoxy)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (8.54 mg, 9.60% yield) as a white solid. LCMS m / z = 398 [M+H]+1H NMR: (400 MHz, CDCl3) δ ppm: 9.03 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.63 (t, J=71.6 Hz, 1H), 7.15 (s, 1H), 3.97 (s, 3H), 2.26 (s, 3H), 2.17 (t, J=18.4 Hz, 3H). Example 62 N-(3-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1-isopropyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide To a solution of N-(3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1-isopropyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 48, 60.0 mg, 0.152 mmol) in MeCN (1.5 mL) was added methylamine (11.3 mg, 0.168 mmol) and TEA (46.3 mg, 0.457 mmol). The reaction was stirred at 80 °C for 16 h. The mixture was concentrated and purified by prep- HPLC (Column: Welch Xtimate C18150×25mmx5μm, Condition: water (NH4HCO3)- MECN; Begin B: 26; End B: 56; Gradient Time (min): 11; Flow Rate (mL / min): 25) to give N-(3-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1-isopropyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (38.2 mg, 64.6% yield) as a white solid. LCMS m / z = 389 [M+H]+1H NMR: (400 MHz, CDCl3) δ: 8.93 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 7.98- 8.05 (m, 1H), 6.76 (s, 1H), 5.26-5.33 (m, 1H), 4.71-4.79 (m, 1H), 3.09 (d, J=5.2 Hz, 3H), 2.25 (s, 3H), 2.10 (t, J=18.8 Hz, 3H), 1.64 (d, J=6.8 Hz, 6H). Example 63 N-(1-(cyclopropylsulfonyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide A mixture of 5-chloro-1-(cyclopropylsulfonyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridine (Preparation 51, 84 mg, 0.203 mmol), acetamide (56 mg, 0.953 mmol), cesium carbonate (171 mg, 0.525 mmol) and BrettPhos Pd G3 (38 mg, 42 μmol) in anhydrous dioxane (2 mL) was degassed, backfilled with N2and heated to 85 °C for 2 h. The mixture was cooled to rt then filtered through Celite®. The pad was rinsed with EtOAc, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30-100 % 3:1 EtOAc: EtOH in heptane.) The product was further purified by HPLC Waters XSelect CSH C18, 5 μm, 30 mm × 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 − 65 % B (0.2% NH4OH final v / v % modifier) with flow rate at 60 mL / min to give N-(1-(cyclopropylsulfonyl)-3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide as a white solid (19 mg, 21 % yield). LCMS m / z = 436.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 10.59 (s, 1H), 9.36 (s, 1H), 8.93 (d, J = 1.0 Hz, 1H), 8.91 (s, 1H), 8.24 (s, 1H), 3.42 - 3.37 (m, 1H), 2.58 (s, 3H), 2.24 (t, J = 19.3 Hz, 3H), 2.13 (s, 3H), 1.43 - 1.38 (m, 2H), 1.23 - 1.17 (m, 2H). Example 64 N-(3-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide To a solution of 2-(1,1-difluoroethyl)-4-(trimethylstannyl)pyrimidine (Preparation 52, 200 mg, 0.652 mmol) and N-(3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (Preparation 54, 130 mg, 0.411 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (75.3 mg, 0.065 mmol) and CuI (24.8 mg, 0.130 mmol) under N2. The reaction was stirred at 90 °C for 16 h under N2. The mixture was concentrated and purified by prep-HPLC (Column: Phenomenex luna C18150*25mm* 10µm; Condition: water (FA)-MeCN; Begin B: 18; End B: 48; Gradient Time(min): 8; Flow Rate (mL / min): 30) to give N-(3-(2-(1,1- difluoroethyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (28.72 mg, 26.5% yield) as yellow solid. LCMS m / z = 333 [M+H]+1H NMR (400 MHz, MeOH-d4) δ ppm 9.24 (s, 1H), 8.87-8.94 (m, 2H), 8.23 (d, J = 5.6 Hz, 1H), 4.31 (s, 3H), 2.21-2.32 (m, 6H). Example 65 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide To a solution of N-(1-methyl-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (Preparation 55, 250 mg, 0.708 mmol) and 4-chloro-2-(1,1-difluoroethyl)-6- methylpyrimidine (Preparation 6, 136.4 mg, 0.708 mmol) in dioxane (10 mL) was added CuI (40.46 mg, 0.212 mmol) and Pd(PPh3)2Cl2 (49.71 mg, 0.071 mmol) under N2. The reaction was stirred at 100 °C for 2 h under N2. The reaction was diluted with aq KF (10 mL) and water (20 mL) and stirred at 25 °C for 0.5 h. The mixture was extracted with EtOAc (30 mL x 3) and the combined organic phase was dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (EtOAc in PE from 20% to 100%) and then purified by prep-HPLC (Column: Phenomenex Gemini NX 150×30mm, 5μm; Condition: water (NH4HCO3)-MeCN; Begin B: 28; End B: 58; Gradient Time (min): 11; Flow Rate (mL / min): 25) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (49 mg, 20.0% yield) as a yellow solid. LCMS m / z = 347 [M+H]+1H NMR: (400 MHz, DMSO-d6) δ ppm: 10.56 (s, 1H), 9.21 (s, 1H), 9.06 (s, 1H), 8.06 (s, 1H), 4.28 (s, 3H), 2.62 (s, 3H), 2.23 (t, J=19.2 Hz, 3H), 2.13 (s, 3H). The following compounds were made according to Examples 1-65:

[0006] The following comparator compounds were synthesized as described in WO 2022 / 242697 WO 2019 / 178079, or WO 2024 / 211708: BIOLOGICAL ASSAYS Compounds of the disclosure were assessed for their ability to inhibit TYK2, JAK1 and JAK2 activity. The inhibitory properties of the compounds of the disclosure described herein can be evidenced by testing in any one of the following protocols. JH2 biochemical assay The inhibitory potency of compounds of the disclosure against the kinase activity of recombinantly generated JH2 domain of human Tyk2 was evaluated in a plate-based assay using a TR-FRET assay platform. Briefly, 2 nM of recombinant JH2 domain [10xHis-tagged TYK2 JH2 domain (amino acid 575-876)] was combined with 2 nM probe ((S)-6-amino-9- (2-carboxy-4-((1-(3-(8-methyl-5-(methylamino)-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2- yl)phenyl)ethyl)carbamoyl)phenyl)-3-iminio-5-sulfo-3H-xanthene-4-sulfonate), 0.1 nM Tb- labeled anti-His antibody, and compounds of disclosure for 60 minutes. Compounds are tested at either 10 µM or 1 µM top concentration, 10 points of 3-fold dilution. The TR-FRET signal inversely correlates to the amount of probe displaced by compounds and signal was calculated by taking the ratio of fluorescence at 520 nm and 495 nm. The data was normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate IC50 curves. pSTAT4 cell assay The inhibitory potency of compounds of the disclosure against the Tyk2 kinase activity on STAT4 was evaluated using an MSD-platform plate-based assay format. NK92 cells natively expressing STAT4 and Tyk2 were serum-starved to reduce background phosphorylation levels, then cells were treated compounds for 1 hr with a 10-point four-fold dilution series starting at 10 µM. Cells were then stimulated with 30 ng / mL IL2 for 15 minutes. Cells were lysed and pSTAT5 levels were quantitated using an MSD plate-based assay with anti-STAT4 antibodies. The data were normalized and the percent activity versus log concentration of compound were fitted with a 4-parameter logistic model to generate to generate IC50 curves. pSTAT5 cell assay Compounds of the disclosure were assessed for their ability to inhibit the JAK2 kinase activity on STAT5 utilizing an MSD-platform plate-based assay format. TF1 cells natively expressing STAT5 and JAK2 were serum-starved to reduce background phosphorylation levels, then cells were treated with compounds of disclosure for 1 hour with a 10-point four- fold dilution series starting at 10 µM. Cells were then stimulated with 30 ng / mL IL-3 for 15 minutes. Cells were then lysed and pSTAT5 levels were quantitated using an MSD plate- based assay with anti-STAT5 antibodies. The data were normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate a curve and an IC50 value. pSTAT3 cell assay The inhibitory potency of compounds of the disclosure against the JAK1 kinase activity on STAT3 was evaluated using an MSD-platform plate-based assay format. TF1 cells natively expressing STAT3 and JAK1 were serum-starved to reduce background phosphorylation levels, then cells were treated with compounds of the disclosure for 1 hour with a 10-point four-fold dilution series starting at 10 µM. Cells were then stimulated with 30 ng / mL interleukin 6 (IL-6) for 15 minutes. Cells were lysed and pSTAT3 levels were quantitated using an MSD plate-based assay with anti-STAT3 antibodies. The data were normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate IC50 curves. Table 1 shows the inhibitory activity of selected compounds of this disclosure to assess their ability to inhibit TYK2, JAK1 and JAK2, wherein each compound number corresponds to the compound numbering set forth in Examples 1-46 described herein. The measured IC50values were scored according to the following hierarchy. ++++ represents: IC50 ≤ 10 nM +++ represents: 10 nM < IC50≤ 100 nM ++ represents: 100 nM < IC50≤ 1000 nM + represents: 1000 nM < IC50 NT represents: not tested Table 1: Experimental Data Permeability Assay . Human MDR1 transfected MDCK cells (NIH cell line in-licensed from Absorption Systems) were used in the assay. . The compounds were tested at 1 µM concentration prepared in transport buffer (Hank’s balanced salt solution with HEPES) . MDR1-MDCK cell were cultured for 7 days in 96 well transwell insert plates (Corning). Insert plates were washed before the assay and TEER (Trans epithelial electric resistance) was measured. . These plates were loaded with test compound solution 85 µL for A-B transport and 260 µL for B-A transport in the respective donor compartment. The volume of receiver buffer (Transport buffer supplemented with 1% BSA) in the respective receiver compartment was 250 and 75 µL. . 10 µL samples was taken from donor compartment (T=0 timepoint) . Assay plates were incubated for 120 minutes. . At 120 minutes (T=120 timepoint) samples from respective donor (10uL) and receiver (50 µL) compartments was taken. ^ After addition of 40 µL transport buffer with BSA to donor samples, crash solution (Acetonitrile with internal standard, 110 µL) was added to all samples. ^ After centrifugation 50 µL supernatant was transferred to separate plate and mixed with 50 µL water. ^ Samples were analyzed using LC-MS / MS coupled with high throughput injection system. ^ Analyte / internal standard area ratios were used for apparent permeability (Papp), efflux ratio and mass recovery estimation based on equations below. Papp= (dCr / dt) x Vr / (A x CE) Mass balance = 100 x ((Vr x Crfinal) + (Vd x Cdfinal)) / (Vd x CE) Where: dCr / dt is the cumulative concentration in the receiver compartment versus time in ^M s-1Vr is the volume of the receiver compartment in cm3Vd is the volume of the donor compartment in cm3A is the area of the insert (0.143 cm2for 96-well insert) CE is the estimated experimental concentration (Time = 0) of the dosing solution Crfinalis the concentration of the receiver at the end of the incubation period Cdfinalis the concentration of the donor at the end of the incubation period. The efflux ratio for the tested compounds is shown in the table below. As can be seen, the compounds described herein have significantly lower efflux ratio compared to tested comparative examples. Equivalents In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described and claimed herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R1is C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, -C(O)R1c, -SO2R1c, phenyl, 5-or 6-membered monocyclic heteroaryl, or 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein the C1-6alkyl and C2-6alkenyl are each optionally substituted by one or more R1a, and wherein the C3-10cycloalkyl, phenyl, 5-or 6-membered monocyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R1b; each R1ais, independently, halo, cyano, OR1d, C3-6cycloalkyl, or 4- to 6- membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, halo, C1-3alkyl, C1-3alkyl-C1-3alkoxy, -OH, -NH2, - N(C1-3alkyl)2, C1-3alkoxy, C1-3haloalkoxy, -C(O)R1c, or cyano; R1cis H, C1-3alkyl, C1-3haloalkyl, –OH, C1-3alkoxy, or C3-6cycloalkyl; R1dis H, C1-3haloalkyl, or C1-3alkyl optionally substituted by phenyl; R2is H, -OR2a, C1-3alkyl, C3-6cycloalkyl, or C1-3haloalkyl, wherein the C1- 3alkyl is optionally substituted by OR2a,cyano, or C3-4cycloalkyl; each R2ais, independently, H, C1-3alkyl, or C1-3haloalkyl; Ring A is 5- or 6-membered monocyclic heteroaryl substituted by 1 to 3 R3; each R3is, independently, C1-6alkyl, C1-6haloalkyl, cyano, -C(O)R3b, -OR3a, - N(R3c)2, C3-6cycloalkyl, 4- to 10- membered monocyclic or bicyclic heterocyclyl, phenyl, or 5- to 6- membered monocyclic heteroaryl, wherein the C1-6alkyl and C1- 6haloalkyl are each optionally substituted by one or more R4, and wherein the C3- 6cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocyclyl, phenyl, and 5- or 6-membered monocyclic heteroaryl are each optionally substituted by one or more R5;R3ais, independently, C1-3alkyl, C1-3haloalkyl, C1-3alkyl-C1-3alkoxy, C3- 6cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R5; R3bis H, C1-3alkyl, C1-3haloalkyl, -OH, or C1-3alkoxy; each R3cis, independently, H, C1-3alkyl, C1-3haloalkyl, C1-3alkoxyC1-3alkyl, or C3-6cycloalkyl, wherein the C3-6cycloalkyl is optionally substituted by one or more R5; each R4is, independently, C1-3alkoxy, or –OH; and each R5is, independently, cyano, C1-3alkyl, C1-3haloalkyl, halo, C1-3alkoxy, or –OH. provided that: (i) when the 4- to 10-membered monocyclic or bicyclic heterocyclyl represented by R3is substituted then Ring A is a 5-membered monocyclic heteroaryl; (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl; (iii) when R3is a cyano substituted cyclopropyl then ring A is pyrimidinyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R1is C1-3alkyl, C3-6cycloalkyl, -C(O)R1c, -SO2R1c, phenyl, 5-or 6-membered monocyclic heteroaryl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C1- 3alkyl is optionally substituted by one or more R1a, and wherein the C3-6cycloalkyl, phenyl, 5-or 6-membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R1b; each R1ais, independently, halo, cyano, C1-3alkoxy, or –OH; each R1bis, independently, halo, C1-3alkyl, -OH, -NH2, -N(C1-3alkyl)2, C1-3alkoxy, -C(O)R1c, or cyano; R1cis H, C1-3alkyl, C1-3haloalkyl, –OH, or C1-3alkoxy; R2is H, -OR2a, C1-3alkyl or C1-3haloalkyl; each R2ais, independently, H, C1-3alkyl, or C1-3haloalkyl; Ring A is 5- or 6-membered monocyclic heteroaryl substituted by 1 to 3 R3; each R3is, independently, C1-6alkyl, C1-6haloalkyl, cyano, -C(O)R3b, -OR3a, - N(R3c)2, C3-6cycloalkyl, 4- to 10- membered monocyclic or bicyclic heterocyclyl, phenyl, or 5- to 6- membered monocyclic heteroaryl, wherein the C1-6alkyl isoptionally substituted by one or more R4, the C3-6cycloalkyl is optionally substituted by one or more halo, and the 4- to 10-membered monocyclic or bicyclic heterocyclyl, phenyl, and 5- or 6-membered monocyclic heteroaryl are each optionally substituted by one or more R5; each R3ais, independently, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; R3bis H, C1-3alkyl, C1-3haloalkyl, –OH, or C1-3alkoxy; each R3cis, independently, H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; each R4is, independently, C1-3alkoxy, or –OH; and each R5is, independently, C1-3allkyl, C1-3haloalkyl, halo, C1-3alkoxy, or –OH. provided that: (i) when the 4- to 10-membered monocyclic or bicyclic heterocyclyl represented by R3is substituted then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is C1-3alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is -CH3, -CH2OH, -CH2-cyclopropyl, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CN, or cyclopropyl.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2is -CH3.

6. The compound of any one od claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered monocyclic heteroaryl comprising at least one N atom, or Ring A is a 5-membered monocyclic heteroaryl comprising at least one S atom and one or more N atoms.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which are substituted with 1 to 3 R3.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which are substituted with 1 to 3 R3.

9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ring,, , or , each of which are substituted with 1 or 2 R3.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Ring,, or , each of which are substituted with 1 or 2 R3.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Ring ,12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein: each R3is, independently, C1-3alkyl, C1-3haloalkyl, -OR3a, -N(R3c)2, C3-6cycloalkyl, 5- or 6-membered monocyclic or bicyclic heterocyclyl, wherein the C1-3alkyl and C1-3haloalkyl are each optionally substituted by -OH or C1-3alkoxy, and wherein the C3-6cycloalkyl and 5- and 6-membered monocyclic or bicyclic heterocyclyl are optionally substituted by 1 to 3 R5; R3ais C1-3alkyl, C1-3haloalkyl, C1-3alkyl-C1-3alkoxy, or C3-4cycloalkyl, or 4-to 5- membered monocyclic heterocyclyl, wherein the C3-4cycloalkyl and 4-to 5-membered monocyclic heterocyclyl are optionally substituted by 1 or 2 R5; each R3cis, independently, H, C1-3alkyl, C1-3alkoxyC1-3alkyl, or C3-4cycloalkyl, wherein the C3-4cycloalkyl is optionally substituted by 1 or 2 R5; each R5is, independently, halo, C1-3alkoxy, cyano, or C1-3alkyl; provided that: (i) when R3is a substituted 5- or 6-membered monocyclic or bicyclic heterocyclyl, then Ring A is a 5-membered monocyclic heteroaryl; (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl; or (iii) when R3is a cyano substituted cyclopropyl then ring A is pyrimidinyl.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein:each R3is, independently, C1-3alkyl, C1-3haloalkyl, -OR3a, C3-4cycloalkyl, or 5- or 6- membered monocyclic or bicyclic heterocyclyl, wherein the C1-3alkyl is optionally substituted by C1-3alkoxy, wherein the C3-4cycloalkyl is optionally substituted by 1 or 2 halo, and the 5- or 6-membered monocyclic or bicyclic heterocyclyl is optionally substituted by 1 or 2 C1-3alkoxy; and R3ais C1-3alkyl or C3-4cycloalkyl, provided that: (i) when R3is a substituted 5- or 6-membered monocyclic or bicyclic heterocyclyl, then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R3is tetrahydrofuranyl then Ring A is a 5-membered monocyclic heteroaryl.

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein: each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CF2CH2OH, -CH2OCH3, CH(OH)CH3, -CH(CH3)2, -CF(CH3)2, -OCH3, -CF2CH2CH3, -CF2CH2OCH3, -OCH3, -OCHF2, - OCH(CH3)2, -OCH2CH2OCH3, -O-cyclopropyl, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, - N(CH3)2, -NHCH2CH2OCH3, -NH-cyclopropyl, -NH-cyclobutyl, -O-oxetanyl, -O- pyrrolidinyl, cyclopropyl, cyclobutyl, bicyclopentanyl, tetrahydrofuranyl, tetrahydropyranyl, or 2-oxabicyclohexanyl, wherein the cyclopropyl, cyclobutyl, bicyclopentanyl, tetrahydrofuranyl, tetrahydropyranyl, and 2-oxabicyclohexanyl represented by R3or as part of an R3group are each optionally substituted by 1 or 2 groups selected from -OCH3, - OCH2CH3, cyano, -CH3, and -F, provided that: (i) when R3is tetrahydrofuranyl, substituted tetrahydropyranyl, or oxabicyclohexanyl, then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R3is a cyano substituted cyclopropyl then ring A is pyrimidinyl.

16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein: each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CH2OCH3, -CF(CH3)2, -OCH3, -O- cyclopropyl, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, or 2- oxabicyclo[2.1.1]hexanyl, wherein the cyclopropyl is optionally substituted by 1 or 2 halo, and the tetrahydrofuranyl is optionally substituted by –OCH3, provided that when R3is tetrahydrofuranyl, substituted tetrahydropyranyl, or 2-oxabicyclo[2.1.1]hexanyl, then Ring A is a 5-membered monocyclic heteroaryl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CF2CH2OH, -CH2OCH3, -CH(OH)CH3, -CH(CH3)2, -CF(CH3)2, -CF2CH2CH3, -CF2CH2OCH3, -OCH3, - OCHF2, -OCH(CH3)2, -OCH2CH2OCH3, -O-cyclopropyl, -NHCH3, -NHCH2CH3, - NHCH(CH3)2, -N(CH3)2, -NHCH2CH2OCH3, -NH-cyclopropyl, -NH-cyclobutyl,provided that: (i) when R3 is, , , then Ring A is a 5-memberedmonocyclic heteroaryl; or (ii) when R3isthen Ring A is pyrimidinyl.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein each R3is, independently, -CH3, CH2CH3, -CF2CH3, -CH2OCH3, -CF(CH3)2, -OCH3, -O-cyclopropyl,, , , , , , providedthat when R3 is, , , then Ring A is a 5-memberedmonocyclic heteroaryl.

19. The compound of claim 1, wherein the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y1, Y3, and Y5are each N or CH; Y2is CRY1; Y4is N or CRY2; provided that no more than 2 of Y1, Y2, Y4, and Y5are N; RY1is C1-3haloalkyl or C3-4cycloalkyl substituted by one or more halo; RY2is H, C1-3alkyl, -ORY2a, or 5-or 6-membered monocyclic heterocyclyl, wherein the C1-3alkyl is optionally substituted by C1-3alkoxy, provided that RY2is not tetrahydrofuranyl; RY2ais C1-3alkyl or C3-4cycloalkyl; R1is C1-3alkyl, C3-6cycloalkyl, -C1-3alkyl-C1-3alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, C1-3alkyl, C1-3alkoxy, or cyano.

20. The compound of claim 19, wherein the compound is represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), or (IIh):or a pharmaceutically acceptable salt thereof.

21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein22. The compound of any one of claims 19 to 21, or a pharmaceutically acceptable salt thereof, wherein RY2is H, -CH3, CH2CH3, -CH2OCH3, -OCH3, -O-cyclopropyl, or tetrahydropyranyl.

23. The compound of claim 1, wherein the compound is represented by Formula (III):or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Z1, Z2, Z3, and Z4are each independently N, S, CH, or CR3; provided that no more than 2 of Z1, Z2, Z3, and Z4are N and no more than 1 of Z1, Z2, Z3, and Z4are S; each R3is, independently, C1-3alkyl, C1-3haloalkyl, -OR3a, C3-6cycloalkyl, 5- or 6-membered monocyclic or bicyclic heterocyclyl, wherein the C3-6cycloalkyl is optionally substituted by 1 or 2 halo, and the 5- or 6-membered monocyclic or bicyclic heterocyclyl is optionally substituted by 1 or 2 C1-3alkoxy or halo; R3ais C1-3alkyl or C3-4cycloalkyl; R1is C1-3alkyl, C3-6cycloalkyl, C1-3alkyl-C1-3alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; and each R1bis, independently, C1-3alkyl, C1-3alkoxy, or cyano.

24. The compound of claim 23, wherein the compound is represented by Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), or (IIIi):or a pharmaceutically acceptable salt thereof.

25. The compound of claim 23 or 24, wherein the compound is represented by Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh):or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 23 to 25, or a pharmaceutically acceptable salt thereof, wherein R3is -CF2CH3, -CF(CH3)2,, tetrahydrofuranyl, tetrahydropyranyl, or 2-oxabicyclo[2.1.1]hexanyl, wherein the tetrahydrofuranyl is optionally substituted with – OCH3 or -F.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein: R1is C1-4alkyl, C2-6alkenyl, -C(O)R1c, -SO2R1c, C3-10cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, wherein the C1-4alkyl and C2-6alkenyl are optionally substituted by one to three R1a, and the C3- 10cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 or 2 R1b;each R1ais, independently, halo, cyano, OR1d, C3-5cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-5cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, halo, C1-3alkyl, C1-3alkyl-C1-3alkyoxy, C1-3alkoxy, C1- 3haloalkoxy, -N(C1-3alkyl)2, or cyano; R1cis C3-4cycloalkyl; R1dis H or C1-3alkyl optionally substituted by phenyl.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein: R1is C1-3alkyl, C3-6cycloalkyl, -C1-3alkyl-C1-3alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R1b; each R1bis, independently, C1-3alkyl, C1-3alkoxy, or cyano.

29. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein: R1is -CH3, -CH2CH3, -CHF2, -CF3, -CH(CH3)2, -CH2CH2OCH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, -CH(CH3)CH2OCH3, -CH2CH2OH, -CH(CH3)CHF2, -CH(CH3)CH2F, - CH2CH2OCH3, -CH2CH2CN, -CH2CH=C(CH3)2, -CH2-cyclopropyl, -CH2-oxetanyl, - CH(CH3)-oxetanyl, -CH2-spiropentanyl, -C(O)-cyclopropyl, -SO2-cyclopropyl,,, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl, spirohexanyl, spiropentanyl, oxaspiroheptanyl, spiroheptanyl, or pyrazolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl spirohexanyl, spiropentanyl, oxaspiroheptanyl, spiroheptanyl, and pyrazolyl represented by R1or as part of an R1group are each optionally substituted by 1 or 2 R1b;each R1bis, independently, -F, -CH3, -CH2CH3, -CH(CH3)2, -CH2OCH3, -OCH3, - OCH2CH3, -OCH(CH3)2, -OCHF2, -N(CH3)2, or cyano.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein: R1is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3, cyclopropyl, cyclobutyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl, wherein the cyclobutyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, and piperdinyl are each optionally substituted by 1 R1b; each R1bis, independently, -CH3, -OCH3, or cyano.

31. The compound of any one of claims 1 to 27, or 29, or a pharmaceutically acceptable salt thereof, wherein R1is -CH3, -CHF2, -CF3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, - CH(CH3)CH2CH3, -CH(CH3)CH2OCH3, -CH2CH2OH, -CH(CH3)CHF2, -CH(CH3)CH2F,- CH2CH2OCH3, -CH2CH2CN, -CH2CH=C(CH3)2, -CH2-cyclopropyl, -C(O)-cyclopropyl, - SO2-cyclopropyl, cyclopropyl, cyclobutyl,, , , , ,,, .

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R1is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3, cyclopropyl, cyclobutyl,33. The compound of claim 1, wherein the compound is represented by Formula (IIe-1):or a pharmaceutically acceptable salt thereof, wherein: R1is C1-3alkyl or C3-4cycloalkyl; RY1is C1-3haloalkyl; and RY2is C1-3alkyl.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1is -CH2CH3 or cyclopropyl.

35. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein RY1is -CF2CH3.

36. The compound of any one of claims 33 to 35, or a pharmaceutically acceptable salt thereof, wherein RY2is -CH2CH3.

37. The compound of claim 1, wherein the compound is any one of Examples 1 to 222, or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, wherein the compound is any one of Examples 1 to 46, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

40. A method of inhibiting tyrosine kinase 2 (TYK2) activity in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39.

41. A method of treating a disease or disorder responsive to inhibition of tyrosine kinase 2 (TYK2) in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39.

42. The method of claim 41, wherein the disease or disorder is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction , thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration , glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis and sunburn.

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